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Balmaceda NB, Kim SS. Evolving Strategies in the Management of Microsatellite Instability-High/Mismatch Repair Deficient Esophagogastric Adenocarcinoma. Curr Oncol Rep 2025; 27:81-94. [PMID: 39832053 DOI: 10.1007/s11912-024-01624-4] [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] [Accepted: 11/18/2024] [Indexed: 01/22/2025]
Abstract
PURPOSE OF REVIEW This review addresses the current treatment paradigm and new advancements in the management of microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) esophagogastric cancer (EGC). RECENT FINDINGS While chemotherapy and surgery remain the cornerstone of EGC treatment, MSI-H/dMMR tumors harbor high tumor mutational burden and represent a subset of patients who benefit from immune checkpoint inhibitors (ICI). ICI has been incorporated in the front line setting with and without chemotherapy for advanced disease. Recently, ICI has been studied in the perioperative setting for resectable disease. Though perioperative ICI results in improved response rates, it is not yet clear whether this translates to a survival benefit. Despite high response rates with ICI in this patient population, many do not respond to therapy, representing a major challenge in treatment. Preclinical studies have highlighted potential mechanisms of resistance which will guide drug development and clinical trials.
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Affiliation(s)
- Nicole Baranda Balmaceda
- Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Sunnie S Kim
- Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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Pereira MA, Ramos MFKP, Cardili L, Dias AR, Alves VAF, de Mello ES, Ribeiro U. Prognostic significance of microsatellite instability in patients with resectable gastric cancer. J Gastrointest Surg 2024; 28:1687-1695. [PMID: 39147611 DOI: 10.1016/j.gassur.2024.07.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 07/03/2024] [Accepted: 07/26/2024] [Indexed: 08/17/2024]
Abstract
BACKGROUND Microsatellite instability (MSI) gastric cancer (GC) generally has a better prognosis than microsatellite-stable (MSS) GC and has been associated with nonsurvival benefit with the addition of chemotherapy (CMT) compared with surgery alone. However, patients with MSI have distinct clinicopathological characteristics. This study aimed to compare the survival outcomes between patients with MSI GC and those with MSS GC. In addition, this study analyzed the survival outcomes of patients with MSI GC who received CMT. METHODS This study reviewed all patients with GC who underwent curative gastrectomy. Patients were divided into MSI group and the MSS group. Propensity score matching (PSM) was used to match clinicopathological factors. RESULTS Among the 378 patients enrolled, 78 (20.6%) had MSI. Older age (P < .001), subtotal gastrectomy (P = .008), pN0 (P = .020), and earlier pTNM stage (P = .012) were associated with MSI GC. Survival analysis showed better disease-free survival (DFS) and overall survival (OS) of patients in the MSI group (P = .012 and P = .019, respectively). After PSM, 78 patients were matched to each group. All variables assigned to the scores were well matched, and both groups became equivalent. After the matching, the differences in DFS and OS according to MSI/MSS status were estimated to be larger than before (DFS: 63.3% vs 41.4%; P = .002; OS: 65.8% vs 42.5%; P = .002). Regarding patients referred for CMT, there was no difference in DFS and OS between patients with MSI GC who underwent CMT and those who underwent surgery alone (P = .255 and P = .178, respectively). CONCLUSION Even after controlling for clinicopathological characteristics, MSI was identified as a prognostic factor for patient survival. MSI GC showed no significant survival benefit with the addition of CMT.
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Affiliation(s)
- Marina Alessandra Pereira
- Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil.
| | - Marcus Fernando Kodama Pertille Ramos
- Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Leonardo Cardili
- Department of Pathology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - André Roncon Dias
- Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Venancio Avancini Ferreira Alves
- Department of Pathology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Evandro Sobroza de Mello
- Department of Pathology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Ulysses Ribeiro
- Department of Gastroenterology, Faculdade de Medicina, Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil
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Ooki A, Osumi H, Yoshino K, Yamaguchi K. Potent therapeutic strategy in gastric cancer with microsatellite instability-high and/or deficient mismatch repair. Gastric Cancer 2024; 27:907-931. [PMID: 38922524 PMCID: PMC11335850 DOI: 10.1007/s10120-024-01523-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 06/12/2024] [Indexed: 06/27/2024]
Abstract
Gastric cancer (GC) is a common malignancy that presents challenges in patient care worldwide. The mismatch repair (MMR) system is a highly conserved DNA repair mechanism that protects genome integrity during replication. Deficient MMR (dMMR) results in an increased accumulation of genetic errors in microsatellite sequences, leading to the development of a microsatellite instability-high (MSI-H) phenotype. Most MSI-H/dMMR GCs arise sporadically, mainly due to MutL homolog 1 (MLH1) epigenetic silencing. Unlike microsatellite-stable (MSS)/proficient MMR (pMMR) GCs, MSI-H/dMMR GCs are relatively rare and represent a distinct subtype with genomic instability, a high somatic mutational burden, favorable immunogenicity, different responses to treatment, and prognosis. dMMR/MSI-H status is a robust predictive biomarker for treatment with immune checkpoint inhibitors (ICIs) due to high neoantigen load, prominent tumor-infiltrating lymphocytes, and programmed cell death ligand 1 (PD-L1) overexpression. However, a subset of MSI-H/dMMR GC patients does not benefit from immunotherapy, highlighting the need for further research into predictive biomarkers and resistance mechanisms. This review provides a comprehensive overview of the clinical, molecular, immunogenic, and therapeutic aspects of MSI-H/dMMR GC, with a focus on the impact of ICIs in immunotherapy and their potential as neoadjuvant therapies. Understanding the complexity and diversity of the molecular and immunological profiles of MSI-H/dMMR GC will drive the development of more effective therapeutic strategies and molecular targets for future precision medicine.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan.
| | - Hiroki Osumi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Koichiro Yoshino
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
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Gao Y, Li H, Qiu L, Yuan H, Fan Q, Niu Z, Xing L, Li M, Yuan D. Efficacy and safety of anti-programmed death-1 antibody-based combination therapy in advanced or metastatic gastric or gastroesophageal junction cancer in Chinese patients: A real-world study. Sci Prog 2024; 107:368504241272703. [PMID: 39166262 PMCID: PMC11339938 DOI: 10.1177/00368504241272703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/22/2024]
Abstract
PURPOSE Programmed death-1 antibody plus chemotherapy has gained approval for the treatment for (human epidermal growth factor receptor 2 negative locally advanced or metastatic gastric or gastroesophageal junction cancer. This study aims to analyze the efficacy and safety of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis therapy in Chinese patients with advanced or metastatic gastric or gastroesophageal junction cancer in a real-world setting. METHODS In total, 122 patients treated with anti-programmed death-1 antibody-based combination therapy between April 2019 and December 2021 were encompassed. Clinical outcomes and safety profile were measured and analyzed. RESULTS In the whole cohort, median overall survival was 17.2 months, median progression-free survival was 10.9 months, and median duration of response was 9.4 months. Notably, in the first-line patients, the median overall survival was not reached, median progression-free survival was 14.8 months, objective response rate was 68.4%. In the second-line group, median overall survival, median progression-free survival, median duration of response, and objective response rate were 10.9 months, 5.9 months, 4.5 months, and 41.5%, respectively. Treatment-related adverse events of any grade were observed in 28.2% of the overall cohort, primarily affecting the hematological and liver function. Grade 3 or 4 adverse events were mainly characterized by increased levels of aspartate aminotransferase, alanine aminotransferase, along with decreased lymphocyte and white blood cells, as well as anemia. CONCLUSIONS Patients in our cohort experienced a clinical benefit from anti-programmed death-1 antibody-combined treatment in first-line treatment settings, with acceptable treatment-related adverse events. The benefit of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis treatment to the second-line patients should be further confirmed by large multi-center randomized, controlled clinical trials.
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Affiliation(s)
- Yifan Gao
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Oncology, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China
| | - Haoqian Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Lei Qiu
- Department of Gastroenterology Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Hongtu Yuan
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Qing Fan
- Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zuoxing Niu
- Department of Gastroenterology Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Ligang Xing
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
| | - Dandan Yuan
- Department of Gastroenterology Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
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Moreau M, Alouani E, Flecchia C, Falcoz A, Gallois C, Auclin E, André T, Cohen R, Hollebecque A, Turpin A, Pernot S, Masson T, Di Fiore F, Dutherge M, Mazard T, Hautefeuille V, Van Laethem JL, De la Fouchardière C, Perkins G, Ben-Abdelghani M, Sclafani F, Aparicio T, Kim S, Vernerey D, Taieb J, Guimbaud R, Tougeron D. A multicenter study evaluating efficacy of immune checkpoint inhibitors in advanced non-colorectal digestive cancers with microsatellite instability. Eur J Cancer 2024; 202:114033. [PMID: 38537314 DOI: 10.1016/j.ejca.2024.114033] [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: 11/18/2023] [Revised: 03/11/2024] [Accepted: 03/17/2024] [Indexed: 04/21/2024]
Abstract
BACKGROUND One randomized phase III trial comparing chemotherapy (CT) with immune checkpoint inhibitors (ICI) has demonstrated significant efficacy of ICI in deficient DNA mismatch repair system/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer. However, few studies have compared ICI with CT in other advanced dMMR/MSI-H digestive tumors. METHODS In this multicenter study, we included patients with advanced dMMR/MSI-H non-colorectal digestive tumors treated with chemotherapy and/or ICIs. Patients were divided retrospectively into two groups, a CT group and an immunotherapy (IO) group. The primary endpoint was progression-free survival (PFS). A propensity score approach using the inverse probability of treatment weighting (IPTW) method was applied to deal with potential differences between the two groups. RESULTS 133 patients (45.1/27.1/27.8% with gastric/small bowel/other carcinomas) were included. The majority of patients received ICI in 1st (29.1%) or 2nd line (44.4%). The 24-month PFS rates were 7.9% in the CT group and 71.2% in the IO group. Using the IPTW method, IO treatment was associated with better PFS (HR=0.227; 95% CI 0.147-0.351; p < 0.0001). The overall response rate was 26.3% in the CT group versus 60.7% in the IO group (p < 0.001) with prolonged duration of disease control in the IO group (p < 0.001). In multivariable analysis, predictive factors of PFS for patients treated with IO were good performance status, absence of liver metastasis and prior primary tumor resection, whereas no association was found for the site of the primary tumor. CONCLUSIONS In the absence of randomized trials, our study highlights the superior efficacy of ICI compared with standard-of-care therapy in patients with unresectable or metastatic dMMR/MSI-H non-colorectal digestive cancer, regardless of tumor type, with acceptable toxicity.
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Affiliation(s)
- Mathilde Moreau
- Hepato-Gastroenterology Department, Poitiers University Hospital, Poitiers 86000, France
| | - Emily Alouani
- Digestive Oncology Department, Toulouse University Hospital, IUCT Rangueil-Larrey, 31059 Toulouse, France
| | - Clémence Flecchia
- Department of Digestive Oncology, Georges-Pompidou European Hospital, Paris 75015, France
| | - Antoine Falcoz
- Methodological and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France; INSERM, Etablissement Français du Sang Bourgogne Franche-Comté, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
| | - Claire Gallois
- Department of Digestive Oncology, Georges-Pompidou European Hospital, Paris 75015, France
| | - Edouard Auclin
- Department of Digestive Oncology, Georges-Pompidou European Hospital, Paris 75015, France
| | - Thierry André
- Sorbonne University, Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC CURAMUS, Centre de Recherche Saint Antoine, Paris, France
| | - Romain Cohen
- Sorbonne University, Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC CURAMUS, Centre de Recherche Saint Antoine, Paris, France
| | - Antoine Hollebecque
- Department of Medical Oncology, Gustave Roussy Institute, Villejuif 94805, France
| | - Anthony Turpin
- Medical Oncology Department, CHU Lille, University of Lille, Lille, France
| | - Simon Pernot
- Medical Oncology Department, Bergonié Institute, Bordeaux 33076, France
| | - Thérèse Masson
- Medical Oncology Department, La Rochelle Hospital, La Rochelle 17019, France
| | - Frederic Di Fiore
- Department of Medical Oncology, Rouen University Hospital, Rouen 76000, France
| | - Marie Dutherge
- Department of Medical Oncology, Rouen University Hospital, Rouen 76000, France
| | - Thibault Mazard
- Department of Medical Oncology, IRCM, INSERM, University of Montpellier, ICM, Montpellier, France
| | - Vincent Hautefeuille
- Department of Hepato-Gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France
| | - Jean-Luc Van Laethem
- Digestive Oncology Department, Erasme Hospital, The Brussels University Hospital, Anderlecht 1070, Belgium
| | | | - Géraldine Perkins
- Department of Medical Oncology, Rennes University Hospital, Ponchaillou, Rennes 35000, France
| | - Meher Ben-Abdelghani
- Department of Medical Oncology, European Oncology Institute of Strasbourg, Strasbourg 67200, France
| | - Francesco Sclafani
- Digestive Oncology Department, Institut Jules Bordet, The Brussels University Hospital, Anderlecht 1070, Belgium
| | - Thomas Aparicio
- Gastroenterology Department, Saint-Louis Hospital, Paris 75010, France
| | - Stefano Kim
- Department of Medical Oncology, Besançon University Hospital, Besançon 25000, France
| | - Dewi Vernerey
- Methodological and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France; INSERM, Etablissement Français du Sang Bourgogne Franche-Comté, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
| | - Julien Taieb
- Department of Digestive Oncology, Georges-Pompidou European Hospital, Paris 75015, France
| | - Rosine Guimbaud
- Digestive Oncology Department, Toulouse University Hospital, IUCT Rangueil-Larrey, 31059 Toulouse, France
| | - David Tougeron
- Hepato-Gastroenterology Department, Poitiers University Hospital, Poitiers 86000, France.
