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Chikatani K, Chika N, Tanabe N, Mori Y, Suzuki O, Matsuyama T, Ishibashi K, Eguchi H, Okazaki Y, Yamaguchi T, Ishida H. Frequency and Molecular Characteristics of Mismatch Repair-deficient Status among Multiple Synchronous Colorectal Cancers. J Anus Rectum Colon 2025; 9:145-155. [PMID: 39882230 PMCID: PMC11772799 DOI: 10.23922/jarc.2024-092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 10/30/2024] [Indexed: 01/31/2025] Open
Abstract
Objectives Mismatch repair (MMR)-deficient (dMMR) colorectal cancer (CRC) have been largely categorized into three subtypes: MLH1-methylated, Lynch syndrome (LS)-associated, and Lynch-like syndrome (LLS)-associated. No studies have examined the prevalence and subtypes of synchronously diagnosed dMMR CRCs in detail. Therefore, this study aimed to examine the frequency and molecular characteristics of the dMMR status among multiple synchronous CRCs to clarify the clinical significance of identifying patients with such tumors. Methods Immunohistochemistry (IHC) of MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed for surgically and endoscopically resected (in conjunction with surgical resection) lesions from consecutive patients with initially diagnosed multiple synchronous CRCs between July 2014 and June 2020. When necessary, MLH1-methylation analysis and testing of germline and somatic MMR genes were performed. Results In total, 133 patients (33 females) had 309 lesions. The combinations of synchronous tumor sites were the left-sided colon/rectum only (n=67, 50.4%), both the right-sided colon and left-sided colon/rectum (n=42, 31.6%), and the right-sided colon only (n=24, 18.0%). IHC showed a loss of expression of at least one MMR protein in 10 (7.5%) of 133 patients and 17 (5.5%) of 309 lesions. Molecular analysis revealed that these 10 patients were categorized as having MLH1-methylated (n=5, 3.8% of all patients), LS-associated (n=4, 3.0%), or LLS-associated (n=1, 0.8%) CRC. Conclusions Our data will be useful for genetic counseling in patients with synchronous CRCs suspected of having LS. Screening for LS using IHC for MMR proteins in individuals with multiple synchronous CRCs is an effective approach.
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Affiliation(s)
- Kenichi Chikatani
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Noriyasu Chika
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Noriko Tanabe
- Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Yoshiko Mori
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
- Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Okihide Suzuki
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
- Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Takatoshi Matsuyama
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Keiichiro Ishibashi
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Hidetaka Eguchi
- Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasushi Okazaki
- Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Tatsuro Yamaguchi
- Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
- Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
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Grigorie TR, Potlog G, Alexandrescu ST. Lynch Syndrome-Impact of the Type of Deficient Mismatch Repair Gene Mutation on Diagnosis, Clinical Presentation, Surveillance and Therapeutic Approaches. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:120. [PMID: 39859102 PMCID: PMC11766940 DOI: 10.3390/medicina61010120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/10/2025] [Accepted: 01/12/2025] [Indexed: 01/27/2025]
Abstract
In today's world, with its continuing advancements in genetics, the identification of Lynch syndrome (LS) increasingly relies on sophisticated genetic testing techniques. Most guidelines recommend a tailored surveillance program, as well as personalized prophylactic and therapeutic approaches, according to the type of dMMR gene mutation. Carriers of path_MLH1 and path_MSH2 genes have a higher risk of developing colorectal cancer (CRC), despite intensive colonoscopic surveillance. Conversely, carriers of path_MSH6 and path_PMS2 genes have a lower risk of developing CRC, which may be due to their lower penetrance and later age of onset. Thus, carriers of path_MLH1 or path_MSH2 would theoretically derive greater benefits from total colectomy, compared to low-risk carriers (path_MSH6 and path_PMS2), in which colonoscopic surveillance might achieve an efficient prophylaxis. Furthermore, regarding the risk of endometrial/ovarian cancer development, there is a global agreement to offer both hysterectomy and bilateral salpingo-oophorectomy to path_MLH1, path_MSH2 and path_MSH6 carriers after the age of 40. In patients with CRC, preoperative knowledge of the diagnosis of LS is of tremendous importance, due to the high risk of metachronous CRC. However, this risk depends on the type of dMMR gene mutation. For carriers of the high-risk variants (MLH1, MSH2 and EPCAM) who have already developed colon cancer, it is strongly recommended a subtotal or total colectomy is performed, while partial colectomy followed by endoscopic surveillance is an appropriate management approach to treat colon cancer in carriers of the low-risk variants (MSH6 and PMS2). On the other hand, extended surgery for index rectal cancer (such as total proctocolectomy) is less effective than extended surgery for index colon cancer from the point of view of metachronous CRC risk reduction, and is associated with a decreased quality of life.
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Affiliation(s)
- Tudor Razvan Grigorie
- Department of Surgery, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Hepato-Bilio-Pancreatic Surgery, Emergency University Hospital Bucharest, Splaiul Independentei 169, Sector 5, 050098 Bucharest, Romania
| | - Gheorghe Potlog
- Center for Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Sorin Tiberiu Alexandrescu
- Department of Surgery, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Hepato-Bilio-Pancreatic Surgery, Emergency University Hospital Bucharest, Splaiul Independentei 169, Sector 5, 050098 Bucharest, Romania
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Biller LH, Mittendorf K, Horiguchi M, Caruso A, Chittenden A, Ukaegbu C, Uno H, Syngal S, Yurgelun MB. Comparison of PREMM5 and PREMMplus Risk Assessment Models to Identify Lynch Syndrome. JCO Precis Oncol 2025; 9:e2400691. [PMID: 39772830 PMCID: PMC11723481 DOI: 10.1200/po-24-00691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/07/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
PURPOSE Clinical risk assessment models can identify patients with hereditary cancer susceptibility, but it is unknown how multigene cancer syndrome prediction models compare with syndrome-specific models in assessing risk for individual syndromes such as Lynch syndrome (LS). Our aim was to compare PREMMplus (a 19-gene cancer risk prediction model) with PREMM5 (a LS gene-specific model) for LS identification. METHODS We analyzed data from two cohorts of patients undergoing germline testing from a commercial laboratory (n = 12,020) and genetics clinic (n = 6,232) with personal and/or family histories of LS-associated cancer. Individual PREMMplus and PREMM5 scores were calculated for all patients. Using a score cutoff of ≥ 2.5%, we calculated the sensitivity, specificity, positive predictive value, and negative predictive value (NPV) for identifying LS with each model. Overall ability to discriminate LS carriers from noncarriers was measured using receiver operating characteristic (ROC)-AUC. RESULTS PREMMplus had higher sensitivity than PREMM5 in the laboratory- (63.7% [95% CI, 57.0 to 70.0] v 89.2% [95% CI, 84.4 to 93.0]) and clinic-based cohorts (60.8% [95% CI, 52.7 to 68.4] v 90.5% [95% CI, 84.8 to 94.6]). NPV was ≥98.8% for both models in both cohorts. PREMM5 had superior discriminatory capacity to PREMMplus in the laboratory- (ROC-AUC, 0.81 [95% CI, 0.77 to 0.84] v 0.71 [95% CI, 0.67 to 0.75]) and clinic-based cohorts (ROC-AUC, 0.79 [95% CI, 0.75 to 0.84] v 0.68 [95% CI, 0.64 to 0.73]). CONCLUSION Both PREMM5 and PREMMplus demonstrated high NPVs (>98%) in LS discrimination across all patient cohorts, and both models may be used to identify individuals at risk of LS. The choice of which model to use can be based on the goals of risk assessment and patient population.
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Affiliation(s)
- Leah H. Biller
- Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Brigham & Women's Hospital, Boston, MA
| | - Kate Mittendorf
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
| | - Miki Horiguchi
- Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | | | | | | | - Hajime Uno
- Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Sapna Syngal
- Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Brigham & Women's Hospital, Boston, MA
| | - Matthew B. Yurgelun
- Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Brigham & Women's Hospital, Boston, MA
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Bissmeyer MA, Velarde A, Salazar AS, Zamorano AS. Use and feasibility of a Lynch Syndrome predictive model for inherited colorectal and endometrial cancer in a low-middle income country. Fam Cancer 2024; 23:563-567. [PMID: 39317871 DOI: 10.1007/s10689-024-00422-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 09/15/2024] [Indexed: 09/26/2024]
Abstract
While universal tumor testing for Lynch Syndrome (LS) is recommended in all new diagnoses of colorectal cancer (CC) and endometrial cancer (EC), the cost and availability of this test in low-resource settings poses challenges. The PREdiction Model for gene Mutations (PREMM5) is a clinical algorithm designed to assess the risk of an individual carrying estimates one's risk of carrying a LS mutation. This study aims to assess the feasibility of using PREMM5 to screen for LS risk in Guatemala. This cross-sectional pilot study enrolled 50 patients with colorectal or endometrial cancer receiving treatment at LIGA-INCAN, a cancer hospital in Guatemala City, between June 2022-July 2022. Patients were contacted by phone and administered the PREMM5 survey, followed by an additional feasibility questionnaire. Of the 50 participants, 62% of patients had a PREMM5 predicted probability of ≥ 2.5%, the threshold above which genetic testing is recommended. Almost all patients found the survey easy to complete (98%), were able to easily recall personal (90%) and family (88%) medical history, understood its purpose (94%), and reported an interest in (96%) and ability to (98%) act on the results if applicable. Our study shows the role of the PREMM5 as a feasible tool for identifying individuals at risk of carrying mutations associated with LS in this low-resource setting. By implementing the PREMM5 model, high risk individuals can be identified early, enabling timely interventions and improving outcomes in this at-risk population.
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Affiliation(s)
- Monica A Bissmeyer
- McGovern Medical School, University of Texas Health Science Center at Houston, Houston, USA
| | - Angel Velarde
- Liga Nacional Contra El Cáncer de Guatemala, Guatemala, Guatemala
| | - Ana S Salazar
- Jackson Memorial Hospital Department of Internal Medicine, University of Miami Miller School of Medicine, Miami, USA
| | - Abigail S Zamorano
- Division of Gynecologic Oncology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, USA.
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Cavic M, Nikolic N, Marinkovic M, Damjanovic A, Krivokuca A, Tanic M, Radulovic M, Stanojevic A, Pejnovic L, Djordjic Crnogorac M, Djuric A, Vukovic M, Stevanovic V, Kijac J, Karadzic V, Nikolic S, Stojanovic-Rundic S, Jankovic R, Spasic J. Two Decades of Progress in Personalized Medicine of Colorectal Cancer in Serbia-Insights from the Institute for Oncology and Radiology of Serbia. Biomedicines 2024; 12:2278. [PMID: 39457591 PMCID: PMC11505512 DOI: 10.3390/biomedicines12102278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/03/2024] [Accepted: 10/04/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND It is projected that, by 2040, the number of new cases of colorectal cancer (CRC) will increase to 3.2 million, and the number of deaths to 1.6 million, highlighting the need for prevention strategies, early detection and adequate follow-up. In this study, we aimed to provide an overview of the progress in personalized medicine of CRC in Serbia, with results and insights from the Institute for Oncology and Radiology of Serbia (IORS), and to propose guidance for tackling observed challenges in the future. METHODS Epidemiological data were derived from official global and national cancer registries and IORS electronic medical records. Germline genetic testing for Lynch syndrome was performed by Next Generation Sequencing. RAS and BRAF mutation analyses were performed using qPCR diagnostic kits. RESULTS Epidemiology and risk factors, prevention and early detection programs, as well as treatment options and scientific advances have been described in detail. Out of 103 patients who underwent germline testing for Lynch syndrome, 19 (18.4%) showed a mutation in MMR genes with pathogenic or likely pathogenic significance and 8 (7.8%) in other CRC-associated genes (APC, CHEK2, MUTYH). Of 6369 tested patients, 50.43% had a mutation in KRAS or NRAS genes, while 9.54% had the V600 mutation in the BRAF gene. CONCLUSIONS Although significant improvements in CRC management have occurred globally in recent years, a strategic approach leading to population-based systemic solutions is required. The high incidence of young-onset CRC and the growing elderly population due to a rise in life expectancy will be especially important factors for countries with limited healthcare resources like Serbia.
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Affiliation(s)
- Milena Cavic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.D.); (M.T.); (M.R.); (A.S.); (A.D.); (M.V.); (V.S.); (J.K.); (R.J.)
| | - Neda Nikolic
- Clinic for Medical Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia;
| | - Mladen Marinkovic
- Clinic for Radiation Oncology and Diagnostics, Department of Radiation Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (M.M.); (S.S.-R.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Ana Damjanovic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.D.); (M.T.); (M.R.); (A.S.); (A.D.); (M.V.); (V.S.); (J.K.); (R.J.)
| | - Ana Krivokuca
- Genetic Counseling for Hereditary Cancers Department, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.K.); (M.D.C.); (V.K.)
| | - Miljana Tanic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.D.); (M.T.); (M.R.); (A.S.); (A.D.); (M.V.); (V.S.); (J.K.); (R.J.)
