• Cholangiocarcinoma
• Durvalumab
• Lynch syndrome
• Mismatch repair deficiency

• Humans
• Male
• Middle Aged
• Cholangiocarcinoma/drug therapy
• Cholangiocarcinoma/pathology
• Cholangiocarcinoma/diagnostic imaging
• Cholangiocarcinoma/genetics
• Deoxycytidine/analogs & derivatives
• Deoxycytidine/administration & dosage
• Deoxycytidine/therapeutic use
• Gemcitabine
• Cisplatin/administration & dosage
• Cisplatin/therapeutic use
• Bile Duct Neoplasms/drug therapy
• Bile Duct Neoplasms/pathology
• Bile Duct Neoplasms/genetics
• Bile Duct Neoplasms/diagnostic imaging
• Colorectal Neoplasms, Hereditary Nonpolyposis/complications
• Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
• Antibodies, Monoclonal/administration & dosage
• Antibodies, Monoclonal/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• DNA Mismatch Repair
• MutL Protein Homolog 1/genetics
• Brain Neoplasms
• Neoplastic Syndromes, Hereditary
• Colorectal Neoplasms

• cancer genetics
• risk factors

• BO/00141/21 Magyar Tudományos Akadémia (Hungarian Academy of Sciences)
• Bolyai Research Fellowship Magyar Tudományos Akadémia (Hungarian Academy of Sciences)

• Dark genetic matter
• Epimutation
• Inversion
• Promoter deletion
• Transposon insertion

• Humans
• Germ-Line Mutation
• Genetic Predisposition to Disease
• Neoplastic Syndromes, Hereditary/genetics
• Neoplastic Syndromes, Hereditary/diagnosis
• Genotyping Techniques/methods
• Genotype

• Humans
• ACTH-Secreting Pituitary Adenoma/genetics
• ACTH-Secreting Pituitary Adenoma/pathology
• Carcinogenesis/genetics
• Ubiquitin Thiolesterase/genetics
• Endosomal Sorting Complexes Required for Transport/genetics
• Adenoma/genetics
• Adenoma/pathology
• Endopeptidases

• Colorectal neoplasms
• Gastrointestinal neoplasms
• Hereditary
• Medical oncology
• Molecular
• Neoplastic syndromes
• Pathology

• Colorectal carcinoma
• Epidermal growth factor receptor
• Immunotherapy
• Lynch syndrome
• Microsatellite instability

• Humans
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• Molecular Diagnostic Techniques
• Biomarkers, Tumor/genetics

• COVID-19
• Cancer
• Cancer hallmarks
• Risk factors
• mRNA vaccines

• Lynch syndrome (LS)
• biliary tract cancer
• hereditary nonpolyposis colon cancer (HNPCC)
• microsatellite instability (MSI)
• pancreatic cancer

• Lynch syndrome
• cancer neoantigens
• colorectal cancer
• granzyme B
• immune infiltration
• immunotherapy
• microsatellite instability
• mismatch repair deficiency

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.

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.

Lynch syndrome (LS) is a hereditary cancer predisposition syndrome associated with increased risk of multiple cancers. While colorectal cancer surveillance decreases mortality in LS and is recommended by guidelines, there is lack of evidence for the efficacy of surveillance for extra-colonic cancers associated with LS, including small intestinal cancer (SIC) and urinary tract cancer (UTC). Given the limited evidence, guidelines do not consistently recommend surveillance for SIC and UTC, and it remains unclear how often individuals will choose to undergo and follow through with extra-colonic surveillance recommendations.

To study factors associated with SIC and UTC surveillance uptake and outcomes in LS.

This is an IRB-approved retrospective analysis of individuals with LS seen at a tertiary care referral center. Included individuals had a pathogenic or likely pathogenic variant in MLH1, MSH2, MSH6, PMS2, or EPCAM, or were a confirmed obligate carrier, and had at least one documented visit to our center. Information regarding SIC and UTC surveillance was captured for each individual, and detailed personal and family history was obtained for individuals who had an initial LS management visit in our center’s dedicated high-risk LS clinic between January 1, 2017 and October 29, 2020. During these initial management visits, all patients had in-depth discussions of SIC and UTC surveillance with 1 of 3 providers experienced in LS management to promote informed decision-making about whether to pursue SIC and/or UTC surveillance. Statistical analysis using Pearson’s chi-squared test and Wilcoxon rank-sum test was completed to understand the factors associated with pursuit and completion of SIC and UTC surveillance, and a P value below 0.05 was deemed statistically significant.