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Urganci N, Kepil N, Ergun S, Bakkaloglu OK. The relationship between DNA mismatch repair gene and other prognostic parameters in pancreatic adenocarcinoma. J Surg Oncol 2024; 129:876-884. [PMID: 38173349 DOI: 10.1002/jso.27579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 12/20/2023] [Indexed: 01/05/2024]
Abstract
The aim of the study was to determine DNA mismatch repair (MMR) proteins by immunohistochemically using MLH1, MSH2, MSH6, and PMS2 antibodies in patients diagnosed as pancreatic ductal adenocarcinoma and to assess its relationship with histopathological and clinical prognostic parameters. Fifty cases with a diagnosis of pancreatic ductal adenocarcinoma who underwent surgical resection, were included in the study. Demographic and histopathological features of the patients were collected from the medical records. The relationships between microsatellite status and prognostic parameters were determined. The mean age of the patients was 66.5 ± 9.5 years (range: 47-87) and male/female ratio was 1.63 (31/19). No errors were detected in DNA MMR proteins in any of the cases, and were classified as microsatellite stable. The mean tumor diameter was 4.01 ± 1.77 cm and 74% of the tumors were localized in the pancreatic head. All of the cases had lymphatic invasion, whereas vascular invasion was detected in only 78% and perineural invasion in 98% of the patients. When the relationship between prognostic parameters and survival was evaluated, statistically significant correlation was observed in patient age and histopathological parameters such as tumor diameter, status of surgical margins, and vascular invasion (p < 0.05). Age, tumor size, presence of tumor at surgical margins, vascular invasion, and adjuvant treatment were correlated with survival. Although microsatellite instability was not detected in our cases, it is important to determine the microsatellite status by immunohistochemistry for predicting the chemotherapy response and determining the immunotherapy option in pancreatic adenocarcinomas.
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Affiliation(s)
- Nil Urganci
- Department of Pathology, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey
| | - Nuray Kepil
- Department of Pathology, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey
| | - Sefa Ergun
- Department of General Surgery, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey
| | - Oguz Kaan Bakkaloglu
- Department of Gastroenterology, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey
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Alotaibi F, Alshammari K, Alotaibi BA, Alsaab H. Destabilizing the genome as a therapeutic strategy to enhance response to immune checkpoint blockade: a systematic review of clinical trials evidence from solid and hematological tumors. Front Pharmacol 2024; 14:1280591. [PMID: 38264532 PMCID: PMC10803447 DOI: 10.3389/fphar.2023.1280591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 12/11/2023] [Indexed: 01/25/2024] Open
Abstract
Background: Genomic instability is increased alterations in the genome during cell division and is common among most cancer cells. Genome instability enhances the risk of initial carcinogenic transformation, generating new clones of tumor cells, and increases tumor heterogeneity. Although genome instability contributes to malignancy, it is also an "Achilles' heel" that constitutes a therapeutically-exploitable weakness-when sufficiently advanced, it can intrinsically reduce tumor cell survival by creating DNA damage and mutation events that overwhelm the capacity of cancer cells to repair those lesions. Furthermore, it can contribute to extrinsic survival-reducing events by generating mutations that encode new immunogenic antigens capable of being recognized by the immune system, particularly when anti-tumor immunity is boosted by immunotherapy drugs. Here, we describe how genome-destabilization can induce immune activation in cancer patients and systematically review the induction of genome instability exploited clinically, in combination with immune checkpoint blockade. Methods: We performed a systematic review of clinical trials that exploited the combination approach to successfully treat cancers patients. We systematically searched PubMed, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, and publication from the reference list of related articles. The most relevant inclusion criteria were peer-reviewed clinical trials published in English. Results: We identified 1,490 studies, among those 164 were clinical trials. A total of 37 clinical trials satisfied the inclusion criteria and were included in the study. The main outcome measurements were overall survival and progression-free survival. The majority of the clinical trials (30 out of 37) showed a significant improvement in patient outcome. Conclusion: The majority of the included clinical trials reported the efficacy of the concept of targeting DNA repair pathway, in combination with immune checkpoint inhibitors, to create a "ring of synergy" to treat cancer with rational combinations.
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Affiliation(s)
- Faizah Alotaibi
- College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, Alahsa, Saudi Arabia
- King Abdullah International Medical Research Center, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
| | - Kanaan Alshammari
- King Abdullah International Medical Research Center, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- Oncology Department, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Badi A. Alotaibi
- King Abdullah International Medical Research Center, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Hashem Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, Saudi Arabia
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8
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Wang Y, Wei X, Ke B, Liu J, Guo Y, Liu Y, Chen Y, Ding T, Wang Y, Meng B, Sun B, Zang F. Exploring the molecular characteristics of the malignant potential of gastric adenocarcinoma with enteroblastic differentiation. Histopathology 2023; 83:631-646. [PMID: 37356975 DOI: 10.1111/his.14998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 05/24/2023] [Accepted: 06/06/2023] [Indexed: 06/27/2023]
Abstract
AIMS Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare subset of alpha-fetoprotein (AFP)-producing carcinomas with poor prognosis. However, the molecular features associated with the malignant potential of GEAD remain partially elucidated. METHODS AND RESULTS In this study, the relationship between clinicopathological parameters and aggressive biological behaviour was analysed in 37 patients with GAED. The results showed that GAED tended to infiltrate the deep layer of the gastric wall and possessed more frequent vascular invasion than conventional gastric adenocarcinoma (CGA) (P < 0.001). All distant metastases were observed in the GAED group, not the CGA group (P < 0.001). High HER2 expression was found in nearly 24.32% of the informative cases, and none showed EBV-encoded RNA positivity or deficient mismatch repair. The most frequently mutated gene in GAED was p53. Programmed cell death-ligand 1 (PD-L1) immunostaining revealed 13 patients with a combined positive score (CPS) ≥ 5 (65%, 13 of 20). Thus, based on these molecular markers (immunostaining, in situ hybridisation and mutation analysis), GAED may be classified as a unique subgroup of the chromosomal instability subtype with HER2+ /EBV- /MSS/TP53+ /PD-L1+ . Next-generation sequencing analyses showed that mutations in the TOPI, ELOA and NOTCH3 genes were found only in GAED, and abnormally expressed genes in GAED were significantly enriched in hepatocellular carcinoma-, gland development-, and gastric cancer-related pathways. CONCLUSION The HER2+ /EBV- /MSS/TP53+ /PD-L1+ profile and hepatocellular carcinoma-related pathways may be significant in the malignant potential of GAED. In addition to anti-HER2 therapy, immune check-point inhibitors may be an effective treatment option for patients with GAED.
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Affiliation(s)
- Yong Wang
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Xiyin Wei
- Public Laboratory, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Bin Ke
- Department of Gastric Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Jia Liu
- Department of Colorectal Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yuhong Guo
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yanxue Liu
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yongzi Chen
- Department of Tumor Cell Biology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Tingting Ding
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yalei Wang
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Bin Meng
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Baocun Sun
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Fenglin Zang
- Department of Pathology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
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9
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Kavun A, Veselovsky E, Lebedeva A, Belova E, Kuznetsova O, Yakushina V, Grigoreva T, Mileyko V, Fedyanin M, Ivanov M. Microsatellite Instability: A Review of Molecular Epidemiology and Implications for Immune Checkpoint Inhibitor Therapy. Cancers (Basel) 2023; 15:cancers15082288. [PMID: 37190216 DOI: 10.3390/cancers15082288] [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: 03/01/2023] [Revised: 04/10/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
Microsatellite instability (MSI) is one of the most important molecular characteristics of a tumor, which occurs among various tumor types. In this review article, we examine the molecular characteristics of MSI tumors, both sporadic and Lynch-associated. We also overview the risks of developing hereditary forms of cancer and potential mechanisms of tumor development in patients with Lynch syndrome. Additionally, we summarize the results of major clinical studies on the efficacy of immune checkpoint inhibitors for MSI tumors and discuss the predictive role of MSI in the context of chemotherapy and checkpoint inhibitors. Finally, we briefly discuss some of the underlying mechanisms causing therapy resistance in patients treated with immune checkpoint inhibitors.
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Affiliation(s)
| | - Egor Veselovsky
- OncoAtlas LLC, 119049 Moscow, Russia
- Department of Evolutionary Genetics of Development, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, 119334 Moscow, Russia
| | | | - Ekaterina Belova
- OncoAtlas LLC, 119049 Moscow, Russia
- Faculty of Physics, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Olesya Kuznetsova
- OncoAtlas LLC, 119049 Moscow, Russia
- N.N. Blokhin Russian Cancer Research Center, 115478 Moscow, Russia
| | - Valentina Yakushina
- OncoAtlas LLC, 119049 Moscow, Russia
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia
| | - Tatiana Grigoreva
- OncoAtlas LLC, 119049 Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia
| | | | - Mikhail Fedyanin
- N.N. Blokhin Russian Cancer Research Center, 115478 Moscow, Russia
- State Budgetary Institution of Health Care of the City of Moscow "Moscow Multidisciplinary Clinical Center" "Kommunarka" of the Department of Health of the City of Moscow, 142770 Moscow, Russia
- Federal State Budgetary Institution "National Medical and Surgical Center named after N.I. Pirogov" of the Ministry of Health of the Russian Federation, 105203 Moscow, Russia
| | - Maxim Ivanov
- OncoAtlas LLC, 119049 Moscow, Russia
- Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
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10
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Danishevich AM, Pospehova NI, Stroganova AM, Golovina DA, Nikulin MP, Kalinin AE, Nikolaev SE, Stilidi IS, Lyubchenko LN. Landscape of KRAS, BRAF, and PIK3CA Mutations and Clinical Features of EBV-Associated and Microsatellite Unstable Gastric Cancer. Mol Biol 2023. [DOI: 10.1134/s0026893323010041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
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11
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Boutin M, Gill S. Controversies and management of deficient mismatch repair gastrointestinal cancers in the neoadjuvant setting. Ther Adv Med Oncol 2023; 15:17588359231162577. [PMID: 37007634 PMCID: PMC10064478 DOI: 10.1177/17588359231162577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 02/17/2023] [Indexed: 03/31/2023] Open
Abstract
High microsatellite instability (MSI-H)/deficient mismatch repair (dMMR) phenotype is a distinct molecular signature across gastrointestinal cancers characterized by high tumor mutational burden and high neoantigen load. Tumors harboring dMMR are highly immunogenic and heavily infiltrated by immune cells; consequently, they are uniquely vulnerable to therapeutic strategies enhancing immune antitumor response such as checkpoint inhibitors. The MSI-H/dMMR phenotype arose as a powerful predictor of response to immune checkpoint inhibitors with evidence supporting significantly improved outcomes in the metastatic setting. On the other hand, the genomic instability characteristic of MSI-H/dMMR tumors appears to be associated with decreased sensitivity to chemotherapy, and the benefits of standard adjuvant or neoadjuvant chemotherapy approaches in this subtype are being increasingly questioned. Here, we review the prognostic and predictive impact of MMR status in localized gastric and colorectal cancers, and highlight the emerging clinical data incorporating checkpoint inhibitors in the neoadjuvant setting.