- Cancer Biology Department, University College London Cancer Institute, London WC1E 6DD, UK
| | - Marko Radulovic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.D.); (M.T.); (M.R.); (A.S.); (A.D.); (M.V.); (V.S.); (J.K.); (R.J.)
| | - Aleksandra Stanojevic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.D.); (M.T.); (M.R.); (A.S.); (A.D.); (M.V.); (V.S.); (J.K.); (R.J.)
| | - Luka Pejnovic
- Clinic for Surgical Oncology Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia;
| | - Marija Djordjic Crnogorac
- Genetic Counseling for Hereditary Cancers Department, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.K.); (M.D.C.); (V.K.)
| | - Ana Djuric
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.D.); (M.T.); (M.R.); (A.S.); (A.D.); (M.V.); (V.S.); (J.K.); (R.J.)
| | - Miodrag Vukovic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.D.); (M.T.); (M.R.); (A.S.); (A.D.); (M.V.); (V.S.); (J.K.); (R.J.)
| | - Vanja Stevanovic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.D.); (M.T.); (M.R.); (A.S.); (A.D.); (M.V.); (V.S.); (J.K.); (R.J.)
| | - Jelena Kijac
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.D.); (M.T.); (M.R.); (A.S.); (A.D.); (M.V.); (V.S.); (J.K.); (R.J.)
| | - Valentina Karadzic
- Genetic Counseling for Hereditary Cancers Department, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.K.); (M.D.C.); (V.K.)
| | - Srdjan Nikolic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
- Clinic for Surgical Oncology Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia;
| | - Suzana Stojanovic-Rundic
- Clinic for Radiation Oncology and Diagnostics, Department of Radiation Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (M.M.); (S.S.-R.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Radmila Jankovic
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia; (A.D.); (M.T.); (M.R.); (A.S.); (A.D.); (M.V.); (V.S.); (J.K.); (R.J.)
| | - Jelena Spasic
- Clinic for Medical Oncology, Institute for Oncology and Radiology of Serbia, 11000 Belgrade, Serbia;
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Dal Buono A, Puccini A, Franchellucci G, Airoldi M, Bartolini M, Bianchi P, Santoro A, Repici A, Hassan C. Lynch Syndrome: From Multidisciplinary Management to Precision Prevention. Cancers (Basel) 2024; 16:849. [PMID: 38473212 DOI: 10.3390/cancers16050849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/10/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND AND AIMS Lynch syndrome (LS) is currently one of the most prevalent hereditary cancer conditions, accounting for 3% of all colorectal cancers and for up to 15% of those with DNA mismatch repair (MMR) deficiency, and it was one of the first historically identified. The understanding of the molecular carcinogenesis of LS tumors has progressed significantly in recent years. We aim to review the most recent advances in LS research and explore genotype-based approaches in surveillance, personalized cancer prevention, and treatment strategies. METHODS PubMed was searched to identify relevant studies, conducted up to December 2023, investigating molecular carcinogenesis in LS, surveillance strategies, cancer prevention, and treatment in LS tumors. RESULTS Multigene panel sequencing is becoming the benchmark in the diagnosis of LS, allowing for the detection of a pathogenic constitutional variant in one of the MMR genes. Emerging data from randomized controlled trials suggest possible preventive roles of resistant starch and/or aspirin in LS. Vaccination with immunogenic frameshift peptides appears to be a promising approach for both the treatment and prevention of LS-associated cancers, as evidenced by pre-clinical and preliminary phase 1/2a studies. CONCLUSIONS Although robust diagnostic algorithms, including prompt testing of tumor tissue for MMR defects and referral for genetic counselling, currently exist for suspected LS in CRC patients, the indications for LS screening in cancer-free individuals still need to be refined and standardized. Investigation into additional genetic and non-genetic factors that may explain residual rates of interval cancers, even in properly screened populations, would allow for more tailored preventive strategies.
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Affiliation(s)
- Arianna Dal Buono
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Alberto Puccini
- Medical Oncology and Haematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Gianluca Franchellucci
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Marco Airoldi
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Michela Bartolini
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Paolo Bianchi
- Clinical Analysis Laboratory, Oncological Molecular Genetics Section, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Armando Santoro
- Medical Oncology and Haematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Alessandro Repici
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Cesare Hassan
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
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Ascrizzi S, Arillotta GM, Grillone K, Caridà G, Signorelli S, Ali A, Romeo C, Tassone P, Tagliaferri P. Lynch Syndrome Biopathology and Treatment: The Potential Role of microRNAs in Clinical Practice. Cancers (Basel) 2023; 15:3930. [PMID: 37568746 PMCID: PMC10417124 DOI: 10.3390/cancers15153930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/27/2023] [Accepted: 07/31/2023] [Indexed: 08/13/2023] Open
Abstract
Lynch syndrome (LS), also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is an autosomal dominant cancer syndrome which causes about 2-3% of cases of colorectal carcinoma. The development of LS is due to the genetic and epigenetic inactivation of genes involved in the DNA mismatch repair (MMR) system, causing an epiphenomenon known as microsatellite instability (MSI). Despite the fact that the genetics of the vast majority of MSI-positive (MSI+) cancers can be explained, the etiology of this specific subset is still poorly understood. As a possible new mechanism, it has been recently demonstrated that the overexpression of certain microRNAs (miRNAs, miRs), such as miR-155, miR-21, miR-137, can induce MSI or modulate the expression of the genes involved in LS pathogenesis. MiRNAs are small RNA molecules that regulate gene expression at the post-transcriptional level by playing a critical role in the modulation of key oncogenic pathways. Increasing evidence of the link between MSI and miRNAs in LS prompted a deeper investigation into the miRNome involved in these diseases. In this regard, in this study, we discuss the emerging role of miRNAs as crucial players in the onset and progression of LS as well as their potential use as disease biomarkers and therapeutic targets in the current view of precision medicine.
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Affiliation(s)
- Serena Ascrizzi
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
| | - Grazia Maria Arillotta
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
| | - Katia Grillone
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
| | - Giulio Caridà
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
| | - Stefania Signorelli
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
| | - Asad Ali
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
| | - Caterina Romeo
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
| | - Pierfrancesco Tassone
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
- Medical Oncology and Translational Medical Oncology Units, University Hospital Renato Dulbecco, 88100 Catanzaro, Italy
| | - Pierosandro Tagliaferri
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (G.M.A.); (K.G.); (G.C.); (S.S.); (A.A.); (C.R.); (P.T.)
- Medical Oncology and Translational Medical Oncology Units, University Hospital Renato Dulbecco, 88100 Catanzaro, Italy
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Saraiva MR, Rosa I, Claro I. Early-onset colorectal cancer: A review of current knowledge. World J Gastroenterol 2023; 29:1289-1303. [PMID: 36925459 PMCID: PMC10011966 DOI: 10.3748/wjg.v29.i8.1289] [Citation(s) in RCA: 66] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/18/2022] [Accepted: 02/15/2023] [Indexed: 02/28/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide. Although most prevalent among older people, its incidence above 50 years old has been decreasing globally in the last decades, probably as a result of better screening. Paradoxically, its incidence in patients below 50 years old [early-onset CRC (EO-CRC)] has been increasing, for reasons not yet fully understood. EO-CRC's increasing incidence is genre independent but shows racial disparities and has been described to occur worldwide. It follows a birth-cohort effect which probably reflects a change in exposure to CRC risk factors. Its incidence is predicted to double until 2030, which makes EO-CRC a serious public health issue. Both modifiable and non-modifiable risk factors have been identified - some are potential targets for preventive measures. EO-CRC is often diagnosed at advanced stages and histological features associated with poor prognosis have been described. EO-CRC presents some distinctive features: Microsatellite in-stability is common, but another subtype of tumours, both microsatellite and chromosome stable also seems relevant. There are no age-specific treatment protocols and studies on EO-CRC survival rates have shown conflicting data. Due to the higher germline pathological mutations found in EO-CRC patients, an accurate genetic risk evaluation should be performed. In this review, we summarize the current evidence on epidemiological, clinical, histopathological and molecular features of EO-CRC and discuss the contribution of genetics and lifestyle risk factors. We further comment on screening strategies and specific dimensions to consider when dealing with a younger cancer patient.
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Affiliation(s)
- Margarida R Saraiva
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa 1099-023, Portugal
| | - Isadora Rosa
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa 1099-023, Portugal
| | - Isabel Claro
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa 1099-023, Portugal
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9
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Adam F, Fluri M, Scherz A, Rabaglio M. Occurrence of variants of unknown clinical significance in genetic testing for hereditary breast and ovarian cancer syndrome and Lynch syndrome: a literature review and analytical observational retrospective cohort study. BMC Med Genomics 2023; 16:7. [PMID: 36647026 PMCID: PMC9843935 DOI: 10.1186/s12920-023-01437-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 01/09/2023] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND AND PURPOSE Over the last decade, the implementation of multigene panels for hereditary tumor syndrome has increased at our institution (Inselspital, University Hospital Berne, Switzerland). The aim of this study was to determine the prevalence of variants of unknown significance (VUS) in patients with suspected Lynch syndrome and suspected hereditary breast and ovarian cancer syndrome, the latter in connection with the trend toward ordering larger gene panels. RESULTS Retrospectively collected data from 1057 patients at our institution showed at least one VUS in 126 different cases (11.9%). In patients undergoing genetic testing for BRCA1/2, the prevalence of VUS was 6%. When < 10 additional genes were tested in addition to BRCA1/2, the prevalence increased to 13.8%, and 31.8% for > 10 additional genes, respectively. The gene most frequently affected with a VUS was ATM. 6% of our patients who were tested for Lynch syndrome had a VUS result in either MLH1, MSH2 or MSH6. CONCLUSIONS Our data demonstrate that panel testing statistically significantly increases VUS rates due to variants in non-BRCA genes. Good genetic counseling before and after obtaining results is therefore particularly important when conducting multigene panels to minimize patient uncertainty due to VUS results.
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Affiliation(s)
- Felicia Adam
- Medical Faculty of the University of Bern, Bern, Switzerland
| | - Muriel Fluri
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Amina Scherz
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Manuela Rabaglio
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
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10
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Kirsten T, Meineke FA, Loeffler-Wirth H, Beger C, Uciteli A, Stäubert S, Löbe M, Hänsel R, Rauscher FG, Schuster J, Peschel T, Herre H, Wagner J, Zachariae S, Engel C, Scholz M, Rahm E, Binder H, Loeffler M. The Leipzig Health Atlas-An Open Platform to Present, Archive, and Share Biomedical Data, Analyses, and Models Online. Methods Inf Med 2022; 61:e103-e115. [PMID: 35915977 PMCID: PMC9788914 DOI: 10.1055/a-1914-1985] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Clinical trials, epidemiological studies, clinical registries, and other prospective research projects, together with patient care services, are main sources of data in the medical research domain. They serve often as a basis for secondary research in evidence-based medicine, prediction models for disease, and its progression. This data are often neither sufficiently described nor accessible. Related models are often not accessible as a functional program tool for interested users from the health care and biomedical domains. OBJECTIVE The interdisciplinary project Leipzig Health Atlas (LHA) was developed to close this gap. LHA is an online platform that serves as a sustainable archive providing medical data, metadata, models, and novel phenotypes from clinical trials, epidemiological studies, and other medical research projects. METHODS Data, models, and phenotypes are described by semantically rich metadata. The platform prefers to share data and models presented in original publications but is also open for nonpublished data. LHA provides and associates unique permanent identifiers for each dataset and model. Hence, the platform can be used to share prepared, quality-assured datasets and models while they are referenced in publications. All managed data, models, and phenotypes in LHA follow the FAIR principles, with public availability or restricted access for specific user groups. RESULTS The LHA platform is in productive mode (https://www.health-atlas.de/). It is already used by a variety of clinical trial and research groups and is becoming increasingly popular also in the biomedical community. LHA is an integral part of the forthcoming initiative building a national research data infrastructure for health in Germany.
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Affiliation(s)
- Toralf Kirsten
- Department of Medical Data Science, Leipzig University Medical Center, Leipzig, Germany,Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany,Interdisciplinary Centre for Bioinformatics, Leipzig University, Leipzig, Germany,Address for correspondence Toralf Kirsten Department of Medical Data Science, Leipzig UniversityHärtelstraße 16-18, 04107 LeipzigGermany
| | - Frank A. Meineke
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany
| | - Henry Loeffler-Wirth
- LIFE Research Centre for Civilization Diseases, Leipzig University, Leipzig, Germany
| | - Christoph Beger
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany
| | - Alexandr Uciteli
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany
| | - Sebastian Stäubert
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany
| | - Matthias Löbe
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany,Interdisciplinary Centre for Bioinformatics, Leipzig University, Leipzig, Germany
| | - René Hänsel
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany
| | - Franziska G. Rauscher
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany,Interdisciplinary Centre for Bioinformatics, Leipzig University, Leipzig, Germany
| | - Judith Schuster
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany
| | - Thomas Peschel
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany
| | - Heinrich Herre
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany
| | - Jonas Wagner
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany,Interdisciplinary Centre for Bioinformatics, Leipzig University, Leipzig, Germany
| | - Silke Zachariae
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany
| | - Christoph Engel
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany,Interdisciplinary Centre for Bioinformatics, Leipzig University, Leipzig, Germany
| | - Markus Scholz
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany
| | - Erhard Rahm
- Department of Computer Sciences, Leipzig University, Leipzig, Germany
| | - Hans Binder
- LIFE Research Centre for Civilization Diseases, Leipzig University, Leipzig, Germany
| | - Markus Loeffler
- Institute for Medical Informatics, Statistics, and Epidemiology, Leipzig University, Leipzig, Germany,Interdisciplinary Centre for Bioinformatics, Leipzig University, Leipzig, Germany,LIFE Research Centre for Civilization Diseases, Leipzig University, Leipzig, Germany
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11
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Dehghani Soufi M, Rezaei Hachesu P, Ferdousi R. Oncology Informatics for Lynch Syndrome Research and Care: A Literature Review. JCO Clin Cancer Inform 2022; 6:e2200087. [DOI: 10.1200/cci.22.00087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
PURPOSE This study aims to review and evaluate available informatics platforms for research and management purposes of Lynch syndrome (LS) to identify gaps and needs for future development. METHODS LS informatics tools were identified through literature search in four publication databases (1 and Scopus). First, the LS and functional elements of every informatics tools for LS were introduced. Then, current existing LS informatics tools were reviewed and explained. RESULTS A detailed review of implemented studies shows that many types of informatics platforms are available for LS management (ie, prediction model, clinical decision support system, database website, and other tools for research and management purposes of LS). Moreover, several dimensions of existing LS informatics tools were discussed and features and positive findings were reported. CONCLUSION Reviewing the literature reveals that several LS informatics tools were focused on gene-specific estimate, cancer risk prediction, identifying/screening patients, supporting personalized care of individuals with LS, and storing mismatch repair mutations information. Nevertheless, these platforms do not fully cover the care and research purposes. For instance, future developments of LS tools require more attention to dynamic knowledgebase, extra-colonic lynch–related cancers on the basis of precision medicine, variants of unknown significance, and support from diagnosis to surveillance for patient follow-up. Insights and recommendations provided in this study could help researchers and developers to meet the existing challenges in future developments.