Of 317 individuals with LS, 86 (27%) underwent a total of 105 SIC surveillance examinations, with 5 leading to additional work-up and no SICs diagnosed. Additionally, 99 (31%) patients underwent a total of 303 UTC surveillance examinations, with 19 requiring further evaluation and 1 UTC identified. Of 155 individuals who had an initial LS management visit between January 1, 2017 and October 29, 2020, 63 (41%) chose to undergo SIC surveillance and 58 (37%) chose to undergo UTC surveillance. However, only 26 (41%) and 32 (55%) of those who initially chose to undergo SIC or UTC surveillance, respectively, successfully completed their surveillance examinations. Individuals with a pathogenic variant in MSH2 or EPCAM were more likely to initially choose to undergo SIC surveillance (P = 0.034), and older individuals were more likely to complete SIC surveillance (P = 0.007). Choosing to pursue UTC surveillance was more frequent among older individuals (P = 0.018), and females more frequently completed UTC surveillance (P = 0.002). Personal history of cancer and family history of SIC or UTC were not significantly associated with electing nor completing surveillance. Lastly, the provider discussing SIC/UTC surveillance was significantly associated with subsequent surveillance choices.

Pursuing and completing SIC/UTC surveillance in LS is influenced by several factors, however broad incorporation in LS management is likely unhelpful due to low yield and frequent false positive results.

• Lynch syndrome
• Urinary tract cancer
• Intestinal neoplasms
• Early diagnosis of cancer
• Patient preference
• Gastrointestinal surgical procedure

• Colorectal carcinoma
• Epidermal growth factor receptor
• Immunotherapy
• Lynch syndrome
• Microsatellite instability

• Colorectal cancer risk profiling
• Early detection
• Metastasis prevention

A large proportion of patients with Lynch syndrome (LS) have MSH2 abnormalities, but genotype-phenotype studies of MSH2 mutations in LS are still lacking. The aim of this study was to comprehensively analyze the clinicopathological characteristics and molecular basis of colorectal cancer (CRC) in patients with uncommon MSH2 cytoplasmic expression.

We retrospectively reviewed 4195 consecutive cases of CRC patients diagnosed between January 2015 and December 2017 at the Cancer Hospital Chinese Academy of Medical Sciences. Of the 4195 patients with CRC, 69 were indicated to have abnormal MSH2 expression through tumor immunohistochemical staining. Genetic tests, such as next-generation sequencing, large genomic rearrangement (LGR) analysis, microsatellite instability status analysis and genomic breakpoint analysis, were performed. Clinicopathological and molecular characteristics and clinical immunotherapy response were analyzed.

Forty-five of 69 patients were identified to have LS with pathogenic germline mutations in MSH2 and/or EPCAM. Of these LS patients, 26.7% were confirmed to harbor large genomic rearrangements (LGRs). Of note, three tumors from two unrelated family pedigrees exhibited a rare cytoplasmic MSH2 staining pattern that was found in LS patients with EPCAM/MSH2 deletions. RNA analysis showed that two novel mRNA fusions of EPCAM and MSH2 resulted in the predicted protein fusion with MSH2 cytoplasmic localization. Analyses of genomic breakpoints indicated that two novel deletions of EPCAM and MSH2 originated from Alu repeat-mediated recombination events. Our study also provides clinical evidence for the beneficial effect of the PD-1 inhibitor pembrolizumab for CRC patients that exhibit cytoplasmic MSH2 staining.

Our study demonstrates that the rare cytoplasmic MSH2 staining pattern should be fully recognized by pathologists and geneticists. Given the specific genotype-phenotype correlation in LS screening, we advocate that all CRC patients with cytoplasmic MSH2 staining in histology should be screened for LGRs of EPCAM and MSH2.

• DNA mismatch repair
• Lynch syndrome
• colorectal cancer
• genetic testing
• immunotherapy

In addition to single nucleotide variations and small-scale indels, structural variations (SVs) also contribute to the genetic diversity of the genome. SVs, such as deletions, duplications, amplifications, or inversions may also affect coding regions of cancer-predisposing genes. These rearrangements may abrogate the open reading frame of these genes or adversely affect their expression and may thus act as germline mutations in hereditary cancer syndromes. With the capacity of disrupting the function of tumor suppressors, structural variations confer an increased risk of cancer and account for a remarkable fraction of heritability. The development of sequencing techniques enables the discovery of a constantly growing number of SVs of various types in cancer predisposition genes (CPGs). Here, we provide a comprehensive review of the landscape of germline SV types, detection methods, pathomechanisms, and frequency in CPGs, focusing on the two most common cancer syndromes: hereditary breast- and ovarian cancer and gastrointestinal cancers. Current knowledge about the possible molecular mechanisms driving to SVs is also summarized.