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Affiliation(s)
- Mélina Boutin
- BC Cancer, University of British Columbia, Vancouver, BC, Canada
- Centre Intégré de Cancérologie de la Montérégie-Centre, Université de Sherbrooke, Greenfield Park, QC, Canada
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12
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Boyer C, Sefrioui D, Cohen R, Chautard R, Perrier M, Lebrun H, Goujon G, Hautefeuille V, Dior M, Walter T, Mary F, Manfredi S, Caroli-Bosc FX, Cervantes B, Coriat R, Deluche E, Zaanan A, Olivier R, Bouché O, Piessen G, Lecomte T, Louvet C, Michel P, Aparicio T, André T, Taieb J, Randrian V, Tougeron D. Prognosis and chemosensitivity of non-colorectal alimentary tract cancers with microsatellite instability. Dig Liver Dis 2023; 55:123-130. [PMID: 35397988 DOI: 10.1016/j.dld.2022.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 03/12/2022] [Accepted: 03/18/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND Data on outcomes of microsatellite instable and/or mismatch repair deficient (dMMR/MSI) digestive non-colorectal tumors are limited. AIMS To evaluate overall survival (OS) of patients with dMMR/MSI digestive non-colorectal tumor. METHODS All consecutive patients with a dMMR/MSI digestive non-colorectal tumor were included in this French retrospective multicenter study. RESULTS One hundred and sixteen patients were included with a mean age of 63.6 years and 32.6% with a Lynch syndrome. Most tumors were oesophago-gastric (54.3%) or small bowel (32.8%) adenocarcinomas and at a localized stage at diagnosis (86.7%). In patients with localized tumors and R0 resection, median OS was 134.0 ± 64.2 months. Median disease-free survival (DFS) was 100.3 ± 65.7 months. Considering oesophago-gastric tumors, median DFS was improved when chemotherapy was added to surgery (not reached versus 22.8 ± 10.0 months, p = 0.03). In patients with advanced tumors treated by chemotherapy, median OS was 14.2 ± 1.9 months and median progression-free survival was 7.4 ± 1.6 months. CONCLUSION dMMR/MSI digestive non-colorectal tumors are mostly diagnosed at a non-metastatic stage with a good prognosis. Advanced dMMR/MSI digestive non-colorectal tumors have a poor prognosis with standard chemotherapy.
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Affiliation(s)
- Claire Boyer
- Hepato-Gastroenterology Department, Poitiers University Hospital, University of Poitiers, 2 rue de la Milétrie, Poitiers 86000, France
| | - David Sefrioui
- Department of Hepatogastroenterology, Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Rouen 76000, France
| | - Romain Cohen
- Medical Oncology Department, Assistance Publique-Hôpitaux de Pari, Saint Antoine Hospital, Sorbonne University, Paris 75012, France
| | - Romain Chautard
- Department of Hepato-Gastroenterology and Digestive Oncology, Tours University hospital, Tours 37000, France
| | - Marine Perrier
- Department of Hepato-Gastroenterology and Digestive Oncology, Robert-Debré University Hospital, Reims 51000, France
| | - Hugo Lebrun
- Department of Digestive and Oncological Surgery, Claude Huriez University Hospital, Lille University, Lille 59000, France
| | - Gael Goujon
- Gastroenterology Department, Bichat Hospital, Paris 75018, France
| | - Vincent Hautefeuille
- Department of Hepato-Gastroenterology and Digestive Oncology, Hôpital Sud, Amiens 80000, France
| | - Marie Dior
- Department of Hepato-Gastroenterology and Digestive Oncology, Louis Mourier Hospital, Colombes 92700, France
| | - Thomas Walter
- Department of Digestive Oncology, Edouard Herriot Hospital, Lyon 69000, France
| | - Florence Mary
- Gastroenterology Department, Avicenne Hospital, Bobigny 93000, France
| | - Silvain Manfredi
- Department of Hepato-Gastroenterology and Digestive Oncology, Dijon University hospital, Dijon 21000, France
| | - Francois-Xavier Caroli-Bosc
- Department of Hepato-Gastroenterology and Digestive Oncology, Angers University hospital, Angers 49000, France
| | - Baptiste Cervantes
- Department of Medical Oncology, Institut Mutualiste Montsouris, Paris 75014, France
| | - Romain Coriat
- Department of Hepato-Gastroenterology and Digestive Oncology, Cochin Hospital, Paris 75014, France
| | - Elise Deluche
- Department of Medical Oncology, Limoges University Hospital, Limoges 87000, France
| | - Aziz Zaanan
- Department of Gastroenterology and Digestive Oncology, Assistance Publique-Hôpitaux de Paris, European Georges Pompidou Hospital, Paris, 75015, France
| | - Raphael Olivier
- Hepato-Gastroenterology Department, Poitiers University Hospital, University of Poitiers, 2 rue de la Milétrie, Poitiers 86000, France
| | - Olivier Bouché
- Department of Hepato-Gastroenterology and Digestive Oncology, Robert-Debré University Hospital, Reims 51000, France
| | - Guillaume Piessen
- Department of Digestive and Oncological Surgery, Claude Huriez University Hospital, Lille University, Lille 59000, France
| | - Thierry Lecomte
- Department of Hepato-Gastroenterology and Digestive Oncology, Tours University hospital, Tours 37000, France
| | - Christophe Louvet
- Department of Medical Oncology, Institut Mutualiste Montsouris, Paris 75014, France
| | - Pierre Michel
- Department of Hepatogastroenterology, Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Rouen 76000, France
| | - Thomas Aparicio
- Gastroenterology and Digestive Oncology Department, Assistance Publique-Hôpitaux de Paris, Saint Louis Hospital, Paris University, Paris 75010, France
| | - Thierry André
- Medical Oncology Department, Assistance Publique-Hôpitaux de Pari, Saint Antoine Hospital, Sorbonne University, Paris 75012, France
| | - Julien Taieb
- Department of Gastroenterology and Digestive Oncology, Assistance Publique-Hôpitaux de Paris, European Georges Pompidou Hospital, Paris, 75015, France
| | - Violaine Randrian
- Hepato-Gastroenterology Department, Poitiers University Hospital, University of Poitiers, 2 rue de la Milétrie, Poitiers 86000, France
| | - David Tougeron
- Hepato-Gastroenterology Department, Poitiers University Hospital, University of Poitiers, 2 rue de la Milétrie, Poitiers 86000, France.
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13
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Agnarelli A, Vella V, Samuels M, Papanastasopoulos P, Giamas G. Incorporating Immunotherapy in the Management of Gastric Cancer: Molecular and Clinical Implications. Cancers (Basel) 2022; 14:cancers14184378. [PMID: 36139540 PMCID: PMC9496849 DOI: 10.3390/cancers14184378] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/30/2022] [Accepted: 09/05/2022] [Indexed: 01/30/2023] Open
Abstract
Simple Summary Gastric cancer is one of the most common malignant tumours worldwide, with the fifth and third highest morbidity and mortality, respectively, of all cancers. Survival is limited, as most of the patients are diagnosed at an advanced stage, and are not suitable for surgery with a curative intent. Chemotherapy has only modestly improved patients’ outcomes and is mainly given with a palliative intent. Immunotherapy has improved overall survival of patients with gastric cancer, and has thus become a new standard of care in clinic. In this review we discuss the strong molecular rationale for the administration of immunotherapy in this disease and analyse the clinical data supporting its use. Abstract Gastric cancer has a median survival of 11 months, and this poor prognosis has not improved over the last 30 years. Recent pre-clinical data suggest that there is high tumour-related neoantigen expression in gastric cancer cells, suggesting that a clinical strategy that enhances the host’s immune system against cancer cells may be a successful approach to improve clinical outcomes. Additionally, there has been an increasing amount of translational evidence highlighting the relevance of PD-L1 expression in gastric cancer cells, indicating that PD-1/PD-L1 inhibitors may be useful. Several molecular subgroups of gastric cancer have been identified to respond with excellent outcomes to immunotherapy, including microsatellite instable tumours, tumours bearing a high tumour mutational burden, and tumours related to a chronic EBV infection. In gastric cancer, immunotherapy has produced durable responses in chemo-refractory patients; however, most recently there has been a lot of enthusiasm as several large-scale clinical trials highlight the improved survival noted from the incorporation of immunotherapy in the first line setting for advanced gastric cancer. Our review aims to discuss current pre-clinical and clinical data supporting the innovative role of immunotherapy in gastric cancer.
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14
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Corso G. Microsatellite instability in gastrointestinal cancers. Eur J Hum Genet 2022; 30:996-997. [PMID: 35726018 PMCID: PMC9437054 DOI: 10.1038/s41431-022-01134-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 05/18/2022] [Accepted: 06/09/2022] [Indexed: 11/08/2022] Open
Affiliation(s)
- Giovanni Corso
- Division of Breast Surgery, European Institute of Oncology (IEO), IRCCS, Milan, 20141, Italy.
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, 20122, Italy.
- European Cancer Prevention Organization (ECP), Milan, 20141, Italy.
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15
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Cherri S, Oneda E, Noventa S, Melocchi L, Zaniboni A. Microsatellite instability and chemosensitivity in solid tumours. Ther Adv Med Oncol 2022; 14:17588359221099347. [PMID: 35620236 PMCID: PMC9127927 DOI: 10.1177/17588359221099347] [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: 02/13/2022] [Accepted: 04/21/2022] [Indexed: 01/01/2023] Open
Abstract
The use of biomarkers that influence a targeted choice in cancer treatments is the future of medical oncology. Within this scenario, in recent years, an important role has been played by knowledge of microsatellite instability (MSI), a molecular fingerprint that identifies defects in the mismatch repair system. This knowledge has changed clinical practice in the adjuvant setting of colon cancer, and its role in the neoadjuvant setting in gastric tumours is becoming increasingly interesting, as well as in endometrial cancers in both early and advanced diseases. Furthermore, it has undoubtedly conditioned the first lines of treatment in the metastatic setting in different types of cancers. The incidence of MSI is different in different cancer types, as well as in early cancers versus metastatic disease. Knowing the incidence of MSI in the various histologies can provide insight into the potential use of this biomarker considering its prognostic value, especially in the early stages, and its predictive role with respect to treatment response. In particular, MSI can guide the choice of chemotherapy treatments in the adjuvant setting of colon and perioperative setting in gastric tumours, which could lead to immunotherapy treatments in these patients in both the early stages of the disease and the metastatic setting where the response to immunotherapy drugs in diseases with MSI is now well established. In this review, we focus on colon, gastric and endometrial cancers, and we briefly discuss other cancer types where MSI could have a potential role in oncological treatment decisions.
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Affiliation(s)
- Sara Cherri
- Department of Clinical Oncology, Fondazione Poliambulanza, Via bissolati 57, 25124, Brescia, Italy
| | - Ester Oneda
- Department of Clinical Oncology, Fondazione Poliambulanza, Brescia, Italy
| | - Silvia Noventa
- Department of Clinical Oncology, Fondazione Poliambulanza, Brescia, Italy
| | - Laura Melocchi
- Department of Anatomical Pathology, Fondazione Poliambulanza, Brescia, Italy
| | - Alberto Zaniboni
- Department of Clinical Oncology, Fondazione Poliambulanza, Brescia, Italy
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16
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Recent insights into the use of immune checkpoint inhibitors in gastric cancer. Porto Biomed J 2022; 7:e162. [PMID: 35146175 PMCID: PMC8824404 DOI: 10.1097/j.pbj.0000000000000162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 11/26/2022] Open
Abstract
Gastric cancer (GC) is the fifth most incident and the fourth deadliest cancer worldwide. GC is a heterogeneous disease from the histological and molecular standpoints. This malignancy is mostly diagnosed at advanced stages of the disease, where the available therapeutic interventions are not effective. The emergence of immunotherapy has transformed the landscape of cancer treatment, including GC, and currently immune checkpoint inhibitors have been approved for the treatment of patients with recurrent/metastatic GC. This review summarizes the main clinical trials evaluating the use of immune checkpoint inhibitors in GC. It also highlights the potential of biomarkers for patient selection for GC immune checkpoint inhibition therapy, including programmed cell death ligand 1 expression and tumor mutational burden, and characteristics of the GC molecular classification, such as microsatellite instability status and Epstein-Barr virus infection, as predictors of response to blockade of the programmed cell death 1/programmed cell death ligand 1 axis.