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Affiliation(s)
- Mahsa Dehghani Soufi
- Department of Health Information Technology, School of Management and Medical Informatics, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Peyman Rezaei Hachesu
- Department of Health Information Technology, School of Management and Medical Informatics, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Ferdousi
- Department of Health Information Technology, School of Management and Medical Informatics, Tabriz University of Medical Sciences, Tabriz, Iran
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12
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Abstract
The traditional approach of one-size-fits-all for colorectal cancer has been replaced by personalized interventions to an individual's unique genetic, molecular, and environmental profile, seeking to identify high-risk individuals who would benefit from individualized screening and surveillance. This change in approach is due, in part, to emerging technologies, such as next-generation DNA sequencing.
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13
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Lynch Syndrome: From Carcinogenesis to Prevention Interventions. Cancers (Basel) 2022; 14:cancers14174102. [PMID: 36077639 PMCID: PMC9454739 DOI: 10.3390/cancers14174102] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/23/2022] [Accepted: 08/23/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary Promoting proper preventive interventions to reduce morbidity and mortality is one of the most important challenges pertaining to inherited conditions. Lynch syndrome (LS) is an inherited disorder that predisposes to several kinds of tumor and is responsible for a relevant proportion of human colorectal and endometrial cancers. Recent knowledge has allowed for a better understanding of the genetic cause, pathogenesis, underlying immunological mechanisms, epidemiological distribution, and prevalence of this disease. This opens up unpredictable perspectives of translating such knowledge into validated programs for prevention and surveillance, in order to reduce the health impact of this disease through medical interventions before cancer development. In our review, we summarize the updated guidelines of the screening, surveillance, and risk-reducing strategies for LS patients. Moreover, we present novel opportunities in the treatment and prevention of LS patients through harnessing the immune system using immunocheckpoint inhibitors and vaccines. Abstract Lynch syndrome (LS) is the most common inherited disorder responsible for an increased risk of developing cancers at different sites, most frequently in the gastrointestinal and genitourinary tracts, caused by a germline pathogenic variant affecting the DNA mismatch repair system. Surveillance and risk-reducing procedures are currently available and warranted for LS patients, depending on underlying germline mutation, and are focused on relevant targets for early cancer diagnosis or primary prevention. Although pharmacological approaches for preventing LS-associated cancer development were started many years ago, to date, aspirin remains the most studied drug intervention and the only one suggested by the main surveillance guidelines, despite the conflicting findings. Furthermore, we also note that remarkable advances in anticancer drug discovery have given a significant boost to the application of novel immunological strategies such as immunocheckpoint inhibitors and vaccines, not only for cancer treatment, but also in a preventive setting. In this review, we outline the clinical, biologic, genetic, and morphological features of LS as well as the recent three-pathways carcinogenesis model. Furthermore, we provide an update on the dedicated screening, surveillance, and risk-reducing strategies for LS patients and describe emerging opportunities of harnessing the immune system.
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14
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Mangas-Sanjuan C, Jover R. Familial colorectal cancer. Best Pract Res Clin Gastroenterol 2022; 58-59:101798. [PMID: 35988967 DOI: 10.1016/j.bpg.2022.101798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/01/2022] [Accepted: 03/08/2022] [Indexed: 01/31/2023]
Abstract
The introduction of average-risk colorectal cancer (CRC) screening programs means that many subjects with family history of CRC and without well-described inherited syndromes can benefit from these public health policies. Therefore, the definition of which individuals should be named under the umbrella of the term "familial CRC" should be reconsidered to include only those who are outside of the protection of population-based screening and need to be moved towards a more intensive surveillance strategy. Two subgroups have been reported as having a high enough CRC risk to be included within the term "familial risk of CRC": individuals who have ≥1 first degree relative (FDR) with CRC diagnosed at age <50 years, and those who have ≥2 FDRs with CRC. Colonoscopy-based screening starting at age 40 years is proposed as the most accepted recommendation for these individuals. Finally, the evolution of Lynch syndrome screening from clinical criteria to tumor tissue analysis and new tools for screening pathogenic gene mutations associated with cancer susceptibility in individuals with early-onset CRC might help to reduce misclassification of familial CRC.
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Affiliation(s)
- Carolina Mangas-Sanjuan
- Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Instituto de Investigación Biomédica ISABIAL, Universidad Miguel Hernández, Alicante, Spain
| | - Rodrigo Jover
- Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Instituto de Investigación Biomédica ISABIAL, Universidad Miguel Hernández, Alicante, Spain.
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15
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Comprehensive assessment of germline pathogenic variant detection in tumor-only sequencing. Ann Oncol 2022; 33:426-433. [PMID: 35074424 PMCID: PMC9172914 DOI: 10.1016/j.annonc.2022.01.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 12/30/2021] [Accepted: 01/13/2022] [Indexed: 12/20/2022] Open
Abstract
Background: Tumor-only sequencing, implemented for the identification of somatic variants, is oftentimes used for the detection of actionable germline variants. We sought to determine whether tumor-only sequencing assays are suitable for detection of actionable germline variants, given their importance for the delivery of targeted therapies and risk-reducing measures. Patients and methods: The detection of germline variants affecting moderate- and high-penetrance cancer susceptibility genes (CSGs) by tumor-only sequencing was compared to clinical germline testing in 21 333 cancer patients who underwent tumor and germline testing using the Food and Drug Administration (FDA)-authorized Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay. Seven homologous recombination deficiency (HRD), two DNA damage response (DDR) and four mismatch repair (MMR) genes, as well as NF1, RB1 and TP53 were included in the analysis. FDA-authorized and New York State Department of Health-approved sequencing methods for germline, tumor/normal and tumor-only sequencing assays and analytical pipelines were employed. Results: In patients who underwent tumor and germline sequencing, as compared to clinical genetic testing, tumor-only sequencing failed to detect 10.5% of clinically actionable pathogenic germline variants in CSGs, including 18.8%, 12.8% and 7.3% of germline variants in MMR, DDR and HRD genes, respectively. The sensitivity for detection of pathogenic germline variants by tumor-only sequencing was 89.5%. Whilst the vast majority of pathogenic germline exonic single-nucleotide variants (SNVs) and small indels were detected by tumor-only sequencing, large percentages of germline copy number variants, intronic variants and repetitive element insertions were not detected. Conclusions: Tumor-only sequencing is adequate for the detection of clinically actionable germline variants, particularly for SNVs and small indels; however, a small subset of alterations affecting HRD, DDR and MMR genes may not be detected optimally. Therefore, for high-risk patients with negative tumor-only sequencing results, clinical genetic testing could be considered given the impact of these variants on therapy and genetic counseling.
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16
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Yamashita K, Fukushima H, Teramoto M, Okita K, Ishikawa A, Sakurai A, Akagi K, Nakase H. Interval between the First Cancer and the Genetic Diagnosis in Lynch Syndrome Probands. Intern Med 2021; 60:2719-2724. [PMID: 33746161 PMCID: PMC8479221 DOI: 10.2169/internalmedicine.6603-20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Objective Little is known about the time from developing a first cancer to confirming the presence of a mismatch repair (MMR) gene mutation for Lynch syndrome (LS) probands. Methods This was a retrospective single center study. LS probands, who have an MMR gene mutation that was confirmed first in a pedigree and thereafter developed at least one cancer, were included in this study. Results There were 21 LS probands who had developed at least one cancer; 6 with MLH1 mutations, 9 with MSH2 mutations, 4 with MSH6 mutations, and 2 with EPCAM deletions. The median ages at the first cancer and the genetic diagnosis were 47 (34-71) and 62 (38-84) years old, respectively. The mean interval between the first cancer and the genetic diagnosis was 11.0 (0-25) years, and 20 years or longer interval was required for the 5 probands. Six (28.6%) probands were older than 70 years, and 3 (14.3%) were in their 80s when they were diagnosed to have LS. The genetic diagnosis was confirmed at the first, second, third, and fourth cancer or later in 5, 5, 6, and 5 probands, respectively. Of the 16 cancers examined, 2 (12.5%) were microsatellite stable (MSS), both of whom had germline MSH6 mutations. All 17 LS probands who developed colorectal cancer met the revised Bethesda guidelines at the genetic diagnosis, but only 7 of 11 (63.6%) met them at the first cancer. Twelve out of 21 (57.1%) met the revised Amsterdam criteria. Conclusion It took 11 years for the LS probands from the first cancer to the diagnostic confirmation by genetic tests. A quarter of the probands were in their 70s or 80s at genetic diagnosis.
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Affiliation(s)
- Kentaro Yamashita
- Department of Gastroenterology and Hepatology, Sapporo Medical University, Japan
| | - Hisayo Fukushima
- Department of Medical Genetics, Sapporo Medical University, Japan
| | - Mizue Teramoto
- Department of Obstetrics and Gynecology, Sapporo Medical University, Japan
| | - Kenji Okita
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Japan
| | - Aki Ishikawa
- Department of Medical Genetics, Sapporo Medical University, Japan
| | - Akihiro Sakurai
- Department of Medical Genetics, Sapporo Medical University, Japan
| | - Kiwamu Akagi
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University, Japan
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17
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Risk factors and clinical characteristics of early-onset colorectal cancer vs. late-onset colorectal cancer: a case-case study. Eur J Gastroenterol Hepatol 2021; 33:1153-1160. [PMID: 33208680 DOI: 10.1097/meg.0000000000002000] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND OBJECTIVES Early-onset colorectal cancer (eoCRC), defined as colorectal cancer (CRC) before the age of 50 is increasing in incidence. We evaluated exogenous and endogenous risk factors, and clinical features of eoCRC, compared to late-onset CRC (loCRC). METHODS In this retrospective case-case study, patients were prospectively enrolled from 2015 to 2018. We collected clinical features (age, sex, time from symptom onset to diagnosis, symptoms, family history, smoking and alcohol habits, diabetes, BMI, and genetic analysis) and tumor characteristics. Independent risk factors for eoCRC and odds ratios (ORs) were identified. RESULTS Fifty-four eoCRCs and 494 loCRCs were enrolled. Patients with eoCRC experienced longer delay time from symptom onset to diagnosis: 40.7% were diagnosed within 6 months from symptoms onset, compared to 85.6% of patients with loCRC (P < 0.0001). They differed for sex, presence of symptoms, family history, smoking habit, alcohol intake, and BMI. Rectal localization was more closely associated with eoCRC (64.8%) than loCRC (34.5%, P < 0.0001). Family history of CRC was associated with eoCRC (OR = 8.8). When family history occurred with hereditary cancer syndromes, the OR for eoCRC increased to 21. CONCLUSION In young adults with alarming symptoms, CRC must be suspected to avoid delay time from symptom onset to diagnosis and genetic risk assessment has to be evaluated. Smoking habits, alcohol intake, and BMI are not associated with eoCRC.
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18
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Kartal K, Guan Z, Tang R, Griffin M, Wang Y, Braun D, Klein AP, Hughes KS. Familial pancreatic cancer: who should be considered for genetic testing? Ir J Med Sci 2021; 191:641-650. [PMID: 33733397 DOI: 10.1007/s11845-021-02572-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 02/26/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Determining how many female patients who underwent breast imaging meet the eligibility criteria for genetic testing for familial pancreatic cancer (FPC). METHODS A total of 42,904 patients seen at the Newton-Wellesley Hospital between 2007 and 2009 were retrospectively reviewed. The first four categories were based on pancreatic cancer-associated syndromes: (1) hereditary breast and ovarian cancer (HBOC), (2) Lynch syndrome (LS), (3) familial atypical multiple mole melanoma (FAMMM), and (4) family history of FPC (FH-FPC). PancPRO (5) and MelaPRO (6) categories were based on risk scores from Mendelian risk prediction tool. RESULTS Exactly 4445 of 42,904 patients were found to be in at least one of the six risk categories. About 5.7% of patients were classified as being at high risk for HBOC, 2.3% as being at high risk for LS, 0.1% as being at high risk for FAMMM, 0.1% as being at high risk for FH-FPC, 2.7% as being at high risk based on PancPRO, and 0.2% as being at high risk based on MelaPRO. CONCLUSION About 10.4% of the female patients were classified as being at high risk for FPC. This finding emphasizes the importance of applying criteria to the general population, in order to ensure that individuals with high risk are identified early.