• cancer–predisposing genes
• copy number variation
• germline mutation
• large genomic rearrangement
• structural variation
• structural variations

Lynch syndrome is an autosomal dominant disorder, most frequent leading to colon cancer. Identification of patients with Lynch syndrome and screening of their family members are available prevention approach that can significantly decrease mortality. Unfortunately, routine screening still does not belong to standard of care in Hungary. In this study, we performed a comprehensive screening in order to identify patients with mismatch repair (MMR) mutation between the years of 2011 and 2014. Identified mutations were compared with those already published in the international databases.

Patients who underwent treatment for colorectal cancer at the Surgical Institute of the University of Debrecen were screened using the modified Amsterdam and Bethesda Criteria. Immunohistochemistry and microsatellite analyses were performed in order to identify possible mutation carrier cases. Suspicious cases underwent DNA sequencing to detect mutations in the mismatch repair genes (hMLH1, hMSH2).

All together 760 colorectal cancer patients were screened. A total of 28 patients were identified as possible MMR mutation carrier and underwent further genetic evaluation. Pathogenic sequence variants of the MMR gene were found in 5 patients. Hypermethylation of the promoter region of the hMLH1 gene was identified in 2 patients. Two out of the 5 pathogenic sequence variants of the MMR gene were first identified by our group while other 2 mutations were previously published as possible founder mutations.

Identification of families with Lynch syndrome, while challenging because of variable phenotypes at diagnosis, is feasible with available molecular biological technologies and crucial to reduce mortality caused by this syndrome.

• Colorectal cancer
• Lynch syndrome
• MMR mutation
• Screening

• Adult
• Biomarkers, Tumor/genetics
• Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis
• Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
• Colorectal Neoplasms, Hereditary Nonpolyposis/surgery
• Colorectal Surgery/methods
• Early Detection of Cancer/methods
• Female
• Follow-Up Studies
• Genetic Predisposition to Disease
• Humans
• Hungary
• Male
• MutL Protein Homolog 1/genetics
• MutS Homolog 2 Protein/genetics
• Mutation
• Prognosis
• Survival Rate

• colorectal tumors
• genetic predisposition
• missing heritability
• molecular biomarkers
• molecular diagnosis
• rare variants

• Adenomatous Polyposis Coli/diagnosis
• Adenomatous Polyposis Coli/genetics
• Adenomatous Polyposis Coli/metabolism
• Adenomatous Polyposis Coli/pathology
• Adenomatous Polyposis Coli Protein/genetics
• Adenomatous Polyposis Coli Protein/metabolism
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis
• Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
• Colorectal Neoplasms, Hereditary Nonpolyposis/metabolism
• Colorectal Neoplasms, Hereditary Nonpolyposis/pathology
• Exome
• Genetic Association Studies
• Genetic Loci
• Genetic Predisposition to Disease
• Genotype
• Humans
• MutL Protein Homolog 1/genetics
• MutL Protein Homolog 1/metabolism
• MutS Homolog 2 Protein/genetics
• MutS Homolog 2 Protein/metabolism
• PTEN Phosphohydrolase/genetics
• PTEN Phosphohydrolase/metabolism
• Penetrance
• Phenotype
• Exome Sequencing

• 779257 Horizon 2020

Colorectal carcinomas from patients with Lynch syndrome (LS) due to EPCAM deletions show loss of MSH2 expression. The aim of our study was to evaluate the usefulness of EPCAM expression in identifying carriers of EPCAM deletion among patients with MSH2-negative lesions. MSH2 and EPCAM immunohistochemistry was performed in a large series of lesions (190) composed of malignant and benign neoplasms as well as precursor lesions of different organs from 71 patients with suspected LS due to MSH2 alterations. Germ-line analysis confirmed LS in 68 patients due to MSH2 mutations (53) and EPCAM deletions (15). Among colorectal lesions with lack of MSH2 expression, only 17 were EPCAM-negative and belonged to patients with EPCAM deletions. We confirm that loss of EPCAM expression identifies EPCAM deletion carriers with 100% specificity and we recommend adding EPCAM IHC to the algorithm of MSH2-negative colorectal neoplasia.