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17
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Quaas A, Rehkaemper J, Rueschoff J, Pamuk A, Zander T, Hillmer A, Siemanowski J, Wittig J, Buettner R, Plum P, Popp F, Gebauer F, Bruns CJ, Loeser H, Alakus H, Schoemig-Markiefka B. Occurrence of High Microsatellite-Instability/Mismatch Repair Deficiency in Nearly 2,000 Human Adenocarcinomas of the Gastrointestinal Tract, Pancreas, and Bile Ducts: A Study From a Large German Comprehensive Cancer Center. Front Oncol 2021; 11:569475. [PMID: 34367937 PMCID: PMC8343401 DOI: 10.3389/fonc.2021.569475] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 07/02/2021] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Knowledge of the high microsatellite-instability (MSI-H)/mismatch repair deficiency (MMRd) status is of increasing interest for personalized neoadjuvant or adjuvant therapy planning. Only a few studies are available on MSI-H distribution in the Northern European Caucasian patient population. In this study, we focused on a large cohort of tumors of the upper gastrointestinal tract. MATERIALS AND METHODS Surgical material from a total of 1,965 patients was analyzed for MSI-H/MMRd status (including 1,267 carcinomas of the esophagus or stomach). All tumors were analyzed with an internationally recommended immunohistochemical panel consisting of four antibodies (MLH1, MSH2, PMS2, and MSH6). The results were molecularly objectified. RESULTS Adenocarcinomas with MSI-H/MMRd were detected with the following distribution: esophagus (1.4%), stomach (8.3%), small intestine (18.2%), large intestine (8.5%), intrahepatic bile ducts (1.9%), and pancreas (0%). In case of gastric tumors with MSI-H/MMRd, neoadjuvant therapy did not influence the prognosis of patients (p = 0.94). Within all tumor entities with MSI-H/MMRd, patients with a UICC stage 4 were also represented. In this advanced stage, 11.7% of patients with MSS tumors were diagnosed compared to 0.5% of patients with MSI-H tumors relative to the entire tumor collective. DISCUSSION In this study, the proportion of MSI-H/MMRd tumors in the stomach is smaller than would have been expected in knowledge of the data published by TCGA or AGRC. Negative prognostic effects regarding MSI-H status and neoadjuvant therapy as described by the MAGIC study group were not seen in our cohort. The extent to which the MSI-H/MMRd status should be known for neoadjuvant therapy planning must be clarified in prospective studies in the future. At present, there is no convincing data to dispense the neoadjuvant therapy for gastric carcinoma. Due to the very convincing, positive data regarding the response rates of MSI-H tumors to treatment with PD1/PD-L1 inhibitors, every metastatic carcinoma of the gastrointestinal tract should be tested for its MSI-H status.
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Affiliation(s)
- Alexander Quaas
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Jan Rehkaemper
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Josef Rueschoff
- Institute of Pathology, Nordhessen and Targos Molecular Pathology GmbH, Kassel, Germany
| | - Aylin Pamuk
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany
| | - Thomas Zander
- Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany
| | - Axel Hillmer
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Janna Siemanowski
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Jana Wittig
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Reinhard Buettner
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Patrick Plum
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany
| | - Felix Popp
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany
| | - Florian Gebauer
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany
| | | | - Heike Loeser
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Hakan Alakus
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Cologne, Germany
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Li F, Li J, Yu J, Pan T, Yu B, Sang Q, Dai W, Hou J, Yan C, Zang M, Zhu Z, Su L, Li YY, Liu B. Identification of ARGLU1 as a potential therapeutic target for gastric cancer based on genome-wide functional screening data. EBioMedicine 2021; 69:103436. [PMID: 34157484 PMCID: PMC8220577 DOI: 10.1016/j.ebiom.2021.103436] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/21/2021] [Accepted: 05/27/2021] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Due to the molecular mechanism complexity and heterogeneity of gastric cancer (GC), mechanistically interpretable biomarkers were required for predicting prognosis and discovering therapeutic targets for GC patients. METHODS Based on a total of 824 GC-specific fitness genes from the Project Score database, LASSOCox regression was performed in TCGA-STAD cohort to construct a GC Prognostic (GCP) model which was then evaluated on 7 independent GC datasets. Targets prioritization was performed in GC organoids. ARGLU1 was selected to further explore the biological function and molecular mechanism. We evaluated the potential of ARGLU1 serving as a promising therapeutic target for GC using patients derived xenograft (PDX) model. FINDINGS The 9-gene GCP model showed a statistically significant prognostic performance for GC patients in 7 validation cohorts. Perturbation of SSX4, DDX24, ARGLU1 and TTF2 inhibited GC organoids tumor growth. The results of tissue microarray indicated lower expression of ARGLU1 was correlated with advanced TNM stage and worse overall survival. Over-expression ARGLU1 significantly inhibited GC cells viability in vitro and in vivo. ARGLU1 could enhance the transcriptional level of mismatch repair genes including MLH3, MSH2, MSH3 and MSH6 by potentiating the recruitment of SP1 and YY1 on their promoters. Moreover, inducing ARGLU1 by LNP-formulated saRNA significantly inhibited tumor growth in PDX model. INTERPRETATION Based on genome-wide functional screening data, we constructed a 9-gene GCP model with satisfactory predictive accuracy and mechanistic interpretability. Out of nine prognostic genes, ARGLU1 was verified to be a potential therapeutic target for GC. FUNDING National Natural Science Foundation of China.
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Affiliation(s)
- Fangyuan Li
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Jianfang Li
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Junxian Yu
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Tao Pan
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Beiqin Yu
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Qingqing Sang
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Wentao Dai
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China; Shanghai Center for Bioinformation Technology, Shanghai Engineering Research Center of Pharmaceutical Translation, Shanghai 201203, PR China
| | - Junyi Hou
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Chao Yan
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Mingde Zang
- Department of Gastric Cancer Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, 200032 Shanghai, PR China
| | - Zhenggang Zhu
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Liping Su
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
| | - Yuan-Yuan Li
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China; Shanghai Center for Bioinformation Technology, Shanghai Engineering Research Center of Pharmaceutical Translation, Shanghai 201203, PR China.
| | - Bingya Liu
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
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19
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Huo X, Xiao X, Zhang S, Du X, Li C, Bai Z, Chen Z. Characterization and clinical evaluation of microsatellite instability and loss of heterozygosity in tumor-related genes in gastric cancer. Oncol Lett 2021; 21:430. [PMID: 33868468 PMCID: PMC8045158 DOI: 10.3892/ol.2021.12691] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 02/10/2021] [Indexed: 12/24/2022] Open
Abstract
Microsatellite instability (MSI) detection is widely used in the diagnosis and prognosis evaluation of colorectal cancer. However, for gastric cancer (GC), there is no standard panel of microsatellites (MSs) used in clinical guidance. The present study aimed to identify useful predictors of the clinical features and for the prognosis of GC, based on an investigation of MSI and loss of heterozygosity (LOH) in tumor-related genes. First, from 20 tumor-related genes which were proven to be important to the development of GC, 91 MSs were identified, and PCR amplification, short tandem repeat scanning analysis and TA clone sequencing were used to analyze MSI and LOH in the first set of 90 GC samples. Subsequently, the same method was used to detect the MSI/LOH of the optimized loci in the second set of 136 GC samples. MSI/LOH in the mismatch repair genes was highly consistent with that in oncogenes and tumor suppressor genes, respectively. The length of the core sequence was a main factor for the MSI/LOH rate. The MSI of 12 single loci was significantly associated with lymph node metastasis. The MSI in TP53-1 and the LOH in MGMT-10 were significantly associated with early stages of tumor infiltration depth. The LOH in MGMT-10, PTN-2 and MCC-17 was significantly associated with TNM stage. The LOH in TP53-1 and ERBB2-12 was associated with adenocarcinoma. The MSI/LOH in 6 single loci of 5 tumor-related genes was associated with poor prognosis of GC. The present study demonstrated that the MSI/LOH of loci in tumor-associated genes was associated with 4 clinicopathological characteristics and outcomes of GC. These results may provide potential specific biomarkers for the clinical prediction and treatment of GC.
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Affiliation(s)
- Xueyun Huo
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China.,Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Xiaoqin Xiao
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China.,Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Shuangyue Zhang
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China.,Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Xiaoyan Du
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China.,Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Changlong Li
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China.,Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Zhigang Bai
- Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China.,Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China.,Department of General Surgery, National Clinical Research Center for Digestive Diseases, Beijing 100050, P.R. China
| | - Zhenwen Chen
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China.,Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
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20
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Puliga E, Corso S, Pietrantonio F, Giordano S. Microsatellite instability in Gastric Cancer: Between lights and shadows. Cancer Treat Rev 2021; 95:102175. [PMID: 33721595 DOI: 10.1016/j.ctrv.2021.102175] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 12/11/2022]
Abstract
Gastric cancer (GC) represents an important contributor to the global burden of cancer, being one of the most common and deadly malignancies worldwide. According to TCGA and ACRG classifications, the microsatellite instable (MSI) group represents a significant subset of GCs and is currently in the limelight of many researches due to its favorable survival outcome in resectable stages compared to microsatellite stable tumors. MSI GCs hypermutated phenotype triggers immunosurveillance, making this molecular subgroup a promising candidate for immune checkpoint inhibitors treatment. Conversely, conflicting outcomes have been reported in chemotherapy settings. Due to the clinical relevance of these observations, in this review we report and discuss the molecular, pathological, prognostic, and predictive features of MSI gastric tumors.
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Affiliation(s)
- Elisabetta Puliga
- Department of Oncology, University of Torino, Candiolo, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
| | - Simona Corso
- Department of Oncology, University of Torino, Candiolo, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Silvia Giordano
- Department of Oncology, University of Torino, Candiolo, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
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21
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Negrete-Tobar G, González-Motta A, Messa-Botero OA, Galvis JC, Garciandía Rozo I, Álvarez Martínez JS, Pineda Ortega J, Londoño de Vivero N, Bruges Maya R. Inestabilidad microsatelital y cáncer gástrico. REVISTA COLOMBIANA DE CIRUGÍA 2021. [DOI: 10.30944/20117582.658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
La inestabilidad microsatelital es causada por una alteración de los sistemas de reparación de apareamientoincorrecto, que puede afectar los microsatélites dentro de todo el genoma humano, produciendo errores en su replicación. Los estudios publicados, principalmente en la literatura inglesa, han encontrado que algunos tumores, como los gástricos, pueden expresar inestabilidad microsatelital. En la siguiente revisión de tema, se presenta una descripción de los sistemas de reparación de apareamientos incorrectos y su relación con la presencia de inestabilidad microsatelital en los tumores gástricos, así como su posible utilidad clínica, como factor asociado en la respuesta al tratamiento con inmunoterapia en los pacientes con dicha patología.
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22
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Mismatch Repair System Genomic Scars in Gastroesophageal Cancers: Biology and Clinical Testing. GASTROINTESTINAL DISORDERS 2020. [DOI: 10.3390/gidisord2040031] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Alterations in the mismatch repair (MMR) system result in genomic instability, neoantigen production, and immune response in cancer. There is evidence that gastroesophageal tumors with MMR deficiency may be susceptible to immune-checkpoint inhibitors treatment, especially in those presenting at advanced-stage disease. Although a number of biomarkers have been developed in histology-agnostic settings to assess MMR status, there is evidence that a tumor-specific testing approach would improve the selection of patients for immunotherapy. However, no testing methods have been developed specifically for gastroesophageal cancers so far. Here, we discuss the state of the art, current advances, and future perspectives of MMR-related biomarkers’ biologic and clinical role in gastroesophageal cancers.
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23
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Liu Q, Zhu X, Lindström M, Shi Y, Zheng J, Hao X, Gustafsson CM, Liu B. Yeast mismatch repair components are required for stable inheritance of gene silencing. PLoS Genet 2020; 16:e1008798. [PMID: 32469861 PMCID: PMC7286534 DOI: 10.1371/journal.pgen.1008798] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 06/10/2020] [Accepted: 04/26/2020] [Indexed: 11/19/2022] Open
Abstract
Alterations in epigenetic silencing have been associated with ageing and tumour formation. Although substantial efforts have been made towards understanding the mechanisms of gene silencing, novel regulators in this process remain to be identified. To systematically search for components governing epigenetic silencing, we developed a genome-wide silencing screen for yeast (Saccharomyces cerevisiae) silent mating type locus HMR. Unexpectedly, the screen identified the mismatch repair (MMR) components Pms1, Mlh1, and Msh2 as being required for silencing at this locus. We further found that the identified genes were also required for proper silencing in telomeres. More intriguingly, the MMR mutants caused a redistribution of Sir2 deacetylase, from silent mating type loci and telomeres to rDNA regions. As a consequence, acetylation levels at histone positions H3K14, H3K56, and H4K16 were increased at silent mating type loci and telomeres but were decreased in rDNA regions. Moreover, knockdown of MMR components in human HEK293T cells increased subtelomeric DUX4 gene expression. Our work reveals that MMR components are required for stable inheritance of gene silencing patterns and establishes a link between the MMR machinery and the control of epigenetic silencing.