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Affiliation(s)
- Kinyas Kartal
- Division of Surgical Oncology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA. .,Department of General Surgery, Koc University Hospital, Istanbul, Turkey.
| | - Zoe Guan
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Rong Tang
- Division of Surgical Oncology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA
| | - Molly Griffin
- Division of Surgical Oncology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA.,University of Massachusetts Medical School, Worcester, MA, USA
| | - Yan Wang
- Division of Surgical Oncology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA.,Department of Breast Surgery, Shanghai Cancer Hospital, Fudan University, Shanghai, China
| | - Danielle Braun
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Alison P Klein
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institution, Baltimore, MD, USA
| | - Kevin S Hughes
- Division of Surgical Oncology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA
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19
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Mannucci A, Furniss CS, Ukaegbu C, Horiguchi M, Fehlmann T, Uno H, Yurgelun MB, Syngal S. Comparison of Colorectal and Endometrial Microsatellite Instability Tumor Analysis and Premm 5 Risk Assessment for Predicting Pathogenic Germline Variants on Multigene Panel Testing. J Clin Oncol 2020; 38:4086-4094. [PMID: 32997573 PMCID: PMC7768341 DOI: 10.1200/jco.20.01470] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/17/2020] [Indexed: 12/30/2022] Open
Abstract
PURPOSE Tumor testing for microsatellite instability and/or mismatch repair-deficiency (MSI/IHC) and clinical prediction models effectively screen for Lynch syndrome (LS)-associated colorectal cancer (CRC) and endometrial cancer (EC), but they have not been assessed for their ability to identify non-LS forms of inherited risk. The aim of this study was to compare MSI/IHC and the PREMM5 prediction model to identify carriers of LS and non-LS pathogenic variants (PVs) among patients with CRC and EC. PATIENTS AND METHODS Data were retrospectively analyzed from two single-institution cohorts: 706 patients with CRC and/or EC referred for genetic evaluation/testing (high-risk cohort) and 1,058 consecutively ascertained patients with CRC (oncology clinic cohort), unselected for familial risk. All participants underwent germline multigene panel testing. PREMM5 scores were calculated from personal/family cancer history. The primary outcome was the proportion of individuals with germline PVs (LS PVs, high-penetrance PVs, and any PVs) who had abnormal MSI/IHC testing and/or PREMM5 score ≥ 2.5%. RESULTS MSI/IHC and PREMM5 had comparable sensitivity for identifying LS carriers in high-risk (89.3% v 85.7%; P = .712) and oncology clinic patients (96.6% v 96.6%; P = 1.000), although MSI/IHC had significantly superior specificity for LS (81.3% v 20.1%; P < .001; 92.3% v 24.3%; P < .001). In both cohorts, PREMM5 had superior sensitivity to MSI/IHC at identifying patients with any high-penetrance PVs and any low-, moderate-, and high-penetrance PVs. Among patients with normal MSI/IHC, PREMM5 identified 84.2% and 83.3% of high-risk patients with CRC/EC and oncology clinic CRC patients with high-penetrance PVs, respectively. CONCLUSION MSI/IHC and PREMM5 effectively identify patients with CRC and/or EC with LS, although MSI/IHC has better specificity for LS. Because PREMM5 identifies non-LS, high-penetrance germline PVs, patients with CRC and/or EC with PREMM5 score ≥ 2.5%, including those with normal MSI/IHC, should be offered multigene panel testing.
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Affiliation(s)
- Alessandro Mannucci
- IRCCS Ospedale San Raffaele Scientific Institute, Milan, Italy
- Dana-Farber Cancer Institute, Boston, MA
| | - C. Sloane Furniss
- Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | | | - Miki Horiguchi
- Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | | | - Hajime Uno
- Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Matthew B. Yurgelun
- Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Brigham and Women’s Hospital, Boston, MA
| | - Sapna Syngal
- Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
- Brigham and Women’s Hospital, Boston, MA
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20
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Ito T, Nomizu T, Eguchi H, Kamae N, Dechamethakun S, Akama Y, Endo G, Sugano K, Yoshida T, Okazaki Y, Ishida H. The first case report of polymerase proofreading-associated polyposis in POLD1 variant, c.1433G>A p.S478N, in Japan. Jpn J Clin Oncol 2020; 50:1080-1083. [PMID: 32548621 DOI: 10.1093/jjco/hyaa090] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 05/22/2020] [Indexed: 01/15/2023] Open
Abstract
Polymerase proofreading-associated polyposis, caused by germline variants in the exonuclease domains of POLD1 and POLE, is a dominantly inherited rare condition characterized by oligo-adenomatous polyposis and increased risk of colorectal cancer, endometrial cancer and brain tumours. We report the first Japanese case of polymerase proofreading-associated polyposis carrying a POLD1 variant. The proband was a Japanese woman who had undergone resections of early colorectal carcinomas repeatedly and a hysterectomy with bilateral oophorectomy for endometrial cancer, all of which were diagnosed within 2 years after the first colectomy at 49 year old. Colonoscopic examinations demonstrated at least 14 non-cancerous polypoid lesions, some of which were histologically confirmed to be adenoma. Multigene panel sequencing identified a missense variant in POLD1 (c.1433G>A). Although her relatives did not undergo genetic testing, her father and paternal grandfather died of brain tumours at 53 and ~30 years of age, respectively.
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Affiliation(s)
- Tetsuya Ito
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe
| | | | - Hidetaka Eguchi
- Diagnosis and Therapeutics of Intractable Disease, Juntendo University Graduate School of Medicine, Tokyo
| | - Nao Kamae
- Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Kawagoe
| | - Sariya Dechamethakun
- Diagnosis and Therapeutics of Intractable Disease, Juntendo University Graduate School of Medicine, Tokyo
| | - Yoshinori Akama
- Department of Genetic Counseling, Hoshi General Hospital, Koriyama
| | - Goichi Endo
- Department of Surgery, Fukushima Red Cross Hospital, Fukushima
| | - Kokichi Sugano
- Oncogene Research Unit/Cancer Prevention Unit, Tochigi Cancer Center Research Institute, Utsunomiya
| | - Teruhiko Yoshida
- Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan
| | - Yasushi Okazaki
- Diagnosis and Therapeutics of Intractable Disease, Juntendo University Graduate School of Medicine, Tokyo
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe
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21
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Cost-Effectiveness of Early Detection and Prevention Strategies for Endometrial Cancer-A Systematic Review. Cancers (Basel) 2020; 12:cancers12071874. [PMID: 32664613 PMCID: PMC7408795 DOI: 10.3390/cancers12071874] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/03/2020] [Accepted: 07/08/2020] [Indexed: 12/24/2022] Open
Abstract
Endometrial cancer is the most common female genital tract cancer in developed countries. We systematically reviewed the current health-economic evidence on early detection and prevention strategies for endometrial cancer based on a search in relevant databases (Medline/Embase/Cochrane Library/CRD/EconLit). Study characteristics and results including life-years gained (LYG), quality-adjusted life-years (QALY) gained, and incremental cost-effectiveness ratios (ICERs) were summarized in standardized evidence tables. Economic results were transformed into 2019 euros using standard conversion methods (GDP-PPP, CPI). Seven studies were included, evaluating (1) screening for endometrial cancer in women with different risk profiles, (2) risk-reducing interventions for women at increased or high risk for endometrial cancer, and (3) genetic testing for germline mutations followed by risk-reducing interventions for diagnosed mutation carriers. Compared to no screening, screening with transvaginal sonography (TVS), biomarker CA-125, and endometrial biopsy yielded an ICER of 43,600 EUR/LYG (95,800 EUR/QALY) in women with Lynch syndrome at high endometrial cancer risk. For women considering prophylactic surgery, surgery was more effective and less costly than screening. In obese women, prevention using Levonorgestrel as of age 30 for five years had an ICER of 72,000 EUR/LYG; the ICER for using oral contraceptives for five years as of age 50 was 450,000 EUR/LYG. Genetic testing for mutations in women at increased risk for carrying a mutation followed by risk-reducing surgery yielded ICERs below 40,000 EUR/QALY. Based on study results, preventive surgery in mutation carriers and genetic testing in women at increased risk for mutations are cost-effective. Except for high-risk women, screening using TVS and endometrial biopsy is not cost-effective and may lead to overtreatment. Model-based analyses indicate that future biomarker screening in women at increased risk for cancer may be cost-effective, dependent on high test accuracy and moderate test costs. Future research should reveal risk-adapted early detection and prevention strategies for endometrial cancer.
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22
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Hart SN, Polley EC, Yussuf A, Yadav S, Goldgar DE, Hu C, LaDuca H, Smith LP, Fujimoto J, Li S, Couch FJ, Dolinsky JS. Mutation prevalence tables for hereditary cancer derived from multigene panel testing. Hum Mutat 2020; 41:e1-e6. [PMID: 32442341 PMCID: PMC7418063 DOI: 10.1002/humu.24053] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/13/2020] [Accepted: 05/18/2020] [Indexed: 11/11/2022]
Abstract
Multigene panel testing for cancer predisposition mutations is becoming routine in clinical care. However, the gene content of panels offered by testing laboratories vary significantly, and data on mutation detection rates by gene and by the panel is limited, causing confusion among clinicians on which test to order. Using results from 147,994 multigene panel tests conducted at Ambry Genetics, we built an interactive prevalence tool to explore how differences in ethnicity, age of onset, and personal and family history of different cancers affect the prevalence of pathogenic mutations in 31 cancer predisposition genes, across various clinically available hereditary cancer gene panels. Over 13,000 mutation carriers were identified in this high-risk population. Most were non-Hispanic white (74%, n = 109,537), but also Black (n = 10,875), Ashkenazi Jewish (n = 10,464), Hispanic (n = 10,028), and Asian (n = 7,090). The most prevalent cancer types were breast (50%), ovarian (6.6%), and colorectal (4.7%), which is expected based on genetic testing guidelines and clinician referral for testing. The Hereditary Cancer Multi-Gene Panel Prevalence Tool presented here can be used to provide insight into the prevalence of mutations on a per-gene and per-multigene panel basis, while conditioning on multiple custom phenotypic variables to include race and cancer type.
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Affiliation(s)
- Steven N Hart
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Eric C Polley
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | | | - Siddhartha Yadav
- Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota
| | - David E Goldgar
- Department of Dermatology, University of Utah, Salt Lake City, Utah
| | - Chunling Hu
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | | | | | - Shuwei Li
- Ambry Genetics, Aliso Viejo, California
| | - Fergus J Couch
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
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23
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Nelson SR, Walsh N. Genetic Alterations Featuring Biological Models to Tailor Clinical Management of Pancreatic Cancer Patients. Cancers (Basel) 2020; 12:E1233. [PMID: 32423157 PMCID: PMC7281628 DOI: 10.3390/cancers12051233] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/11/2020] [Accepted: 05/12/2020] [Indexed: 12/19/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide. This high mortality rate is due to the disease's lack of symptoms, resulting in a late diagnosis. Biomarkers and treatment options for pancreatic cancer are also limited. In order to overcome this, new research models and novel approaches to discovering PDAC biomarkers are required. In this review, we outline the hereditary and somatic causes of PDAC and provide an overview of the recent genome wide association studies (GWAS) and pathway analysis studies. We also provide a summary of some of the systems used to study PDAC, including established and primary cell lines, patient-derived xenografts (PDX), and newer models such as organoids and organ-on-chip. These ex vitro laboratory systems allow for critical research into the development and progression of PDAC.
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Affiliation(s)
| | - Naomi Walsh
- National Institute for Cellular Biotechnology, School of Biotechnology, Dublin City University, Dublin 9, Ireland;
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24
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MSH6 gene pathogenic variant identified in familial pancreatic cancer in the absence of colon cancer. Eur J Gastroenterol Hepatol 2020; 32:345-349. [PMID: 31851094 DOI: 10.1097/meg.0000000000001617] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
OBJECTIVES Lynch syndrome is characterized by pathogenetic variants in the mismatch repair genes and autosomal dominant inheritance with incomplete penetrance. Lynch syndrome is characterized by colorectal and, with lesser and variable extent, extracolonic cancers. We describe a family with MSH6-dependent Lynch syndrome and familial pancreatic cancer and other tumours (gastric and endometrial), in the absence of colorectal neoplasia. METHODS Patients were analysed by sequencing, Next Generation or Sanger, to identify germinal pathogenic variants in hereditary cancer genes. RESULTS We identified the MSH6 gene pathogenic variant c.2194C>T, p.(Arg732Ter) in a family with hereditary pancreatic cancer without diagnosed cases of colorectal adenocarcinoma. Seven family members were affected by the MSH6 pathogenic variant. Three had pancreatic adenocarcinoma at 65, 57 and 44 years; one had endometrial cancer at 36 years. None of the remaining three subjects (75, 45 and 17 years old) had developed any cancer yet. CONCLUSIONS Lynch syndrome should be suspected in families with familial pancreatic cancer, even in the absence of colon cancers. Specifically, our observation supports the association between the MSH6 c.2194C>T pathogenic variant and extracolonic tumours and it suggests that MSH6 pathogenic variants are associated with familial pancreatic cancer more frequently than assumed.