The use of epithelial cell adhesion molecule (EPCAM) immunohistochemistry (IHC) is not included in the colorectal cancer (CRC) screening algorithm to detect Lynch syndrome (LS) patients. The aim of the present study was to demonstrate that EPCAM IHC is a useful tool to guide the LS germ-line analysis when a loss of MSH2 expression was present. We retrospectively studied MSH2 and EPCAM IHC in a large series of 190 lesions composed of malignant neoplasms (102), precursor lesions of gastrointestinal (71) and extra-gastrointestinal origin (9), and benign neoplasms (8) from different organs of 71 patients suspicious of being LS due to MSH2 alterations. LS was confirmed in 68 patients, 53 with MSH2 mutations and 15 with EPCAM 3′-end deletions. Tissue microarrays were constructed with human normal tissues and their malignant counterparts to assist in the evaluation of EPCAM staining. Among 154 MSH2-negative lesions, 17 were EPCAM-negative, including 10 CRC and 7 colorectal polyps, and 5 of them showed only isolated negative glands. All lesions showing a lack of EPCAM expression belonged to patients with EPCAM 3′-end deletions. EPCAM IHC is a useful screening tool, with 100% specificity to identify LS patients due to EPCAM 3′-end deletions in MSH2-negative CRC and MSH2-negative colorectal polyps.

• EPCAM
• colon polyps
• colorectal cancer
• immunohistochemistry
• lynch syndrome

• DNA mismatch repair
• Hereditary non-polyposis colorectal cancer
• constitutional epimutation
• familial colorectal cancer type X
• genomic instability
• germline mutation
• lynch syndrome

EpCAM, a carcinoma cell-surface marker protein and a therapeutic target, has been primarily addressed as a cell adhesion molecule. With regard to recent discoveries of its role in signaling with implications in cell proliferation and differentiation, and findings contradicting a direct role in mediating adhesion contacts, we provide a comprehensive and updated overview on the available structural data on EpCAM and interpret it in the light of recent reports on its function. First, we describe the structure of extracellular part of EpCAM, both as a subunit and part of a cis-dimer which, according to several experimental observations, represents a biologically relevant oligomeric state. Next, we provide a thorough evaluation of reports on EpCAM as a homophilic cell adhesion molecule with a structure-based explanation why direct EpCAM participation in cell–cell contacts is highly unlikely. Finally, we review the signaling aspect of EpCAM with focus on accessibility of signaling-associated cleavage sites.

• Keywords: EpCAM
• adhesion
• dimer
• disease
• regulated intramembrane proteolysis
• signaling
• structure
• transmembrane protein

• Animals
• Disease
• Epithelial Cell Adhesion Molecule/chemistry
• Epithelial Cell Adhesion Molecule/metabolism
• Humans
• Models, Molecular
• Protein Multimerization
• Proteolysis
• Signal Transduction

Despite recent findings that epithelial cell adhesion molecule (EPCAM) deletions can cause Lynch syndrome (LS), its clinical characteristics are still unknown. We present the first case of ileum cancer in a patient with germline EPCAM gene deletion, which was discovered during ovarian tumor surgery.

A 59-year-old woman presented with a history of colon cancer occurring at 38 and 55 years old. Five of her siblings had a history of colon cancer, and an elder sister had confirmed LS. As imaging examination revealed an ovarian tumor, and we performed hysterectomy and bilateral salpingo-oophorectomy. Careful observation during surgery revealed a cherry-sized tumor in the ileum, prompting partial ileal resection. Pathological examination showed the ovarian tumor to be a metastasis of ileum cancer. Genetic testing with blood-relative information using multiplex ligation-dependent probe amplification showed EPCAM exons 8 and 9 deletions, confirming LS. The patient received adjuvant chemotherapy with CAPOX (capecitabine and oxaliplatin) and has remained disease-free for 24 months.

We were fortunate to identify ileum cancer that would have been difficult to find preoperatively through careful observation during ovarian tumor surgery and successfully treated the patient by using surgical resection and CAPOX chemotherapy. When treating patients with hereditary cancer syndromes including LS, we should keep all associated cancers in mind.