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Affiliation(s)
- Qian Liu
- Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan, Goteborg, Sweden
| | - Xuefeng Zhu
- Institute of Biomedicine, University of Gothenburg, Goteborg, Sweden
- * E-mail: (XZ); (BL)
| | - Michelle Lindström
- Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan, Goteborg, Sweden
| | - Yonghong Shi
- Institute of Biomedicine, University of Gothenburg, Goteborg, Sweden
| | - Ju Zheng
- Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan, Goteborg, Sweden
- Department of Biology, Functional Biology, KU Leuven, Heverlee, Belgium
| | - Xinxin Hao
- Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan, Goteborg, Sweden
| | | | - Beidong Liu
- Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan, Goteborg, Sweden
- Center for Large-scale cell-based screening, Faculty of Science, University of Gothenburg, Medicinaregatan, Goteborg, Sweden
- * E-mail: (XZ); (BL)
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24
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Prinz C, Weber D. MicroRNA (miR) dysregulation during Helicobacter pylori-induced gastric inflammation and cancer development: critical importance of miR-155. Oncotarget 2020; 11:894-904. [PMID: 32206186 PMCID: PMC7075464 DOI: 10.18632/oncotarget.27520] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 02/06/2020] [Indexed: 02/03/2023] Open
Abstract
Dysregulation of noncoding microRNA molecules has been associated with immune cell activation in the context of Helicobacter pylori induced gastric inflammation as well as carcinogenesis, but also with downregulation of mismatch repair genes, and may interfere with immune checkpoint proteins that lead to the overexpression of antigens on gastric tumor cells. Numerous miR-molecules have been described as important tools and markers in gastric inflammation and cancer development -including miR-21, miR-143, miR-145, miR-201, and miR-335- all of which are downregulated in gastric tumors, and involved in cell cycle growth or tumor invasion. Among the many microRNAs involved in gastric inflammation, adenocarcinoma development and immune checkpoint regulation, miR-155 is notable in that its upregulation is considered a key marker of chronic gastric inflammation that predisposes a patient to gastric carcinogenesis. Among various other miRs, miR-155 is highly expressed in activated B and T cells and in monocytes/macrophages present in chronic gastric inflammation. Notably, miR-155 was shown to downregulate the expression of certain MMR genes, such as MLH1, MSH2, and MSH6. In tumor-infiltrating miR-155-deficient CD8+ T cells, antibodies against immune checkpoint proteins restored the expression of several derepressed miR-155 targets, suggesting that miR-155 may regulate overlapping pathways to promote antitumor immunity. It may thus be of high clinical impact that gastric pathologies mediated by miR-155 result from its overexpression. This suggests that it may be possible to therapeutically attenuate miR-155 levels for gastric cancer treatment and/or to prevent the progression of chronic gastric inflammation into cancer.
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Affiliation(s)
- Christian Prinz
- Lehrstuhl für Innere Medizin1, University of Witten gGmbH, Helios Universitätsklinikum, D-42283 Wuppertal, Germany
| | - David Weber
- Lehrstuhl für Innere Medizin1, University of Witten gGmbH, Helios Universitätsklinikum, D-42283 Wuppertal, Germany
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25
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Renaud F, Svrcek M. [Hereditary gastric cancer: Challenges for the pathologist in 2020]. Ann Pathol 2020; 40:95-104. [PMID: 32147190 DOI: 10.1016/j.annpat.2020.02.007] [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: 01/04/2020] [Revised: 01/26/2020] [Accepted: 02/05/2020] [Indexed: 12/24/2022]
Abstract
Gastric cancer is the third most common cancer worldwide. The majority of gastric cancers are sporadic but familial clustering is seen in more than 10% of cases. This manuscript is divided into two parts. The first part is dedicated to the non-syndromic hereditary gastric cancer, particularly the hereditary diffuse gastric cancer (HDGC) and other gastric polyposes including the recently described GAPPS (Gastric adenocarcinoma and proximal polyposis of the stomach). The second part concerns the syndromic gastric cancer, namely the HNPCC syndrome (Hereditary Non Polyposis Colorectal Cancer) occurring as part of a genetic predisposition syndrome to cancer. Recent advances in oncogenetics and next generation sequencing technology have enabled the identification of new entities. This enhancement in knowledge regarding inherited syndromes predisposing to gastric cancer has consequently improved the management of patients and their families. In this context, pathologists play a major role in identifying particular morphologic entities prompting genetic investigation. The aim of this manuscript is to provide an update on the current knowledge about hereditary gastric cancer.
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Affiliation(s)
- Florence Renaud
- Sorbonne université, Inserm, unité Mixte de Recherche Scientifique 938, SIRIC CURAMUS, centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, 75012 Paris, France; Service d'anatomie et cytologie pathologiques, hôpital Saint-Antoine, AP-HP, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France.
| | - Magali Svrcek
- Sorbonne université, Inserm, unité Mixte de Recherche Scientifique 938, SIRIC CURAMUS, centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, 75012 Paris, France; Service d'anatomie et cytologie pathologiques, hôpital Saint-Antoine, AP-HP, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France
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26
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Di Bartolomeo M, Morano F, Raimondi A, Miceli R, Corallo S, Tamborini E, Perrone F, Antista M, Niger M, Pellegrinelli A, Randon G, Pagani F, Martinetti A, Fucà G, Pietrantonio F. Prognostic and Predictive Value of Microsatellite Instability, Inflammatory Reaction and PD-L1 in Gastric Cancer Patients Treated with Either Adjuvant 5-FU/LV or Sequential FOLFIRI Followed by Cisplatin and Docetaxel: A Translational Analysis from the ITACA-S Trial. Oncologist 2020; 25:e460-e468. [PMID: 32162808 PMCID: PMC7066701 DOI: 10.1634/theoncologist.2019-0471] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 10/16/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Patients with high microsatellite instability (MSI) gastric cancer (GC) show improved survival and no benefit or harm from adjuvant and/or perioperative chemotherapy. The role of immune microenvironment in GC is largely unknown. MATERIALS AND METHODS In the present study, 256 tumor tissue blocks were centrally collected from patients enrolled in ITACA-S, a randomized adjuvant trial of 5-FU/LV versus sequential FOLFIRI and cisplatin-docetaxel. MSI status was assessed by multiplex PCR, inflammatory reaction by H&E morphological assessment, and programmed death-ligand 1 (PD-L1) expression by immunohistochemistry. RESULTS Overall, 9% patients had MSI-high tumors, 23% had high inflammatory reaction, 11% had tumor PD-L1 ≥ 1%, and 11% had stromal PD-L1 ≥ 1%. A significant association with disease-free survival (DFS) and overall survival (OS) was found for MSI-high (hazard ratio [HR], 0.43; p = .02; HR, 0.40; p = .02) and high inflammatory reaction (HR, 0.55; p = .010; HR, 0.53; p = .008) but not for PD-L1. At multivariable analysis, only MSI showed an independent association with both DFS (p = .02) and OS (p = .01), whereas inflammatory reaction showed an independent association only with OS (p = .04). Patients with tumor PD-L1 ≥ 1% had a significantly longer DFS in sequential chemotherapy than in than 5-FU/LV arm (interaction p = .04) and a trend for OS (interaction p = .12). CONCLUSION Our data suggest that MSI status could be a useful prognostic biomarker in patients with radically resected stage II-III GC and should be used as stratification factor in future trials. Tumor PD-L1 ≥ 1% should be further investigated as a potential predictor of benefit from intensive chemotherapy. IMPLICATIONS FOR PRACTICE In this post hoc analysis of patients with radically resected gastric cancer randomized to an intensive sequential chemotherapy regimen versus 5-FU/LV monotherapy as adjuvant treatment in the ITACA-S trial, MSI-high status was independently associated with better disease-free survival and overall survival (OS) and inflammatory reaction was independently associated with better OS. Moreover, tumor PD-L1 expression ≥1% was associated with greater benefit from intensive sequential chemotherapy compared with 5-fluorouracil plus leucovorin (5-FU/LV), whereas PD-L1 expression <1% was not, conditioning a statistically significant interaction between such biomarker and treatment arms. The meta-analysis of individual patients' data from available studies could yield data on the role of MSI status that could inform clinical decisions.
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Affiliation(s)
- Maria Di Bartolomeo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Federica Morano
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Alessandra Raimondi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Rosalba Miceli
- Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Salvatore Corallo
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Elena Tamborini
- Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Federica Perrone
- Pathology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Maria Antista
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Monica Niger
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | | | - Giovanni Randon
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Filippo Pagani
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Antonia Martinetti
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Giovanni Fucà
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoMilanItaly
- Department of Oncology and Hemato‐oncology, University of MilanMilanItaly
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27
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Ratti M, Lampis A, Hahne JC, Passalacqua R, Valeri N. Microsatellite instability in gastric cancer: molecular bases, clinical perspectives, and new treatment approaches. Cell Mol Life Sci 2018; 75:4151-4162. [PMID: 30173350 PMCID: PMC6182336 DOI: 10.1007/s00018-018-2906-9] [Citation(s) in RCA: 157] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 08/13/2018] [Accepted: 08/14/2018] [Indexed: 12/15/2022]
Abstract
Gastric cancer is one of the most aggressive malignancies, with limited treatment options in both locally advanced and metastatic setting, resulting in poor prognosis. Based on genomic characterization, stomach tumour has recently been described as a heterogeneous disease composed by different subtypes, each of them with peculiar molecular aspects and specific clinical behaviour. With an incidence of 22% among all western gastric tumour cases, stomach cancer with microsatellite instability was identified as one of these subgroups. Retrospective studies and limited prospective trials reported differences between gastric cancers with microsatellite stability and those with instability, mainly concerning clinical and pathological features, but also in regard to immunological microenvironment, correlation with prognostic value, and responses to treatment. In particular, gastric cancer with microsatellite instability constitutes a small but relevant subgroup associated with older age, female sex, distal stomach location, and lower number of lymph-node metastases. Emerging data attribute to microsatellite instability status a favourable prognostic meaning, whereas the poor outcomes reported after perioperative chemotherapy administration suggest a detrimental role of cytotoxic drugs in this gastric cancer subgroup. The strong immunogenicity and the widespread expression of immune-checkpoint ligands make microsatellite instability subtype more vulnerable to immunotherapeutic approach, e.g., with anti-PD-L1 and anti-CTLA4 antibodies. Since gastric cancer with microsatellite instability shows specific features and clinical behaviour not overlapping with microsatellite stable disease, microsatellite instability test might be suitable for inclusion in a diagnostic setting for all tumour stages to guarantee the most targeted and effective treatment to every patient.
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Affiliation(s)
- Margherita Ratti
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Division of Oncology, Medical Department, ASST di Cremona, Ospedale di Cremona, Cremona, Italy
| | - Andrea Lampis
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Jens C Hahne
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
| | - Rodolfo Passalacqua
- Division of Oncology, Medical Department, ASST di Cremona, Ospedale di Cremona, Cremona, Italy
| | - Nicola Valeri
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Department of Medicine, The Royal Marsden NHS Foundation Trust, London, UK
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28
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Polom K, Marrelli D, Voglino C, Roviello G, De Franco L, Vindigni C, Generali D, Roviello F. Familial aggregation of gastric cancer with microsatellite instability. Acta Chir Belg 2018; 118:287-293. [PMID: 30071769 DOI: 10.1080/00015458.2017.1379789] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
BACKGROUND Microsatellite instability (MSI) is currently a new molecular subtype of gastric cancer (GC). About 90% of GC cases appear sporadically. MSI seems to be responsible for both sporadic and familial GC. The aim of this study was to analyze the frequency of MSI in GC with familial history of GC. METHODS The MSI analysis was conducted using five quasi-monomorphic mononucleotide repeats: BAT-26, BAT-25, NR-24, NR-21 and NR-27. From our database, we analyzed 457 patients in terms of cancer history across family members, particularly focusing on GC. RESULTS MSI status in patients without familial history of GC was present in 22.1% of the cases, whereas in the patients with familial history of GC it was present in 28% of the cases (p = 0.220). For 1st or 2nd degree family members with GC, MSI was observed in 27.6% and in 30.8%, respectively (p = 0.812). MSI was observed in hereditary gastric cancer (HGC) in 33.3% and in familial gastric cancer (FGC) in 30%. No difference in survival rates was observed between the analyzed groups. CONCLUSIONS In our publication, we could not find any link between familial background and the MSI status in GC patients. More detailed molecular and genetic analysis of subgroups of these patients is required.