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25
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Kastrinos F, Samadder NJ, Burt RW. Use of Family History and Genetic Testing to Determine Risk of Colorectal Cancer. Gastroenterology 2020; 158:389-403. [PMID: 31759928 DOI: 10.1053/j.gastro.2019.11.029] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 11/11/2019] [Accepted: 11/18/2019] [Indexed: 12/20/2022]
Abstract
Approximately 35% of patients with colorectal cancer (CRC) have a family history of the disease attributed to genetic factors, common exposures, or both. Some families with a history of CRC carry genetic variants that cause CRC with high or moderate penetrance, but these account for only 5% to 10% of CRC cases. Most families with a history of CRC and/or adenomas do not carry genetic variants associated with cancer syndromes; this is called common familial CRC. Our understanding of familial predisposition to CRC and cancer syndromes has increased rapidly due to advances in next-generation sequencing technologies. As a result, there has been a shift from genetic testing for specific inherited cancer syndromes based on clinical criteria alone, to simultaneous testing of multiple genes for cancer-associated variants. We summarize current knowledge of common familial CRC, provide an update on syndromes associated with CRC (including the nonpolyposis and polyposis types), and review current recommendations for CRC screening and surveillance. We also provide an approach to genetic evaluation and testing in clinical practice. Determination of CRC risk based on family cancer history and results of genetic testing can provide a personalized approach to cancer screening and prevention, with optimal use of colonoscopy to effectively decrease CRC incidence and mortality.
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Affiliation(s)
- Fay Kastrinos
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York; Division of Digestive and Liver Diseases, Columbia University Irving Medical Center and the Vagelos College of Physicians and Surgeons, New York, New York.
| | - N Jewel Samadder
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona
| | - Randall W Burt
- Department of Gastroenterology, University of Utah, Salt Lake City, Utah; Emeritus Professor of Medicine, University of Utah, Salt Lake City, Utah
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26
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Abstract
Purpose of review: Identification of Lynch syndrome is important from an individual patient and public health standpoint. As paradigms for Lynch syndrome diagnosis have shifted in recent years, this review will discuss rationale and limitations for current strategies as well as provide an overview of future directions in the field. Recent findings: In recent years, the use of clinical criteria and risk scores for identification of Lynch syndrome have been augmented by universal testing of all newly diagnosed colorectal cancers with molecular methods to screen for mismatch repair deficiency with high sensitivity and specificity. Studies of implementation and outcomes of universal testing in clinical practice have demonstrated significant heterogeneity that results in suboptimal uptake and contributes to disparities in diagnosis. Emerging technologies, such as next-generation sequencing, hold significant promise as a screening strategy for Lynch syndrome. Summary: Universal testing for Lynch syndrome is being performed with increasing frequency, although real-world outcomes have demonstrated room for improvement. Future directions in Lynch syndrome diagnosis will involve optimization of universal testing workflow and application of new genetics technologies.
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27
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Kim JY, Byeon JS. Genetic Counseling and Surveillance Focused on Lynch Syndrome. JOURNAL OF THE ANUS RECTUM AND COLON 2019; 3:60-68. [PMID: 31559369 PMCID: PMC6752118 DOI: 10.23922/jarc.2019-002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 02/08/2019] [Indexed: 12/20/2022]
Abstract
Lynch syndrome is a hereditary cancer syndrome caused by germline mutations in one of several DNA mismatch repair genes. Lynch syndrome leads to an increased lifetime risk of various cancers, particularly colorectal, and endometrial cancers. After identifying patients suspected of having Lynch syndrome by clinical criteria, computational prediction models, and/or universal tumor testing, genetic testing is performed to confirm the diagnosis. Before and after genetic testing, genetic counseling should be provided. Genetic counseling should involve a detailed personal and family history, information on the disorder and genetic tests, discussion of the management and surveillance of the disease, career plan, family plan, and psychosocial support. Surveillance of colorectal cancer and other malignancies is of paramount importance for properly managing Lynch syndrome. This review focuses on important considerations in genetic counseling and the latest insights into the surveillance of individuals and families with Lynch syndrome.
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Affiliation(s)
- Jin Yong Kim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jeong-Sik Byeon
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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28
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Gupta S, Provenzale D, Llor X, Halverson AL, Grady W, Chung DC, Haraldsdottir S, Markowitz AJ, Slavin Jr TP, Hampel H, Ness RM, Weiss JM, Ahnen DJ, Chen LM, Cooper G, Early DS, Giardiello FM, Hall MJ, Hamilton SR, Kanth P, Klapman JB, Lazenby AJ, Lynch PM, Mayer RJ, Mikkelson J, Peter S, Regenbogen SE, Dwyer MA, Ogba N. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 2.2019. J Natl Compr Canc Netw 2019; 17:1032-1041. [DOI: 10.6004/jnccn.2019.0044] [Citation(s) in RCA: 143] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Identifying individuals with hereditary syndromes allows for improved cancer surveillance, risk reduction, and optimized management. Establishing criteria for assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the assessment and management of patients with high-risk colorectal cancer syndromes. These NCCN Guidelines Insights focus on criteria for the evaluation of Lynch syndrome and considerations for use of multigene testing in the assessment of hereditary colorectal cancer syndromes.
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Affiliation(s)
| | | | | | - Amy L. Halverson
- 4Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | - William Grady
- 5Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | | | | | | | | | | | | | - Lee-may Chen
- 14UCSF Helen Diller Family Comprehensive Cancer Center
| | - Gregory Cooper
- 15Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Dayna S. Early
- 16Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
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29
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Tian W, Bi R, Ren Y, He H, Shi S, Shan B, Yang W, Wang Q, Wang H. Screening for hereditary cancers in patients with endometrial cancer reveals a high frequency of germline mutations in cancer predisposition genes. Int J Cancer 2019; 145:1290-1298. [PMID: 31054147 DOI: 10.1002/ijc.32389] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 04/24/2019] [Accepted: 04/26/2019] [Indexed: 12/20/2022]
Abstract
As inherited genetic alterations are important etiological factors causing endometrial cancer (EC), our study aimed to outline the ethnic-related prevalence and the associated clinical and biological characteristics of germline mutations in cancer predisposition genes in Chinese EC patients. One hundred ninety-eight Chinese EC patients were screened for germline mutations in a panel of cancer susceptibility genes using next-generation sequencing combined with multiplex ligation-dependent probe amplification. First, we found that among patients under 50 years of age, 26% (18/69) carried germline genetic mutations, all involving mismatch repair (MMR) genes except for one mutation affecting BRCA1. Second, when we focused on Lynch syndrome (LS) with additional selected patients, 45 were identified to carry pathogenic mutations in MMR genes, with a higher frequency found in MSH2 and MSH6. We found that age at onset, personal and familial history together with immunohistochemical assay results were the most useful criteria for the diagnosis of LS although limitations in routine practice and the sensitivity and specificity of each parameter should be taken into account. One pathogenic mutation in the PALB2 gene was detected in a patient with no breast cancer in her family. Interestingly, we identified a family carrying pathogenic variant in both PMS2 and BRCA1 genes with distinct clinical phenotypes. Multigene panel testing should be recommended to patients based on their clinical information and tumor phenotype. Our study also showed the genetic complexity in EC, which requires further investigations.
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Affiliation(s)
- Wenjuan Tian
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Rui Bi
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yulan Ren
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hongsheng He
- Shanghai Topgen Bio-Pharm Co, Ltd., Shanghai, China
| | - Shanfu Shi
- Shanghai Topgen Bio-Pharm Co, Ltd., Shanghai, China
| | - Boer Shan
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wentao Yang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Qing Wang
- Centre Léon Bérard, Plateforme de Génomique des Cancers, Département de la Recherche Translationnelle et d'Innovation, Lyon, France.,Laboratoire de la Génétique Constitutionnelle des Cancers Fréquents HCL-CLB, Lyon, France
| | - Huaying Wang
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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30
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Valle L, Vilar E, Tavtigian SV, Stoffel EM. Genetic predisposition to colorectal cancer: syndromes, genes, classification of genetic variants and implications for precision medicine. J Pathol 2019; 247:574-588. [PMID: 30584801 PMCID: PMC6747691 DOI: 10.1002/path.5229] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/21/2018] [Accepted: 12/23/2018] [Indexed: 12/15/2022]
Abstract
This article reviews genes and syndromes associated with predisposition to colorectal cancer (CRC), with an overview of gene variant classification. We include updates on the application of preventive and therapeutic measures, focusing on the use of non-steroidal anti-inflammatory drugs (NSAIDs) and immunotherapy. Germline pathogenic variants in genes conferring high or moderate risk to cancer are detected in 6-10% of all CRCs and 20% of those diagnosed before age 50. CRC syndromes can be subdivided into nonpolyposis and polyposis entities, the most common of which are Lynch syndrome and familial adenomatous polyposis, respectively. In addition to known and novel genes associated with highly penetrant CRC risk, identification of pathogenic germline variants in genes associated with moderate-penetrance cancer risk and/or hereditary cancer syndromes not traditionally linked to CRC may have an impact on genetic testing, counseling, and surveillance. The use of multigene panels in genetic testing has exposed challenges in the classification of variants of uncertain significance. We provide an overview of the main classification systems and strategies for improving these. Finally, we highlight approaches for integrating chemoprevention in the care of individuals with genetic predisposition to CRC and use of targeted agents and immunotherapy for treatment of mismatch repair-deficient and hypermutant tumors. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Laura Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Barcelona, Spain
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
| | - Eduardo Vilar
- Departments of Clinical Cancer Prevention, GI Medical Oncology and Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sean V. Tavtigian
- Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, United States
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Elena M. Stoffel
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
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31
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Yozu M, Kumarasinghe MP, Brown IS, Gill AJ, Rosty C. Australasian Gastrointestinal Pathology Society (AGPS) consensus guidelines for universal defective mismatch repair testing in colorectal carcinoma. Pathology 2019; 51:233-239. [DOI: 10.1016/j.pathol.2018.11.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 11/18/2018] [Accepted: 11/25/2018] [Indexed: 01/28/2023]
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32
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Cohen SA, Pritchard CC, Jarvik GP. Lynch Syndrome: From Screening to Diagnosis to Treatment in the Era of Modern Molecular Oncology. Annu Rev Genomics Hum Genet 2019; 20:293-307. [PMID: 30848956 DOI: 10.1146/annurev-genom-083118-015406] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline alterations in the mismatch repair genes and is the most common etiology of hereditary colorectal cancer. While Lynch syndrome was initially defined by the clinical Amsterdam criteria, these criteria lack the sensitivity needed for clinical utility. This review covers the evolution of screening for Lynch syndrome from the use of tumor microsatellite instability and/or somatic alterations in mismatch repair protein expression by immunohistochemistry to the newest methods using next-generation sequencing. Additionally, it discusses the clinical implications of the diagnosis of Lynch syndrome as it affects cancer therapeutics and the role of screening in noncolorectal Lynch-associated cancers. As molecular oncology continues to evolve, it is crucial to remain current on the increasing complexity of Lynch syndrome diagnostics and treatment options.
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Affiliation(s)
- Stacey A Cohen
- Division of Oncology, University of Washington, Seattle, Washington 98109, USA; .,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
| | - Colin C Pritchard
- Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA
| | - Gail P Jarvik
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.,Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA
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33
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Clarke EV, Muessig KR, Zepp J, Hunter JE, Syngal S, Acheson LS, Wiesner GL, Peterson SK, Bergen KM, Shuster E, Davis JV, Schneider JL, Kauffman TL, Gilmore MJ, Reiss JA, Rope AF, Cook JE, Goddard KAB. Implementation of a Systematic Tumor Screening Program for Lynch Syndrome in an Integrated Health Care Setting. Fam Cancer 2019; 18:317-325. [PMID: 30729418 DOI: 10.1007/s10689-019-00123-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
A subset of colorectal cancer (CRC) cases are attributable to Lynch syndrome (LS), a hereditary form of CRC. Effective evaluation for LS can be done on CRC tumors to guide diagnostic testing. Increased diagnosis of LS allows for surveillance and risk reduction, which can mitigate CRC-related burden and prevent cancer-related deaths. We evaluated participation in LS screening among newly diagnosed adult CRC patients. Some cases were referred for genetics evaluation prior to study recruitment (selective screening). Those not referred directly were randomized to the intervention or control (usual care) arms. Control cases were observed for one year, then given information about LS screening. Patients who declined participation were followed through the medical record. Of 601 cases of CRC, 194 (32%) enrolled in our study and were offered LS screening, 43 (7%) were followed as a control group, 148 (25%) declined participation and 216 (36%) were ineligible [63 (10%) of which received prior selective screening]. Six and nine cases of LS were identified through the intervention and selective screening groups, respectively. Overall, a higher proportion of PMS2 variants were identified in the intervention (3/6, 50%) versus selective screening groups (2/9, 22%) (not statistically significant). Eighty-eight percent and 23% of intervention and control patients, respectively, received LS screening. No control patients were found to have LS. Systems-based approaches are needed to ensure we fully identify LS cases. The proportion of LS cases from this program was 4% of newly diagnosed cases of CRC, similar to other programs.