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Affiliation(s)
- Karol Polom
- Department of Medicine, Surgery and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, Siena, Italy
- Department of Surgical Oncology, Medical University of Gdansk, Gdansk, Poland
| | - Daniele Marrelli
- Department of Medicine, Surgery and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, Siena, Italy
| | - Costantino Voglino
- Department of Medicine, Surgery and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, Siena, Italy
| | - Giandomenico Roviello
- Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
- Department of Oncology, Medical Oncology Unit, San Donato Hospital, Arezzo, Italy
| | - Lorenzo De Franco
- Department of Medicine, Surgery and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, Siena, Italy
| | - Carla Vindigni
- Department of Pathology, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Daniele Generali
- Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Franco Roviello
- Department of Medicine, Surgery and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, Siena, Italy
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29
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Giampieri R, Del Prete M, Cantini L, Baleani MG, Bittoni A, Maccaroni E, Berardi R. Optimal management of resected gastric cancer. Cancer Manag Res 2018; 10:1605-1618. [PMID: 29950898 PMCID: PMC6016582 DOI: 10.2147/cmar.s151552] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Although advances in medical treatment for gastric cancer (GC) have been made, surgery remains the mainstay of cure for patients with localized disease. Improvement in surgical modalities leads to increased chance of cure for resected patients, but a non-negligible number of patients eventually relapse. On this basis, it has been hypothesized that the addition of complementary systemic or local treatments (such as chemotherapy and radiotherapy) could help in improving patients' survival by reducing the risk of recurrence. Several studies have tried to identify the best approach in localized GC: some of them have assessed the role of perioperative chemotherapy [CT] with different drug combinations, while others have focused on the benefit obtained by addition of radiotherapy, whose role is still under investigation. In particular, the role of chemoradiotherapy, both in adjuvant and neoadjuvant settings, is still uncertain. In the last few years, several clinicopathological and molecular factors have been investigated and identified as potential prognostic markers in GC. Many of these factors could have influenced the outcome of patients receiving combined treatments in the abovementioned studies. Patients have not been generally distinguished by the site of disease (esophageal, gastric and junctional cancers) and surgical approach, making data difficult to be interpreted. The purpose of this review was to shed light on these highly controversial topics.
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Affiliation(s)
- Riccardo Giampieri
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Michela Del Prete
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Luca Cantini
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Maria Giuditta Baleani
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Alessandro Bittoni
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Elena Maccaroni
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
| | - Rossana Berardi
- Oncology Clinic, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy
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Polom K, Marrelli D, D'Ignazio A, Roviello F. Hereditary diffuse gastric cancer: how to look for and how to manage it. Updates Surg 2018; 70:161-166. [PMID: 29869323 DOI: 10.1007/s13304-018-0545-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 05/13/2018] [Indexed: 02/07/2023]
Abstract
With a current molecular revolution, hereditary gastric cancer represents a small group of patients that require a special multidisciplinary treatment. Surgeons being a member of the multidisciplinary teams are an important part of the diagnosis, treatment and follow-up of these patients. The prophylactic nature of the gastrectomy with all different problems associated with this procedure need to be widely discussed with patients. We present a review of how to look for and how to manage a hereditary diffuse-type gastric cancer.
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Affiliation(s)
- Karol Polom
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100, Siena, Italy.
| | - Daniele Marrelli
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100, Siena, Italy
| | - Alessia D'Ignazio
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100, Siena, Italy
| | - Franco Roviello
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100, Siena, Italy
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31
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A mononucleotide repeat in PRRT2 is an important, frequent target of mismatch repair deficiency in cancer. Oncotarget 2018; 8:6043-6056. [PMID: 27907910 PMCID: PMC5351611 DOI: 10.18632/oncotarget.13464] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Accepted: 10/21/2016] [Indexed: 02/06/2023] Open
Abstract
The DNA mismatch repair (MMR) system corrects DNA replication mismatches thereby contributing to the maintenance of genomic stability. MMR deficiency has been observed in prostate cancer but its impact on the genomic landscape of these tumours is not known. In order to identify MMR associated mutations in prostate cancer we have performed whole genome sequencing of the MMR deficient PC346C prostate cancer cell line. We detected a total of 1196 mutations in PC346C which was 1.5-fold higher compared to a MMR proficient prostate cancer sample (G089). Of all different mutation classes, frameshifts in mononucleotide repeat (MNR) sequences were significantly enriched in the PC346C sample. As a result, a selection of genes with frameshift mutations in MNR was further assessed regarding its mutational status in a comprehensive panel of prostate, ovarian, endometrial and colorectal cancer cell lines. We identified PRRT2 and DAB2IP to be frequently mutated in MMR deficient cell lines, colorectal and endometrial cancer patient samples. Further characterization of PRRT2 revealed an important role of this gene in cancer biology. Both normal prostate cell lines and a colorectal cancer cell line showed increased proliferation, migration and invasion when expressing the mutated form of PRRT2 (ΔPRRT2). The wild-type PRRT2 (PRRT2wt) had an inhibitory effect in proliferation, consistent with the low expression level of PRRT2 in cancer versus normal prostate samples.
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Clinicopathologic Characteristics of Microsatellite Instable Gastric Carcinomas Revisited: Urgent Need for Standardization. Appl Immunohistochem Mol Morphol 2017; 25:12-24. [PMID: 26371427 PMCID: PMC5147042 DOI: 10.1097/pai.0000000000000264] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Microsatellite instable gastric cancer (MSI-GC) is a specific molecular subtype of GC. We studied the phenotypes, genotypes, and clinicopathologic characteristics of MSI-GC in a white GC cohort and compared our findings with an extended literature review. The study cohort consisted of 482 patients. Specimens were available from 452 cases and were used for immunostaining (MLH1, PMS2, MSH2, MSH6) and molecular biological analyses (BAT-25, BAT-26, NR-21, NR-24, NR-27; Epstein-Barr virus in situ hybridization). Thirty-four (7.5%) GCs were MSI. Loss of MLH1 and/or PMS2 was found in 30 (88%) MSI-GC, 3 (9%) showed loss of MSH2 and/or MSH6. One (3%) MSI-GC was identified only by molecular biological testing. A single case was heterogeneous and contained microsatellite-stable and instable tumor areas. Twenty-one (62%) MSI-GCs showed unusual histologic features. MSI-GC was not found in diffuse-type or Epstein-Barr virus-positive GC. MSI-GC was significantly more prevalent in elderly patients, distal stomach, and was associated with a significantly lower number of lymph node metastases and a significantly better overall and tumor-specific survival. MSI-GC constitutes a small but relevant subgroup of GC with distinct clinicopathologic characteristics. Our literature review illustrates the shortcomings of missing standardized testing algorithms with prevalences of MSI-GC ranging from 0% to 44.5%. Future studies should test the hypothesis that patients with MSI-GCs may not need adjuvant/perioperative chemotherapy. However, this will require a standardized, quality-controlled diagnostic algorithm of MSI for GC.
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Abstract
Gastric cancer is the fifth most incident and the third most common cause of cancer-related death in the world. Infection with Helicobacter pylori is the major risk factor for this disease. Gastric cancer is the final outcome of a cascade of events that takes decades to occur and results from the accumulation of multiple genetic and epigenetic alterations. These changes are crucial for tumor cells to expedite and sustain the array of pathways involved in the cancer development, such as cell cycle, DNA repair, metabolism, cell-to-cell and cell-to-matrix interactions, apoptosis, angiogenesis, and immune surveillance. Comprehensive molecular analyses of gastric cancer have disclosed the complex heterogeneity of this disease. In particular, these analyses have confirmed that Epstein-Barr virus (EBV)-positive gastric cancer is a distinct entity. The identification of gastric cancer subtypes characterized by recognizable molecular profiles may pave the way for a more personalized clinical management and to the identification of novel therapeutic targets and biomarkers for screening, prognosis, prediction of response to treatment, and monitoring of gastric cancer progression.
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Chmiela M, Karwowska Z, Gonciarz W, Allushi B, Stączek P. Host pathogen interactions in Helicobacter pylori related gastric cancer. World J Gastroenterol 2017; 23:1521-1540. [PMID: 28321154 PMCID: PMC5340805 DOI: 10.3748/wjg.v23.i9.1521] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 10/26/2016] [Accepted: 02/16/2017] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori), discovered in 1982, is a microaerophilic, spiral-shaped gram-negative bacterium that is able to colonize the human stomach. Nearly half of the world's population is infected by this pathogen. Its ability to induce gastritis, peptic ulcers, gastric cancer and mucosa-associated lymphoid tissue lymphoma has been confirmed. The susceptibility of an individual to these clinical outcomes is multifactorial and depends on H. pylori virulence, environmental factors, the genetic susceptibility of the host and the reactivity of the host immune system. Despite the host immune response, H. pylori infection can be difficult to eradicate. H. pylori is categorized as a group I carcinogen since this bacterium is responsible for the highest rate of cancer-related deaths worldwide. Early detection of cancer can be lifesaving. The 5-year survival rate for gastric cancer patients diagnosed in the early stages is nearly 90%. Gastric cancer is asymptomatic in the early stages but always progresses over time and begins to cause symptoms when untreated. In 97% of stomach cancer cases, cancer cells metastasize to other organs. H. pylori infection is responsible for nearly 60% of the intestinal-type gastric cancer cases but also influences the development of diffuse gastric cancer. The host genetic susceptibility depends on polymorphisms of genes involved in H. pylori-related inflammation and the cytokine response of gastric epithelial and immune cells. H. pylori strains differ in their ability to induce a deleterious inflammatory response. H. pylori-driven cytokines accelerate the inflammatory response and promote malignancy. Chronic H. pylori infection induces genetic instability in gastric epithelial cells and affects the DNA damage repair systems. Therefore, H. pylori infection should always be considered a pro-cancerous factor.
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35
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Genetic instability and increased mutational load: which diagnostic tool best direct patients with cancer to immunotherapy? J Transl Med 2017; 15:17. [PMID: 28109293 PMCID: PMC5251272 DOI: 10.1186/s12967-017-1119-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 01/06/2017] [Indexed: 12/17/2022] Open
Abstract
The occurrence of high rates of somatic mutations in cancer is believed to correspond to increased frequency of neo-epitope formation and tumor immunogenicity. Thus, classification of patients with cancer according to degree a somatic hyper-mutational status could be proposed as a predictive biomarker of responsiveness to immunotherapy with immune checkpoint inhibitors. Here, we discuss the suitable and reliable tests easily adoptable in clinical practice to assess somatic mutational status in patients with advanced cancer.
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36
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Patel TN, Roy S, Ravi R. Gastric cancer and related epigenetic alterations. Ecancermedicalscience 2017; 11:714. [PMID: 28144288 PMCID: PMC5243136 DOI: 10.3332/ecancer.2017.714] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer, a malignant and highly proliferative condition, has significantly affected a large population around the globe and is known to be caused by various factors including genetic, epigenetic, and environmental influences. Though the global trend of these cancers is declining, an increase in its frequency is still a threat because of changing lifestyles and dietary habits. However, genetic and epigenetic alterations related to gastric cancers also have an equivalent contribution towards carcinogenic development. DNA methylation is one of the major forms of epigenetic modification which plays a significant role in gastric carcinogenesis. Methylation leads to inactivation of some of the most important genes like DNA repair genes, cell cycle regulators, apoptotic genes, transcriptional regulators, and signalling pathway regulators; which subsequently cause uncontrolled proliferation of cells. Mutations in these genes can be used as suitable prognostic markers for early diagnosis of the disease, since late diagnosis of gastric cancers has a huge negative impact on overall patient survival. In this review, we focus on the important epigenetic mutations that contribute to the development of gastric cancer and the molecular pathogenesis underlying each of them. Methylation, acetylation, and histone modifications play an integral role in the onset of genomic instability, one of the many contributory factors to gastric cancer. This article also covers the constraints of incomplete knowledge of epigenetic factors influencing gastric cancer, thus throwing light on our understanding of the disease.
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Affiliation(s)
- Trupti N Patel
- Department of Medical Biotechnology, VIT University, Vellore 632014, Tamil Nadu, India
| | - Soumyadipta Roy
- Department of Medical Biotechnology, VIT University, Vellore 632014, Tamil Nadu, India
| | - Revathi Ravi
- Department of Medical Biotechnology, VIT University, Vellore 632014, Tamil Nadu, India
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37
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Figueiredo C, Camargo MC, Leite M, Fuentes-Pananá EM, Rabkin CS, Machado JC. Pathogenesis of Gastric Cancer: Genetics and Molecular Classification. Curr Top Microbiol Immunol 2017. [PMID: 28124158 DOI: 10.1007/978-3-319-50520-6_12.erratum.in:currtopmicrobiolimmunol.2017;400:e1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
Gastric cancer is the fifth most incident and the third most common cause of cancer-related death in the world. Infection with Helicobacter pylori is the major risk factor for this disease. Gastric cancer is the final outcome of a cascade of events that takes decades to occur and results from the accumulation of multiple genetic and epigenetic alterations. These changes are crucial for tumor cells to expedite and sustain the array of pathways involved in the cancer development, such as cell cycle, DNA repair, metabolism, cell-to-cell and cell-to-matrix interactions, apoptosis, angiogenesis, and immune surveillance. Comprehensive molecular analyses of gastric cancer have disclosed the complex heterogeneity of this disease. In particular, these analyses have confirmed that Epstein-Barr virus (EBV)-positive gastric cancer is a distinct entity. The identification of gastric cancer subtypes characterized by recognizable molecular profiles may pave the way for a more personalized clinical management and to the identification of novel therapeutic targets and biomarkers for screening, prognosis, prediction of response to treatment, and monitoring of gastric cancer progression.
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Affiliation(s)
- Ceu Figueiredo
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal.,Faculty of Medicine of the University of Porto, Porto, Portugal
| | - M C Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, ML, USA
| | - Marina Leite
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
| | - Ezequiel M Fuentes-Pananá
- Research Unit of Cancer and Virology, Children's Hospital of Mexico "Federico Gomez", Mexico City, Mexico
| | - Charles S Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, ML, USA
| | - José C Machado
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. .,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal. .,Faculty of Medicine of the University of Porto, Porto, Portugal.
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Kim YB, Lee SY, Kim JH, Sung IK, Park HS, Shim CS, Han HS. Microsatellite Instability of Gastric and Colorectal Cancers as a Predictor of Synchronous Gastric or Colorectal Neoplasms. Gut Liver 2016; 10:220-7. [PMID: 26087787 PMCID: PMC4780451 DOI: 10.5009/gnl14310] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND/AIMS Microsatellite instability (MSI) plays a crucial role in gastrointestinal carcinogenesis. The aim of this study was to clarify whether MSI is a useful marker for predicting synchronous gastric and colorectal neoplasms. METHODS Consecutive patients who underwent both esophagogastroduodenoscopy and colonoscopy before the resection of gastric or colorectal cancers were included. MSI was analyzed using two mononucleotide and three dinucleotide markers. RESULTS In total, 434 gastric cancers (372 microsatellite stability [MSS], 21 low incidence of MSI [MSI-L], and 41 high incidence of MSI [MSI-H]) and 162 colorectal cancers (138 MSS, 9 MSI-L, and 15 MSI-H) were included. Patients with MSI gastric cancer had a higher prevalence of synchronous colorectal cancer, colorectal adenoma, and gastric adenoma than those with MSS gastric cancers (4.8% vs 0.5%, p=0.023; 11.3% vs 3.2%, p=0.011; 3.2% vs 1.2%, p=0.00, respectively). The prevalence of synchronous colorectal adenomas was highest in MSI-L gastric cancers (19.0%), compared with MSI-H (7.3%) or MSS (3.2%) gastric cancers (p=0.002). In addition, there were no significant differences in the prevalence rates of synchronous colorectal adenoma among the MSI-H (13.3%), MSI-L (11.1%), and MSS (12.3%) colorectal cancers (p=0.987). CONCLUSIONS The presence of MSI in gastric cancer may be a predictor of synchronous gastric and colorectal neoplasms, whereas MSI in colorectal cancer is not a predictor of synchronous colorectal adenoma.
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Affiliation(s)
- Young Beak Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Sun-Young Lee
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Jeong Hwan Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - In-Kyung Sung
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Hyung Seok Park
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Chan Sup Shim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Hye Seung Han
- Department of Pathology, Konkuk University School of Medicine, Seoul, Korea
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Guo J, Yu W, Su H, Pang X. Genomic landscape of gastric cancer: molecular classification and potential targets. SCIENCE CHINA-LIFE SCIENCES 2016; 60:126-137. [PMID: 27460193 DOI: 10.1007/s11427-016-0034-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 04/06/2016] [Indexed: 12/11/2022]
Abstract
Gastric cancer imposes a considerable health burden worldwide, and its mortality ranks as the second highest for all types of cancers. The limited knowledge of the molecular mechanisms underlying gastric cancer tumorigenesis hinders the development of therapeutic strategies. However, ongoing collaborative sequencing efforts facilitate molecular classification and unveil the genomic landscape of gastric cancer. Several new drivers and tumorigenic pathways in gastric cancer, including chromatin remodeling genes, RhoA-related pathways, TP53 dysregulation, activation of receptor tyrosine kinases, stem cell pathways and abnormal DNA methylation, have been revealed. These newly identified genomic alterations await translation into clinical diagnosis and targeted therapies. Considering that loss-of-function mutations are intractable, synthetic lethality could be employed when discussing feasible therapeutic strategies. Although many challenges remain to be tackled, we are optimistic regarding improvements in the prognosis and treatment of gastric cancer in the near future.
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Affiliation(s)
- Jiawei Guo
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Weiwei Yu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Hui Su
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Xiufeng Pang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
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40
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Hudler P. Challenges of deciphering gastric cancer heterogeneity. World J Gastroenterol 2015; 21:10510-10527. [PMID: 26457012 PMCID: PMC4588074 DOI: 10.3748/wjg.v21.i37.10510] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 06/19/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is in decline in most developed countries; however, it still accounts for a notable fraction of global mortality and morbidity related to cancer. High-throughput methods are rapidly changing our view and understanding of the molecular basis of gastric carcinogenesis. Today, it is widely accepted that the molecular complexity and heterogeneity, both inter- and intra-tumour, of gastric adenocarcinomas present significant obstacles in elucidating specific biomarkers for early detection of the disease. Although genome-wide sequencing and gene expression studies have revealed the intricate nature of the molecular changes that occur in tumour landscapes, the collected data and results are complex and sometimes contradictory. Several aberrant molecules have already been tested in clinical trials, although their diagnostic and prognostic utilities have not been confirmed thus far. The gold standard for the detection of sporadic gastric cancer is still the gastric endoscopy, which is considered invasive. In addition, genome-wide association studies have confirmed that genetic variations are important contributors to increased cancer risk and could participate in the initiation of malignant transformation. This hypothesis could in part explain the late onset of sporadic gastric cancers. The elaborate interplay of polymorphic low penetrance genes and lifestyle and environmental risk factors requires additional research to decipher their relative impacts on tumorigenesis. The purpose of this article is to present details of the molecular heterogeneity of sporadic gastric cancers at the DNA, RNA, and proteome levels and to discuss issues relevant to the translation of basic research data to clinically valuable tools. The focus of this work is the identification of relevant molecular changes that could be detected non-invasively.
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Toda K, Nagasaka T, Umeda Y, Tanaka T, Kawai T, Fuji T, Taniguchi F, Yasui K, Kubota N, Takehara Y, Tazawa H, Kagawa S, Sun DS, Nishida N, Goel A, Fujiwara T. Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer with chromosomal instability. Clin Epigenetics 2015. [PMID: 26207151 PMCID: PMC4511994 DOI: 10.1186/s13148-015-0096-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background The gene expressions of netrin-1 dependence receptors, DCC and UNC5C, are frequently downregulated in many cancers. We hypothesized that downregulation of DCC and UNC5C has an important growth regulatory function in gastric tumorigenesis. Results In the present study, a series of genetic and epigenetic analyses for DCC and UNC5C were performed in a Japanese cohort of 98 sporadic gastric cancers and corresponding normal gastric mucosa specimens. Loss of heterozygosity (LOH) analyses and microsatellite instability (MSI) analysis was applied to determine chromosomal instability (CIN) and MSI phenotypes, respectively. More than 5 % methylation in the DCC and UNC5C promoters were found in 45 % (44/98) and 32 % (31/98) gastric cancers, respectively, and in 9 % (9/105) and 5 % (5/105) normal gastric mucosa, respectively. Overall, 70 % (58 of 83 informative cases) and 51 % (40 of 79 informative cases) of gastric cancers harbored either LOH or aberrant methylation in the DCC and UNC5C genes, respectively. In total, 77 % (51 of 66 informative cases) of gastric cancers showed cumulative defects in these two dependence receptors and were significantly associated with chromosomal instability. Both DCC and UNC5C were inactivated in 97 % of CIN-positive gastric cancers and in 55 % of CIN-negative gastric cancers. Conclusions Defect in netrin receptors is a common feature in gastric cancers. DCC alterations are apparent in the early stages, and UNC5C alterations escalate with the progression of the disease, suggesting that the cumulative alterations of netrin-1 receptors was a late event in gastric cancer progression and emphasizing the importance of this growth regulatory pathway in gastric carcinogenesis. Electronic supplementary material The online version of this article (doi:10.1186/s13148-015-0096-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Keisuke Toda
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan
| | - Takeshi Nagasaka
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan
| | - Yuzo Umeda
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan
| | - Takehiro Tanaka
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan
| | - Takashi Kawai
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan
| | - Tomokazu Fuji
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan
| | - Fumitaka Taniguchi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan
| | - Kazuya Yasui
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan
| | - Nobuhito Kubota
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan
| | - Yuko Takehara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan
| | - Hiroshi Tazawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan
| | - Shunsuke Kagawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan
| | - Dong-Sheng Sun
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan ; Department of Oncology, Kailuan General Hospital in Tangshan of Hebei Province, Tangshan, Hebei 063000 China
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, 337-2 Ohno-higashi, Osaka-sayama, Osaka 589-8511 Japan
| | - Ajay Goel
- Center for Gastrointestinal Cancer Research, Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75246 USA
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558 Japan
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Kim SY, Choi YY, An JY, Shin HB, Jo A, Choi H, Seo SH, Bang HJ, Cheong JH, Hyung WJ, Noh SH. The benefit of microsatellite instability is attenuated by chemotherapy in stage II and stage III gastric cancer: Results from a large cohort with subgroup analyses. Int J Cancer 2015; 137:819-25. [DOI: 10.1002/ijc.29449] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 01/13/2015] [Indexed: 12/24/2022]
Affiliation(s)
- Soo Young Kim
- Department of Surgery; Yonsei University College of Medicine; Seoul Republic of Korea
| | - Yoon Young Choi
- Department of Surgery; Yonsei University College of Medicine; Seoul Republic of Korea
| | - Ji Yeong An
- Department of Surgery; Yonsei University College of Medicine; Seoul Republic of Korea
| | - Hyun Beak Shin
- Department of Surgery; Yonsei University College of Medicine; Seoul Republic of Korea
| | - Ara Jo
- Brain Korea 21 Plus Project for Medical Science; Yonsei University Health System, Yonsei University College of Medicine; Seoul Republic of Korea
| | - Hyeji Choi
- Brain Korea 21 Plus Project for Medical Science; Yonsei University Health System, Yonsei University College of Medicine; Seoul Republic of Korea
| | - Sang Hyuk Seo
- Department of Surgery; Yonsei University College of Medicine; Seoul Republic of Korea
| | - Hui-Jae Bang
- Department of Surgery; Yonsei University College of Medicine; Seoul Republic of Korea
| | - Jae-Ho Cheong
- Department of Surgery; Yonsei University College of Medicine; Seoul Republic of Korea
| | - Woo Jin Hyung
- Department of Surgery; Yonsei University College of Medicine; Seoul Republic of Korea
| | - Sung Hoon Noh
- Department of Surgery; Yonsei University College of Medicine; Seoul Republic of Korea
- Brain Korea 21 Plus Project for Medical Science; Yonsei University Health System, Yonsei University College of Medicine; Seoul Republic of Korea
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Inada R, Sekine S, Taniguchi H, Tsuda H, Katai H, Fujiwara T, Kushima R. ARID1A expression in gastric adenocarcinoma: Clinicopathological significance and correlation with DNA mismatch repair status. World J Gastroenterol 2015; 21:2159-2168. [PMID: 25717252 PMCID: PMC4326154 DOI: 10.3748/wjg.v21.i7.2159] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2014] [Revised: 08/30/2014] [Accepted: 09/30/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the mismatch repair (MMR) status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.