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Affiliation(s)
- Elizabeth V Clarke
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97227, USA
| | - Kristin R Muessig
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97227, USA
| | - Jamilyn Zepp
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97227, USA
| | - Jessica E Hunter
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97227, USA
| | - Sapna Syngal
- Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Louise S Acheson
- Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Georgia L Wiesner
- Vanderbilt Hereditary Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Susan K Peterson
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kellene M Bergen
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97227, USA
| | - Elizabeth Shuster
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97227, USA
| | - James V Davis
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97227, USA
| | - Jennifer L Schneider
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97227, USA
| | - Tia L Kauffman
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97227, USA
| | - Marian J Gilmore
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97227, USA
| | - Jacob A Reiss
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97227, USA
| | - Alan F Rope
- Northwest Permanente, Kaiser Permanente Northwest, Portland, OR, USA
| | - Jennifer E Cook
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97227, USA
| | - Katrina A B Goddard
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97227, USA.
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Bucheit L, Johansen Taber K, Ready K. Validation of a digital identification tool for individuals at risk for hereditary cancer syndromes. Hered Cancer Clin Pract 2019; 17:2. [PMID: 30651894 PMCID: PMC6330430 DOI: 10.1186/s13053-018-0099-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 11/15/2018] [Indexed: 01/05/2023] Open
Abstract
Background The number of individuals meeting criteria for genetic counseling and testing for hereditary cancer syndromes (HCS) is far less than the number that actually receive it. To facilitate identification of patients at risk for HCS, Counsyl developed a digital identification tool (digital ID tool) to match personal and family cancer history to National Comprehensive Cancer Network (NCCN) BRCA-related Hereditary Breast and Ovarian Cancer (HBOC), Lynch syndrome, and polyposis testing criteria in one-to-one, automated fashion. The purpose of this study was to validate the ability of the digital ID tool to accurately identify histories that do and do not meet NCCN testing criteria. Methods Third-party recorded three-generation pedigrees were retrospectively reviewed by a certified genetic counselor (CGC) to determine if independent events included in pedigree histories met NCCN guidelines, and were then sorted into groups: high risk events (meets criteria) and low risk events (does not meet criteria). Events were entered into the digital ID tool to determine the extent of its concordance with events sorted by CGC review. Statistical tests of accuracy were calculated at a 95% confidence interval (CI). Results One hundred ninety-seven pedigrees were reviewed consecutively representing 765 independent events for analysis across groups. 382/382 (100%) high risk events identified by the digital ID tool and 381/383 (99.47%) low risk events identified by the digital ID tool were concordant with CGC sorting. The digital ID tool had a sensitivity of 100% (99.04–100% CI) and specificity of 99.48% (98.13–99.94% CI). The overall accuracy of the digital ID tool was estimated to be 99.74% (99.06–99.97% CI), reflecting the rate at which the digital ID tool reached the same conclusion as that of CGC review of pedigree events for the recommendation of genetic testing for individuals at risk for HCS. Conclusions The digital ID tool accurately matches NCCN criteria in one-to-one fashion to identify at-risk individuals for HCS and may be useful in clinical practice, specifically for BRCA-related HBOC and Lynch Syndrome. Electronic supplementary material The online version of this article (10.1186/s13053-018-0099-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Leslie Bucheit
- Counsyl, 180 Kimball Way, South San Francisco, CA 98040 USA
| | | | - Kaylene Ready
- Counsyl, 180 Kimball Way, South San Francisco, CA 98040 USA
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Pan JY, Haile RW, Templeton A, Macrae F, Qin F, Sundaram V, Ladabaum U. Worldwide Practice Patterns in Lynch Syndrome Diagnosis and Management, Based on Data From the International Mismatch Repair Consortium. Clin Gastroenterol Hepatol 2018; 16:1901-1910.e11. [PMID: 29702294 PMCID: PMC6440473 DOI: 10.1016/j.cgh.2018.04.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 03/22/2018] [Accepted: 04/08/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Families with a history of Lynch syndrome often do not adhere to guidelines for genetic testing and screening. We investigated practice patterns related to Lynch syndrome worldwide, to ascertain potential targets for research and public policy efforts. METHODS We collected data from the International Mismatch Repair Consortium (IMRC), which comprises major research and clinical groups engaged in the care of families with Lynch syndrome worldwide. IMRC institutions were invited to complete a questionnaire to characterize diagnoses of Lynch syndrome and management practice patterns. RESULTS Fifty-five providers, representing 63 of 128 member institutions (49%) in 21 countries, completed the questionnaire. For case finding, 55% of respondents reported participating in routine widespread population tumor testing among persons with newly diagnosed Lynch syndrome-associated cancers, whereas 27% reported relying on clinical criteria with selective tumor and/or germline analyses. Most respondents (64%) reported using multigene panels for germline analysis, and only 28% reported testing tumors for biallelic mutations for cases in which suspected pathogenic mutations were not confirmed by germline analysis. Respondents reported relying on passive dissemination of information to at-risk family members, and there was variation in follow through of genetic testing recommendations. Reported risk management practices varied-nearly all programs (98%) recommended colonoscopy every 1 to 2 years, but only 35% recommended chemoprevention with aspirin. CONCLUSIONS There is widespread heterogeneity in management practices for Lynch syndrome worldwide among IMRC member institutions. This may reflect the rapid pace of emerging technology, regional differences in resources, and the lack of definitive data for many clinical questions. Future efforts should focus on the large numbers of high-risk patients without access to state-of-the-art Lynch syndrome management.
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Affiliation(s)
- Jennifer Y Pan
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California; Division of Gastroenterology, Department of Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California.
| | - Robert W Haile
- Department of Medicine, Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Allyson Templeton
- International Mismatch Repair Consortium, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Finlay Macrae
- Department of Medicine, University of Melbourne, Melbourne, Australia; Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia
| | - FeiFei Qin
- Quantitative Sciences Unit, Stanford University School of Medicine, Palo Alto, California
| | - Vandana Sundaram
- Quantitative Sciences Unit, Stanford University School of Medicine, Palo Alto, California
| | - Uri Ladabaum
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California
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He Y, Tao X, Huang F, Jia N, Du Y, Yu J, Feng W. Clinicopathologic features of endometrial cancer in Chinese patients younger than 50 years with a family history of cancer. Medicine (Baltimore) 2018; 97:e12968. [PMID: 30412119 PMCID: PMC6221721 DOI: 10.1097/md.0000000000012968] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Genetic factors play an important role in shaping the biologic characteristics of malignant tumors, especially in young patients. We aimed to determine the clinicopathologic features of endometrial cancer (EC) in patients younger than 50 years with a family history of cancer.Overall, 229 patients with EC, including 40 with a positive family history of cancer (PFH) and 189 with a negative family history of cancer (NFH), were enrolled in this case-control study. The family history of cancer in a 2-generation pedigree was recorded for the PFH group. Clinicopathologic features such as menarche age, body mass index, personal cancer history, grade, and histologic type were compared between the 2 groups. Mismatch repair (MMR) proteins including MLH1, PMS2, MSH2, and MSH6 were assessed by immunohistochemistry (IHC) in surgical samples. Univariate (Pearson Chi-squared test, Fisher exact test, T test, Wilcoxon rank sum test, logistic regression) statistics and stepwise multivariate logistic regression were used to identify factors associated with PFH in the analysis.Among young patients with EC, the PFH group had younger age-of-onset age of endometrial cancer (≤40 years) (odds ratio [OR] = 2.21, 95% confidence interval [95% CI]: 1.01-4.82) than the NFH group. The proportion of overweight/obese patients was high in both the NFH (58.7%) and PFH (80%) groups. Colorectal, lung, endometrial, breast, and hepatocellular carcinoma accounted for 58.6% of all cancer types among 1st- and 2nd-degree relatives. Additionally, 19.2% of patients displayed deficiency in at least 1 MMR protein, with a significantly higher proportion of MMR protein deficiency in the PFH group than in the NFH group (adjusted OR = 4.81, 95% CI: 2.14-8.83).Clinicopathologic features differ for young patients with EC with and without a family history of cancer. Surveillance of age-of-onset and family history of endometrial cancer, reduction of barriers to healthy lifestyles, and development of risk-appropriate Lynch syndrome screening tools, such as IHC, are needed for these women in Shanghai and other developing cities in China.
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Affiliation(s)
- Yuan He
- School of Public Health, Fudan University
- Obstetrics and Gynecology Hospital of Fudan University
| | - Xiang Tao
- Obstetrics and Gynecology Hospital of Fudan University
| | - Feifei Huang
- Obstetrics and Gynecology Hospital of Fudan University
| | - Nan Jia
- Obstetrics and Gynecology Hospital of Fudan University
| | - Yan Du
- Obstetrics and Gynecology Hospital of Fudan University
| | - Jinming Yu
- School of Public Health, Fudan University
| | - Weiwei Feng
- Obstetrics and Gynecology Hospital of Fudan University
- Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Adar T, Rodgers LH, Shannon KM, Yoshida M, Ma T, Mattia A, Lauwers GY, Iafrate AJ, Hartford NM, Oliva E, Chung DC. Universal screening of both endometrial and colon cancers increases the detection of Lynch syndrome. Cancer 2018; 124:3145-3153. [PMID: 29750335 DOI: 10.1002/cncr.31534] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 03/31/2018] [Accepted: 04/10/2018] [Indexed: 01/04/2023]
Abstract
BACKGROUND Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC) and endometrial cancer (EC). Screening of all CRCs for LS is currently recommended, but screening of ECs is inconsistent. The objective of this study was to determine the added value of screening both CRC and EC tumors in the same population. METHODS A prospective, immunohistochemistry (IHC)-based screening program for all patients with newly diagnosed CRCs and ECs was initiated in 2011 and 2013, respectively, at 2 centers (primary and tertiary). Genetic testing was recommended for those who had tumors with absent mutS homolog 2 (MSH2), MSH6, or postmeiotoic segregation increased 2 (PMS2) expression and for those who had tumors with absent mutL homolog 1 (MLH1) expression and no v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation or MLH1 promoter methylation. Amsterdam II criteria, revised Bethesda criteria, and scores from prediction models for gene mutations (the PREMM1,2,6 and PREMM5 prediction models) were ascertained in patients with LS. RESULTS In total, 1290 patients with CRC and 484 with EC were screened for LS, and genetic testing was recommended for 137 patients (10.6%) and 32 patients (6.6%), respectively (P = .01). LS was identified in 16 patients (1.2%) with CRC and in 8 patients (1.7%) with EC. Among patients for whom genetic testing was recommended, the LS diagnosis rate was higher among those with EC (25.0% vs 11.7%, P = .052). The Amsterdam II criteria, revised Bethesda criteria, and both PREMM calculators would have missed 62.5%, 50.0%, and 12.5% of the identified patients with LS, respectively. CONCLUSIONS Expanding a universal screening program for LS to include patients who had EC identified 50% more patients with LS, and many of these patients would have been missed by risk assessment tools (including PREMM5 ). Universal screening programs for LS should include both CRC and EC. Cancer 2018. © 2018 American Cancer Society.
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Affiliation(s)
- Tomer Adar
- Gastroenterology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Linda H Rodgers
- Center for Cancer Risk Analysis, Cancer Center, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Kristen M Shannon
- Center for Cancer Risk Analysis, Cancer Center, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
| | - Makoto Yoshida
- Gastroenterology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Tianle Ma
- Gastroenterology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Anthony Mattia
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Department of Pathology, North Shore Medical Center, Danvers, Massachusetts
| | - Gregory Y Lauwers
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Anthony J Iafrate
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Nicole M Hartford
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Esther Oliva
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Daniel C Chung
- Gastroenterology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Center for Cancer Risk Analysis, Cancer Center, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
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Chan GHJ, Ong PY, Low JJH, Kong HL, Ow SGW, Tan DSP, Lim YW, Lim SE, Lee SC. Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers. Oncotarget 2018; 9:30649-30660. [PMID: 30093976 PMCID: PMC6078133 DOI: 10.18632/oncotarget.25769] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 06/23/2018] [Indexed: 01/01/2023] Open
Abstract
Background Developing multiple cancers is an indicator of underlying hereditary cancer predisposition, but there is a paucity of data regarding the clinical genetic testing outcomes of these patients. Methods We compared cancer index patients with ≥2 primary malignancies versus 1 primary cancer who underwent clinical evaluation and testing with multi-gene panels comprising up to 49 genes from 1998-2016. Results Among 1191 cancer index patients, 80.6%, 17.2%, and 2.2% respectively had 1, 2, and ≥3 primary malignancies. For patients with 2 primary cancers (n=205), the most common cancer pairs were bilateral breast (37.5%), breast-ovary (11.7%), endometrium-ovary (9.2%), colon-endometrium (3.9%) and colon-colon (3.4%). 42.3% patients underwent gene testing including 110/231 (47.6%) with multiple malignancies. Pathogenic variants were found more frequently in younger patients, in those with a family history of cancer related to the suspected syndrome, and a trend towards significance in those with multiple primary cancers (35.5% vs. 25.6%, p = 0.09). In patients with multiple cancers, pathogenic variants were most commonly identified in BRCA1 (38.5%), BRCA2 (17.9%), and the mismatch repair genes (20.5%), while 23.1% of pathogenic mutations were in other moderate- to high-penetrance cancer predisposition genes including APC, ATM, MUTYH, PALB2, RAD50 and TP53. Conclusion Patients with multiple cancers were more likely to carry pathogenic mutations than those with single cancer. About three-quarters of deleterious mutations in patients with multiple primary cancers were in BRCA1/2 and the mismatch repair genes, but multi-gene panel testing facilitated the detection of mutations in another 6 genes and is warranted in this high-risk population.
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Affiliation(s)
- Gloria H J Chan
- Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), Singapore
| | - Pei Yi Ong
- Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), Singapore
| | - Jeffrey J H Low
- Department of Obstetrics and Gynaecology, National University Hospital, Singapore
| | - Hwai Loong Kong
- Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), Singapore
| | - Samuel G W Ow
- Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), Singapore
| | - David S P Tan
- Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), Singapore.,Cancer Science Institute, Singapore
| | - Yi Wan Lim
- Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), Singapore
| | - Siew Eng Lim
- Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), Singapore
| | - Soo-Chin Lee
- Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), Singapore.,Cancer Science Institute, Singapore
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Stoffel EM. Updates on Translational Research on Prevention of Polyps and Colorectal Cancer. Clin Colon Rectal Surg 2018; 31:153-160. [PMID: 29720901 DOI: 10.1055/s-0037-1602235] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Morbidity and mortality from colorectal cancer (CRC) can be effectively reduced through early detection and prevention. To date, strategies for managing CRC risk have focused primarily on secondary prevention, through screening asymptomatic individuals for colorectal neoplasia. In the United States, implementation of screening among individuals age ≥50 has led to not only decreased CRC-related mortality but also reduced CRC incidence through colonoscopic removal of precancerous polyps. In contrast to screening's endpoint of early detection, the goal of primary prevention of CRC is to arrest and/or reverse colorectal carcinogenesis. Observational studies and randomized clinical trials continue to examine effects of specific pharmacologic agents (chemoprevention) and dietary interventions on development of advanced colorectal neoplasia. This review will present an overview of strategies for primary and secondary prevention of CRC, including endoscopic, pharmacologic, and dietary interventions.
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Affiliation(s)
- Elena M Stoffel
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
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Stoffel EM, Koeppe E, Everett J, Ulintz P, Kiel M, Osborne J, Williams L, Hanson K, Gruber SB, Rozek LS. Germline Genetic Features of Young Individuals With Colorectal Cancer. Gastroenterology 2018; 154:897-905.e1. [PMID: 29146522 PMCID: PMC5847426 DOI: 10.1053/j.gastro.2017.11.004] [Citation(s) in RCA: 224] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 10/31/2017] [Accepted: 11/03/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS The incidence of colorectal cancer (CRC) in individuals younger than 50 years is increasing. We sought to ascertain the proportion of young CRC cases associated with genetic predisposition. METHODS We performed a retrospective study of individuals diagnosed with CRC at an age younger than 50 years, evaluated by the clinical genetics service at a single tertiary care cancer center from 1998 through 2015. We collected data on patient histories, tumor phenotypes, and results of germline DNA sequencing. For subjects with uninformative clinical evaluations, germline DNA samples were (re)sequenced using a research-based next-generation sequencing multigene panel. The primary outcome was identification of a pathogenic germline mutation associated with cancer predisposition. RESULTS Of 430 young CRC cases, 111 (26%) had a first-degree relative with CRC. Forty-one of the subjects with CRC (10%) had tumors with histologic evidence for mismatch repair deficiency. Of 315 subjects who underwent clinical germline sequencing, 79 had mutations associated with a hereditary cancer syndrome and 21 had variants of uncertain significance. Fifty-six subjects had pathogenic variants associated with Lynch syndrome (25 with mutations in MSH2, 24 with mutations in MLH1, 5 with mutations in MSH6, and 2 with mutations in PMS2) and 10 subjects had pathogenic variants associated with familial adenomatous polyposis. Thirteen subjects had mutations in other cancer-associated genes (8 in MUTYH, 2 in SMAD4, 1 in BRCA1, 1 in TP53, and 1 in CHEK2), all identified through multigene panel tests. Among 117 patients with uninformative clinical evaluations, next-generation sequence analysis using a multigene panel detected actionable germline variants in 6 patients (5%). Only 43 of the 85 subjects with germline mutations associated with a hereditary cancer syndrome (51%) reported a CRC diagnosis in a first-degree relative. CONCLUSIONS Approximately 1 in 5 individuals diagnosed with CRC at age younger than 50 years carries a germline mutation associated with cancer; nearly half of these do not have clinical histories typically associated with the identified syndrome. Germline testing with multigene cancer panels should be considered for all young patients with CRC.
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Affiliation(s)
- Elena M. Stoffel
- Division of Gastroenterology, University of Michigan Health System Ann Arbor MI
| | - Erika Koeppe
- Division of Gastroenterology, University of Michigan Health System Ann Arbor MI
| | - Jessica Everett
- Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Health System Ann Arbor MI
| | - Peter Ulintz
- BRCF Bioinformatics Core, University of Michigan Medical School, Ann Arbor MI
| | | | - Jenae Osborne
- Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Health System Ann Arbor MI
| | | | - Kristen Hanson
- Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Health System Ann Arbor MI
| | - Stephen B. Gruber
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles CA
| | - Laura S. Rozek
- Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI
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Hunter JE, Arnold KA, Cook JE, Zepp J, Gilmore MJ, Rope AF, Davis JV, Bergen KM, Esterberg E, Muessig KR, Peterson SK, Syngal S, Acheson L, Wiesner G, Reiss J, Goddard KAB. Universal screening for Lynch syndrome among patients with colorectal cancer: patient perspectives on screening and sharing results with at-risk relatives. Fam Cancer 2018; 16:377-387. [PMID: 28176204 DOI: 10.1007/s10689-017-9972-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Universal screening for Lynch syndrome (LS) among all cases of colorectal cancer (CRC) could increase the diagnosis of LS and reduce morbidity and mortality of LS-associated cancers. Given universal screening includes all patients, irrespective of high risk factors such early age at onset or family history of CRC, it is important to understand perspectives of all patients and not just those at high risk. As part of a study to assess the feasibility and implementation of universal screening, 189 patients newly diagnosed with CRC were surveyed about their interest in screening for LS and communication of results with at-risk family members. Overall, participants responded positively regarding screening for LS, with most wanting to know their genetic risks in general (86%) and risk of hereditary CRC (93%). Prior to receiving screening results, most participants stated they intended to share their screening results with parents (89%), siblings (96%), and children (96%). Of the 28 participants who received a positive LS screening result, 26 (93%) reported sharing their result with at least one first-degree family member. Interest in screening for LS and communication of screening results with family members was not associated with high risk factors. This study indicates that patients are interested in being screened for LS and that sharing information on the risk of LS with at-risk family members is not a significant barrier. These findings provide novel insight into patient perspectives about screening for LS and can guide successful implementation of universal screening programs.
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Affiliation(s)
- Jessica Ezzell Hunter
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97229, USA.
| | - Kathleen A Arnold
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97229, USA
| | - Jennifer E Cook
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97229, USA
| | - Jamilyn Zepp
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97229, USA
| | - Marian J Gilmore
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97229, USA
| | - Alan F Rope
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97229, USA
| | - James V Davis
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97229, USA
| | - Kellene M Bergen
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97229, USA
| | - Elizabeth Esterberg
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97229, USA
| | - Kristin R Muessig
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97229, USA
| | - Susan K Peterson
- Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sapna Syngal
- Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Louise Acheson
- Departments of Family Medicine and Community Health, Reproductive Biology, and Oncology, Case Western Reserve University, Cleveland, OH, USA
| | - Georgia Wiesner
- Vanderbilt Hereditary Cancer Program, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA
| | - Jacob Reiss
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97229, USA
| | - Katrina A B Goddard
- Center for Health Research, Kaiser Permanente Northwest, 3800 N. Interstate Avenue, Portland, OR, 97229, USA
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Which Lynch syndrome screening programs could be implemented in the "real world"? A systematic review of economic evaluations. Genet Med 2018; 20:1131-1144. [PMID: 29300371 PMCID: PMC8660650 DOI: 10.1038/gim.2017.244] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 11/17/2017] [Indexed: 12/14/2022] Open
Abstract
Purpose Lynch syndrome (LS) screening can significantly reduce cancer morbidity and mortality in mutation carriers. Our aim was to identify cost-effective LS screening programs that can be implemented in the “real world.” Methods We performed a systematic review of full economic evaluations of genetic screening for LS in different target populations; health outcomes were estimated in life-years gained or quality-adjusted life-years. Results Overall, 20 studies were included in the systematic review. Based on the study populations, we identified six categories of LS screening program: colorectal cancer (CRC)–based, endometrial cancer–based, general population–based, LS family registry–based, cascade testing–based, and genetics clinic–based screening programs. We performed an in-depth analysis of CRC-based LS programs, classifying them into three additional subcategories: universal, age-targeted, and selective. In five studies, universal programs based on immunohistochemistry, either alone or in combination with the BRAF test, were cost-effective compared with no screening, while in two studies age-targeted programs with a cutoff of 70 years were cost-effective when compared with age-targeted programs with lower age thresholds. Conclusion Universal or <70 years–age-targeted CRC-based LS screening programs are cost-effective and should be implemented in the “real world.”
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Luba DG, DiSario JA, Rock C, Saraiya D, Moyes K, Brown K, Rushton K, Ogara MM, Raphael M, Zimmerman D, Garrido K, Silguero E, Nelson J, Yurgelun MB, Kastrinos F, Wenstrup RJ, Syngal S. Community Practice Implementation of a Self-administered Version of PREMM 1,2,6 to Assess Risk for Lynch Syndrome. Clin Gastroenterol Hepatol 2018; 16:49-58. [PMID: 28668538 PMCID: PMC5734958 DOI: 10.1016/j.cgh.2017.06.038] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 06/20/2017] [Accepted: 06/20/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Lynch syndrome is a genetic disorder that greatly increases risk for colorectal and other cancers, although it is underdiagnosed. Prediction of MLH1, MSH2, and MSH6 (PREMM1,2,6) is a web-based tool that analyzes individuals' personal/family histories of cancer to quantify their likelihood of carrying a germline mutation associated with Lynch syndrome. We investigated the feasibility of systematic risk assessment for Lynch syndrome in a community gastroenterology practice using a patient-completed version of PREMM1,2,6. METHODS PREMM1,2,6 was adapted into a computer tablet version designed for self-administration by patients. Individuals presenting to a community gastroenterology office and endoscopy facility in California completed the PREMM1,2,6 assessment before their visit (n = 3134). The total study duration (8 months) comprised a 2-month initiation period (May 1-June 30, 2013) and a 6-month study period (July 1-December 31, 2013). Genetic counseling and germline analysis for mutations in genes associated with Lynch syndrome (MLH1, MSH2, MSH6, PMS2, and EPCAM) were offered to individuals with PREMM1,2,6 scores of 5% or higher. Patients and providers completed surveys to evaluate the feasibility and satisfaction with the process. RESULTS Of the 3134 individuals assessed by PREMM1,2,6 during the 6-month study period, 177 individuals (5.6%) had scores of 5% or higher. Of these, 146 individuals underwent genetic testing, along with 28 additional participants recruited nonconsecutively during the initiation period. Mutations associated with Lynch syndrome were detected in 3 of the 146 individuals (2.1%) with PREMM1,2,6 scores of 5% or higher who underwent germline testing, and 3 of the 28 patients (10.7%) recruited during study initiation with PREMM1,2,6 scores of 5% or higher. Of the participants who underwent genetic analysis, 98.6% stated that they understood the information provided to them. All of the surveyed providers stated that they were satisfied with the incorporation of PREMM1,2,6 into their clinical practice, and that they would continue using it to assess risk for Lynch syndrome. CONCLUSIONS A patient self-administered version of the PREMM1,2,6 Lynch syndrome risk assessment model can be used systematically in community-based gastroenterology and endoscopy practices.
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Affiliation(s)
- Daniel G. Luba
- Monterey Bay GI Consultants Medical Group and Research Institute, Inc., Monterey, CA
| | - James A. DiSario
- Monterey Bay GI Consultants Medical Group and Research Institute, Inc., Monterey, CA
| | - Colleen Rock
- Myriad Genetic Laboratories, Inc., Salt Lake City, UT
| | - Devki Saraiya
- Myriad Genetic Laboratories, Inc., Salt Lake City, UT
| | - Kelsey Moyes
- Myriad Genetic Laboratories, Inc., Salt Lake City, UT
| | - Krystal Brown
- Myriad Genetic Laboratories, Inc., Salt Lake City, UT
| | | | - Maydeen M. Ogara
- Monterey Bay GI Consultants Medical Group and Research Institute, Inc., Monterey, CA
| | - Mona Raphael
- Monterey Bay GI Consultants Medical Group and Research Institute, Inc., Monterey, CA
| | - Dayna Zimmerman
- Monterey Bay GI Consultants Medical Group and Research Institute, Inc., Monterey, CA
| | - Kimmie Garrido
- Monterey Bay GI Consultants Medical Group and Research Institute, Inc., Monterey, CA
| | - Evelyn Silguero
- Monterey Bay GI Consultants Medical Group and Research Institute, Inc., Monterey, CA
| | | | | | | | | | - Sapna Syngal
- Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.