METHODS: We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas. The results were further correlated with clinicopathological variables.
RESULTS: The loss of any MMR protein expression, indicative of MMR deficiency, was observed in 38 cases (7.8%) and was significantly associated with an older age (68.6 ± 9.2 vs 60.4 ± 11.7, P < 0.001), a female sex (55.3% vs 31.3%, P = 0.004), an antral location (44.7% vs 25.7%, P = 0.021), and a differentiated histology (57.9% vs 39.7%, P = 0.023). Abnormal ARID1A expression, including reduced or loss of ARID1A expression, was observed in 109 cases (22.3%) and was significantly correlated with lymphatic invasion (80.7% vs 69.5%, P = 0.022) and lymph node metastasis (83.5% vs 73.7%, P = 0.042). The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency (47.4% vs 20.2%, P < 0.001). A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor (HR = 1.36, 95%CI: 1.01-1.84; P = 0.040).
CONCLUSION: Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion, lymph node metastasis, poor prognosis, and MMR deficiency in gastric adenocarcinomas.
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Shigeyasu K, Nagasaka T, Mori Y, Yokomichi N, Kawai T, Fuji T, Kimura K, Umeda Y, Kagawa S, Goel A, Fujiwara T. Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers in Patients with Gastric Cancer. PLoS One 2015; 10:e0130409. [PMID: 26121593 PMCID: PMC4488282 DOI: 10.1371/journal.pone.0130409] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 05/20/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND To improve the outcome of patients suffering from gastric cancer, a better understanding of underlying genetic and epigenetic events in this malignancy is required. Although CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) have been shown to play pivotal roles in gastric cancer pathogenesis, the clinical significance of these events on survival outcomes in patients with gastric cancer remains unknown. METHODS This study included a patient cohort with pathologically confirmed gastric cancer who had surgical resections. A cohort of 68 gastric cancers was analyzed. CIMP and MSI statuses were determined by analyzing promoter CpG island methylation status of 28 genes/loci, and genomic instability at 10 microsatellite markers, respectively. A Cox's proportional hazards model was performed for multivariate analysis including age, stage, tumor differentiation, KRAS mutation status, and combined CIMP/MLH1 methylation status in relation to overall survival (OS). RESULTS By multivariate analysis, longer OS was significantly correlated with lower pathologic stage (P = 0.0088), better tumor differentiation (P = 0.0267) and CIMP-high and MLH1 3' methylated status (P = 0.0312). Stratification of CIMP status with regards to MLH1 methylation status further enabled prediction of gastric cancer prognosis. CONCLUSIONS CIMP and/or MLH1 methylation status may have a potential to be prognostic biomarkers for patients with gastric cancer.
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Affiliation(s)
- Kunitoshi Shigeyasu
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, Japan
- Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, United States of America
| | - Takeshi Nagasaka
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, Japan
- * E-mail: (TN); (AG)
| | - Yoshiko Mori
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, Japan
| | - Naosuke Yokomichi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, Japan
| | - Takashi Kawai
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, Japan
| | - Tomokazu Fuji
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, Japan
| | - Keisuke Kimura
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, Japan
| | - Yuzo Umeda
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, Japan
| | - Shunsuke Kagawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, Japan
| | - Ajay Goel
- Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, United States of America
- * E-mail: (TN); (AG)
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama, Japan
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Velho S, Fernandes MS, Leite M, Figueiredo C, Seruca R. Causes and consequences of microsatellite instability in gastric carcinogenesis. World J Gastroenterol 2014; 20:16433-16442. [PMID: 25469011 PMCID: PMC4248186 DOI: 10.3748/wjg.v20.i44.16433] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 07/24/2014] [Accepted: 09/05/2014] [Indexed: 02/06/2023] Open
Abstract
Loss of DNA mismatch repair (MMR) function, due to somatic or germline epi/genetic alterations of MMR genes leads to the accumulation of numerous mutations across the genome, creating a molecular phenotype known as microsatellite instability (MSI). In gastric cancer (GC), MSI occurs in about 15% to 30% of the cases. This review summarizes the current knowledge on the molecular mechanisms underlying the acquisition of MSI in GC as well as on the clinic, pathologic and molecular consequences of the MSI phenotype. Additionally, current therapeutic strategies for GC and their applicability in the MSI subset are also discussed.
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Pinheiro DDR, Ferreira WAS, Barros MBL, Araújo MD, Rodrigues-Antunes S, Borges BDN. Perspectives on new biomarkers in gastric cancer: Diagnostic and prognostic applications. World J Gastroenterol 2014; 20:11574-11585. [PMID: 25206265 PMCID: PMC4155351 DOI: 10.3748/wjg.v20.i33.11574] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 03/14/2014] [Accepted: 05/05/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is considered one of the most deadly tumors worldwide. Even with the decline in its incidence, the mortality rate of this disease has remained high, mainly due to its late diagnosis and to the lack of precise prognostic markers. The main purpose of this review is to present genetic, epigenetic and proteomic molecular markers that may be used in a diagnostic and prognostic manner and to discuss the pros and cons of each type of marker for improving clinical practice. In this sense, we observed that the use of genetic markers, especially mutations and polymorphisms, should be carefully considered, as they are strongly affected by ethnicity. Proteomic-based markers show promise, but the higher costs of the associated techniques continue to make this approach expensive for routine use. Alternatively, epigenetic markers appear to be very promising, as they can be detected in bodily fluids as well as tissues. However, such markers must be used carefully because epigenetic changes may occur due to environmental factors and aging. Despite the advances in technology and its access, to date, there are few defined biomarkers of prognostic and diagnostic use for gastric tumors. Therefore, the use of a panel of several approaches (genetic, epigenetic and proteomic) should be considered the best alternative for clinical practice.
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Zhao Y, Zheng ZC, Luo YH, Piao HZ, Zheng GL, Shi JY, Zhang T, Zhang JJ. Low-Frequency Microsatellite Instability in Genomic Di-Nucleotide Sequences Correlates with Lymphatic Invasion and Poor Prognosis in Gastric Cancer. Cell Biochem Biophys 2014; 71:235-41. [DOI: 10.1007/s12013-014-0189-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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The analysis of microsatellite instability in extracolonic gastrointestinal malignancy. Pathology 2014; 45:540-52. [PMID: 24018804 DOI: 10.1097/pat.0b013e3283653307] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Microsatellite instability (MSI) is a genetic feature of sporadic and familial cancers of multiple sites and is related to defective mismatch repair (MMR) protein function. Lynch syndrome (LS) is a familial form of MMR deficiency that may present with a spectrum of MSI positive cancers including gastrointestinal (GI) malignancies. The incidence of high level MSI (MSI-H) in colorectal carcinoma is well defined in both familial and sporadic cases and these tumours portend a better overall prognosis in colorectal carcinoma (CRC). There are certain morphological features that suggest MSI-H CRC and international guidelines have been established for the evaluation of MSI in CRC. The prevalence and morphological features of extracolonic GI MSI-H tumours are less well documented. Furthermore, it is unclear whether the guidelines for the assessment of MSI in CRC are appropriate for application to extracolonic GI malignancies. This review aims to summarise the recent literature on MSI in extracolonic LS-related GI tract malignancies with special attention to the assessment of the MMR system by evaluation of specific microsatellite markers and/or immunohistochemical evaluation of MMR protein expression. The reported prevalence of sporadic and LS-related MSI-H tumours along with their associated unique morphological patterns and related prognostic or therapeutic implications will be discussed.
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Kamat N, Khidhir MA, Alashari MM, Rannug U. Microsatellite instability and loss of heterozygosity detected in middle-aged patients with sporadic colon cancer: A retrospective study. Oncol Lett 2013; 6:1413-1420. [PMID: 24179534 PMCID: PMC3813818 DOI: 10.3892/ol.2013.1573] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Accepted: 08/05/2013] [Indexed: 02/01/2023] Open
Abstract
Microsatellite instability (MSI) is a mutator phenotype that results from a defective mismatch repair (MMR) pathway. The present study examined the incidence of MSI and loss of heterozygosity (LOH) according to five markers from the panel of the National Cancer Institute (NCI) in 38 colorectal cancer (CRC) patients from the United Arab Emirates (UAE). MSI and LOH were analyzed using fragment analyses in a multiplex PCR setting on a capillary array electrophoresis platform. The expression of the MMR proteins, hMLH1 and hMSH2, was analyzed using immunohistochemistry. The cohort consisted of 17 females (44.7%) and 21 males (55.3%) with mean ages of 59.9 and 63.3 years, respectively. The overall MSI incidence was 31.3% (95% CI, 16.1–50.0), and included three patients with high MSI (MSI-H; 9.4%; 95% CI, 2.0–25.0) and seven patients with low MSI (MSI-L; 21.9%; 95% CI, 10.7–39). LOH was detected in three patients, while the remaining 25 patients (65.8%) showed no instability and were therefore classified as microsatellite stable (MSS). MSI was detected in the following screened markers: Bat25 in seven patients, Bat26 in three patients, adenomatous polyposis coli (APC; D5S346) in five patients, AFM093xh3 (D2S123) in two patients and Mfd15 (D17S250) in three patients. Of the five MSI-positive patients, four (80%) were evidently younger, aged 38, 48, 49 and 59 years, respectively. The MSI-H incidence (9.4%) was lower compared with that of other ethnic groups. In terms of the MMR proteins, hMLH1 expression was deficient in seven patients, of whom three were MSI-H patients, and hMSH2 was deficient in three patients. Fisher’s exact test showed significant associations between hMLH1 and MSI when classified as MSS, MSI-L or MSI-H (P=0.0003). No such association was observed with abnormal MMR protein expression, age, cancer stage or gender.
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Affiliation(s)
- Nasir Kamat
- Department of Molecular Biosciences, The Wenner-Gren Institute (MBW), Stockholm University, Stockholm, Sweden
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Park HJ, Kim HS, Kim JW, Park SY, Kim BR, Ryu HY, Lee IY, Lee YK, Cho MY. Is microsatellite instability (MSI) associated with multiplicity in early stage gastric neoplasias? Clin Res Hepatol Gastroenterol 2013; 37:400-5. [PMID: 23273496 DOI: 10.1016/j.clinre.2012.10.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Revised: 09/26/2012] [Accepted: 10/18/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS The aim of this study was to investigate the relationship between microsatellite instability (MSI) and clinicopathologic features including multiplicity in early stage gastric neoplasias (ESGN). METHODS From November 2004 until September 2009, 372 patients with consecutive resected gastric neoplasias were retrospectively enrolled. The gastric neoplasias were composed of 117 advanced gastric cancers (AGCs) and 255 ESGNs including 31 gastric dysplasias (including low and high grade dysplasia) and 224 early gastric cancers (EGCs). RESULTS Based on microsatellite markers, high MSI (MSI-H) was observed in 61 cases (16.4%) and low MSI (MSI-L) in 14 cases (3.8%) of 372 cases. There was a positive correlation between the presence of MSI-H and progression of gastric adenoma to gastric tumor. We compared ESGNs with microsatellite stable (MSS; 223 cases, 87.5%) and ESGNs with MSI-H (24 cases, 9.4%). The ESGNs with MSI-H were only associated with older age and female gender. There were no association with Helicobacter pylori infection, intestinal metaplasia, and distal location in contrast with EGCs with MSI-H. Furthermore, multiplicity of ESGNs was not associated with MSI status. CONCLUSIONS The clinicopatholgic features of MSI-H phenotype were different according to the progression of gastric neoplasias from ESGNs to AGCs. ESGNs with MSI-H were only associated with old age, female sex. In addition ESGNs with MSI-H were not associated with an increased risk of multifocal tumors.
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Affiliation(s)
- Hong Jun Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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