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45
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Byrne RM, Tsikitis VL. Colorectal polyposis and inherited colorectal cancer syndromes. Ann Gastroenterol 2017; 31:24-34. [PMID: 29333064 PMCID: PMC5759610 DOI: 10.20524/aog.2017.0218] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 10/30/2017] [Indexed: 12/30/2022] Open
Abstract
The majority of colorectal cancer (CRC) cases are sporadic, with hereditary factors contributing to approximately 35% of CRC cases. Less than 5% of CRC is associated with a known genetic syndrome. Although adenomatous polyposis syndromes, hamartomatous polyposis syndromes, and those previously classified as non-polyposis CRC syndromes are quite rare, it is important for clinicians to know the characteristics of each syndrome and to understand the differences in cancer risks between the different conditions. This information is very important when treatment and surveillance plans are formulated for each individual patient.
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Affiliation(s)
- Raphael M Byrne
- Department of Surgery, Division of GI and General Surgery, Oregon Health & Science University, Portland, OR, USA
| | - Vassiliki Liana Tsikitis
- Department of Surgery, Division of GI and General Surgery, Oregon Health & Science University, Portland, OR, USA
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46
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Steyerberg EW, Uno H, Ioannidis JPA, van Calster B. Poor performance of clinical prediction models: the harm of commonly applied methods. J Clin Epidemiol 2017; 98:133-143. [PMID: 29174118 DOI: 10.1016/j.jclinepi.2017.11.013] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 10/24/2017] [Accepted: 11/17/2017] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To evaluate limitations of common statistical modeling approaches in deriving clinical prediction models and explore alternative strategies. STUDY DESIGN AND SETTING A previously published model predicted the likelihood of having a mutation in germline DNA mismatch repair genes at the time of diagnosis of colorectal cancer. This model was based on a cohort where 38 mutations were found among 870 participants, with validation in an independent cohort with 35 mutations. The modeling strategy included stepwise selection of predictors from a pool of over 37 candidate predictors and dichotomization of continuous predictors. We simulated this strategy in small subsets of a large contemporary cohort (2,051 mutations among 19,866 participants) and made comparisons to other modeling approaches. All models were evaluated according to bias and discriminative ability (concordance index, c) in independent data. RESULTS We found over 50% bias for five of six originally selected predictors, unstable model specification, and poor performance at validation (median c = 0.74). A small validation sample hampered stable assessment of performance. Model prespecification based on external knowledge and using continuous predictors led to better performance (c = 0.836 and c = 0.852 with 38 and 2,051 events respectively). CONCLUSION Prediction models perform poorly if based on small numbers of events and developed with common but suboptimal statistical approaches. Alternative modeling strategies to best exploit available predictive information need wider implementation, with collaborative research to increase sample sizes.
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Affiliation(s)
- Ewout W Steyerberg
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands; Department of Public Health, Erasmus MC, Rotterdam, The Netherlands.
| | - Hajime Uno
- Division of Population Sciences, Dana-Farber Cancer Institute, 02215 MA, Boston, USA
| | - John P A Ioannidis
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA; Department of Statistics, Stanford University School of Humanities and Sciences, Stanford, CA, USA; Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, CA, USA
| | - Ben van Calster
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands; Department of Development and Regeneration, KU Leuven, Leuven, Belgium
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47
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Guivatchian T, Koeppe ES, Baker JR, Moisa C, Demerath M, Foor-Pessin C, Chey WD, Eswaran SL, Kolars JC, Menees SB, Rajala M, Rice MD, Rizk R, Rubenstein JH, Sharma P, Todisco A, Stoffel EM. Family history in colonoscopy patients: feasibility and performance of electronic and paper-based surveys for colorectal cancer risk assessment in the outpatient setting. Gastrointest Endosc 2017; 86:684-691. [PMID: 28174125 DOI: 10.1016/j.gie.2017.01.036] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 01/20/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Family history is crucial in stratifying patients' risk for colorectal cancer (CRC). Previous risk assessment tools developed for use in clinic or endoscopy settings have demonstrated suboptimal specificity for identifying patients with hereditary cancer syndromes. Our aim was to test the feasibility and performance of 2 family history surveys (paper and electronic) in individuals presenting for outpatient colonoscopy. METHODS Patients presenting for outpatient colonoscopy at a tertiary care center were asked to complete a 5-question paper risk assessment survey (short paper survey) either alone or in conjunction with a second, comprehensive electronic family risk assessment survey (comprehensive tablet survey). Each subject's survey results, along with the electronic medical record, were reviewed, and 10 high-risk criteria and PREMM1,2,6 model scores (a predictive model for carrying a Lynch syndrome-associated gene mutation) were used to identify patients warranting genetic evaluation for suspected hereditary cancer syndromes. RESULTS Six hundred patients completed the short paper survey (cohort 1), with an additional 100 patients completing both the short paper and comprehensive tablet survey (cohort 2). Using 10 high-risk criteria and/or a PREMM1,2,6 score ≥5%, we identified 10% and 9% of patients as high risk for CRC in cohorts 1 and 2, respectively. Of the 69 high-risk subjects, 23 (33%) underwent genetic evaluations and 7 (10%) carried germline mutations associated with cancer predisposition. Both patients and endoscopists reported the tools were user-friendly and helpful for CRC risk stratification. CONCLUSIONS Systematic assessment of family history in colonoscopy patients is feasible and can help endoscopists identify high-risk patients who would benefit from genetic evaluation.
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Affiliation(s)
- Tannaz Guivatchian
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, Michigan, USA
| | - Erika S Koeppe
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, Michigan, USA
| | - Jason R Baker
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, Michigan, USA
| | - Cristina Moisa
- Comprehensive Cancer Center, University of Michigan Hospital, Ann Arbor, Michigan, USA
| | - Matthew Demerath
- Comprehensive Cancer Center, University of Michigan Hospital, Ann Arbor, Michigan, USA
| | - Caitlin Foor-Pessin
- Division of Gastroenterology, Department of Internal Medicine, University of Rochester, Rochester, New York, USA
| | - William D Chey
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, Michigan, USA
| | - Shanti L Eswaran
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, Michigan, USA
| | - Joseph C Kolars
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, Michigan, USA
| | - Stacy B Menees
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, Michigan, USA
| | - Michael Rajala
- Division of Gastroenterology, Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Michael D Rice
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, Michigan, USA
| | - Rafat Rizk
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, Michigan, USA
| | - Joel H Rubenstein
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, Michigan, USA
| | - Pratima Sharma
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, Michigan, USA
| | - Andrea Todisco
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, Michigan, USA
| | - Elena M Stoffel
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, Michigan, USA
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48
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Cabreira V, Pinto C, Pinheiro M, Lopes P, Peixoto A, Santos C, Veiga I, Rocha P, Pinto P, Henrique R, Teixeira MR. Performance of Lynch syndrome predictive models in quantifying the likelihood of germline mutations in patients with abnormal MLH1 immunoexpression. Fam Cancer 2017; 16:73-81. [PMID: 27581132 DOI: 10.1007/s10689-016-9926-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Lynch syndrome (LS) accounts for up to 4 % of all colorectal cancers (CRC). Detection of a pathogenic germline mutation in one of the mismatch repair genes is the definitive criterion for LS diagnosis, but it is time-consuming and expensive. Immunohistochemistry is the most sensitive prescreening test and its predictive value is very high for loss of expression of MSH2, MSH6, and (isolated) PMS2, but not for MLH1. We evaluated if LS predictive models have a role to improve the molecular testing algorithm in this specific setting by studying 38 individuals referred for molecular testing and who were subsequently shown to have loss of MLH1 immunoexpression in their tumors. For each proband we calculated a risk score, which represents the probability that the patient with CRC carries a pathogenic MLH1 germline mutation, using the PREMM1,2,6 and MMRpro predictive models. Of the 38 individuals, 18.4 % had a pathogenic MLH1 germline mutation. MMRpro performed better for the purpose of this study, presenting a AUC of 0.83 (95 % CI 0.67-0.9; P < 0.001) compared with a AUC of 0.68 (95 % CI 0.51-0.82, P = 0.09) for PREMM1,2,6. Considering a threshold of 5 %, MMRpro would eliminate unnecessary germline mutation analysis in a significant proportion of cases while keeping very high sensitivity. We conclude that MMRpro is useful to correctly predict who should be screened for a germline MLH1 gene mutation and propose an algorithm to improve the cost-effectiveness of LS diagnosis.
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Affiliation(s)
- Verónica Cabreira
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
- Medical Faculty, University of Porto, Porto, Portugal
| | - Carla Pinto
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Manuela Pinheiro
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Paula Lopes
- Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Ana Peixoto
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Catarina Santos
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Isabel Veiga
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Patrícia Rocha
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Pedro Pinto
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Rui Henrique
- Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
- Institute of Biomedical Sciences, University of Porto, Porto, Portugal
| | - Manuel R Teixeira
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
- Institute of Biomedical Sciences, University of Porto, Porto, Portugal.
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Abstract
Lynch syndrome is the most common cause of inherited colorectal and endometrial cancers. Individuals with Lynch syndrome have a 10-80 % lifetime risk for colorectal cancer and a 15-60 % lifetime risk for endometrial cancer. Both cancers are preventable through chemoprevention, intensive cancer surveillance, and risk-reducing surgery options. Efforts to identify as many individuals with Lynch syndrome as possible will prevent cancers and save lives. This includes the traditional cancer genetic counseling model whereby individuals with and without cancer are evaluated for a possible Lynch syndrome diagnosis based on their personal and family history of colon polyps and cancers. It also includes universal tumor screening for Lynch syndrome whereby all individuals with colorectal or endometrial cancer are screened for tumor features of Lynch syndrome at the time of diagnosis. Those with tumors suspicious for Lynch syndrome are referred for cancer genetic counseling regardless of their family history of cancer. This two approaches must be maximized to attain high patient reach. Finally, and perhaps most importantly, cascade testing among the at-risk relatives of those diagnosed with Lynch syndrome is critically important to maximize the diagnosis of individuals with Lynch syndrome. In fact, the cost-effectiveness of universal tumor screening for Lynch syndrome relies entirely on counseling and testing as many at-risk individuals as possible since young unaffected individuals stand to benefit the most from an early diagnosis of Lynch syndrome. This approach must be optimized to achieve high family reach. It will take a concerted effort from patients, clinicians and public health officials to improve current approaches to the diagnosis of Lynch syndrome and the prevention and treatment of Lynch syndrome-associated cancer but these lessons can be applied to other conditions as the ultimate example of personalized medicine.
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Affiliation(s)
- Heather Hampel
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, 2001 Polaris Parkway, Columbus, OH, 43240, USA.
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50
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Fujiyoshi K, Yamaguchi T, Kakuta M, Takahashi A, Arai Y, Yamada M, Yamamoto G, Ohde S, Takao M, Horiguchi SI, Natsume S, Kazama S, Nishizawa Y, Nishimura Y, Akagi Y, Sakamoto H, Akagi K. Predictive model for high-frequency microsatellite instability in colorectal cancer patients over 50 years of age. Cancer Med 2017; 6:1255-1263. [PMID: 28544821 PMCID: PMC5463087 DOI: 10.1002/cam4.1088] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 04/02/2017] [Accepted: 04/09/2017] [Indexed: 12/19/2022] Open
Abstract
Microsatellite instability (MSI) is an important biomarker for screening for Lynch syndrome, and also of response to immune checkpoint inhibitors. The aim of this study is to create a predictive model to determine which elderly patients with colorectal cancer (CRC) should undergo MSI and/or immunohistochemistry testing on the basis of clinicopathological data. We analyzed a test cohort of CRC patients aged ≥50 years (n = 2219) by multivariate logistic regression analyses to identify predictors of high‐frequency MSI (MSI‐H). The created prediction model was validated in an external cohort (n = 992). The frequency of MSI‐H was 5.5% among CRC patients aged ≥ 50 years. The following five predictors of MSI‐H were identified in the test cohort: female (1 point), mucinous component (2 points), tumor size ≥ 60 mm (2 points), location in proximal colon (3 points), and BRAF mutation (6 points). The area under curve (AUC) in the receiver‐operating characteristic (ROC) analysis of this prediction model was 0.832 (95% confidence interval: 0.790–0.874). The sensitivity and specificity were 74.4% and 77.7%, respectively, for a cut‐off score of 4 points. The receiver‐operating characteristic curve of the validation cohort also showed an AUC of 0.856 (95% CI: 0.806–0.905). This prediction model is useful to select elderly CRC patients who should undergo MSI testing, and who may benefit from treatment with 5‐FU‐based adjuvant chemotherapy and cancer immunotherapy.
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Affiliation(s)
- Kenji Fujiyoshi
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan.,Department of Surgery, Kurume University, Fukuoka, Japan
| | - Tatsuro Yamaguchi
- Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.,Hereditary Tumor Research Project, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Miho Kakuta
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan
| | - Akemi Takahashi
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan
| | - Yoshiko Arai
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan
| | - Mina Yamada
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan
| | - Gou Yamamoto
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan
| | - Sachiko Ohde
- Center for Clinical Epidemiology, Graduate School of Public Health Planning Office, St. Luke's International University, OMURA Susumu & Mieko Memorial, St. Luke's Center for Clinical Academia, Tokyo, Japan
| | - Misato Takao
- Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.,Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Shin-Ichiro Horiguchi
- Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Soichiro Natsume
- Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - Shinsuke Kazama
- Division of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan
| | - Yusuke Nishizawa
- Division of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan
| | - Yoji Nishimura
- Division of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan
| | - Yoshito Akagi
- Department of Surgery, Kurume University, Fukuoka, Japan
| | - Hirohiko Sakamoto
- Division of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan
| | - Kiwamu Akagi
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan
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