• EPCAM
• Ileum cancer
• Lynch syndrome
• Ovarian metastases

• Brain tumor
• CMMRD
• Cancer predisposition syndrome
• MMR

• Adenomatous Polyposis Coli/complications
• Adenomatous Polyposis Coli/pathology
• Brain Neoplasms/genetics
• Genetic Predisposition to Disease
• Humans

• DNA mismatch repair
• TP53
• adrenal tumor

• 2017/26345-5 Fundação de Amparo à Pesquisa do Estado de São Paulo

• Lynch syndrome
• MSH2
• chemotherapy resistance
• genetic variation
• mismatch repair gene

• Lynch syndrome
• cancer screening
• colorectal cancer
• colorectal surgery
• hereditary cancer
• immunohistochemistry

• congenital tufting enteropathy
• differentiation
• enteroid
• epithelial cell adhesion molecule

• Clinical exome sequencing
• Comparative effectiveness
• Hereditary colorectal cancer/polyposis

• Adenomatous Polyposis Coli/diagnosis
• Adenomatous Polyposis Coli/genetics
• Aged
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• Communication
• Comparative Effectiveness Research
• Confidentiality
• Cost-Benefit Analysis
• Exome
• Female
• Genetic Predisposition to Disease/genetics
• Health Resources/statistics & numerical data
• Health Services/statistics & numerical data
• Humans
• Male
• Middle Aged
• Research Design
• Sequence Analysis, DNA
• Socioeconomic Factors

• U01 HG006507 NHGRI NIH HHS
• U24 HG007307 NHGRI NIH HHS
• U01 HG010233 NHGRI NIH HHS
• K12 HS021686 AHRQ HHS
• U01 HG007307 NHGRI NIH HHS

• Constitutional mismatch repair deficiency
• Immune checkpoint inhibitor
• Lynch syndrome
• Microsatellite instability
• Mismatch repair gene

Inherited epimutations of Mismatch Repair (MMR) genes are responsible for Lynch Syndrome (LS) in a small, but well defined, subset of patients. Methylation of the MSH2 promoter consequent to the deletion of the upstream EPCAM gene is found in about 1%–3% of the LS patients and represents a classical secondary, constitutional and tissue‐specific epimutation. Several different EPCAM deletions have been reported worldwide, for the most part representing private variants caused by an Alu‐mediated recombination.

712 patients with suspected LS were tested for MMR mutation in our Institute. EPCAM deletions were detected by multiplex ligation‐dependent probe amplification (MLPA) and then defined by Long‐Range polymerase chain reaction (PCR)/Sanger sequencing. A comprehensive molecular characterization of colorectal cancer (CRC) tissues was carried out by immunohistochemistry of MMR proteins, Microsatellite Instability (MSI) assay, methylation specific MLPA and transcript analyses. In addition, somatic deletions and/or variants were investigated by MLPA and next generation sequencing (NGS).

An EPCAM deletion was found in five unrelated probands in Italy: variants c.556‐490_*8438del and c.858+1193_*5826del are novel; c.859‐1430_*2033del and c.859‐670_*530del were previously reported. All probands were affected by CRC at young age; tumors showed MSI and abnormal MSH2/MSH6 proteins expression. MSH2 promoter methylation, as well as aberrant in‐frame or out‐of‐frame EPCAM/MSH2 fusion transcripts, were detected in CRCs and normal mucosae.

An EPCAM deletion was the causative variant in about 2% of our institutional series of 224 LS patients, consistent with previously estimated frequencies. Early age and multiple CRCs was the main clinical feature of this subset of patients.

• EPCAM
• MSH2
• Lynch Syndrome
• deletion
• epigenetics
• methylation

• Colorectal cancer
• Endometrial cancer
• Hereditary cancer
• Hereditary nonpolyposis colorectal cancer
• Lynch syndrome
• Mismatch repair

• EPCAM
• Lynch syndrome
• congenital tufting enteropathy
• genotype-phenotype correlation
• in silico simulation
• protein modeling

• Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
• Colorectal Neoplasms, Hereditary Nonpolyposis/pathology
• Diarrhea, Infantile/genetics
• Diarrhea, Infantile/pathology
• Epithelial Cell Adhesion Molecule/chemistry
• Epithelial Cell Adhesion Molecule/genetics
• Epithelial Cells/metabolism
• Genetic Association Studies
• Humans
• Malabsorption Syndromes/genetics
• Malabsorption Syndromes/pathology
• Models, Molecular
• MutS Homolog 2 Protein/genetics
• Mutation, Missense/genetics
• RNA Splice Sites/genetics

• R01 DK107764 NIH HHS
• R01 GM26017 NIH GM
• RC2 DK118640 NIDDK NIH HHS
• R01 DK107764 NIDDK NIH HHS
• K08 DK078672 NIDDK NIH HHS
• P30 DK041301 NIDDK NIH HHS
• R01 CA072851 NCI NIH HHS
• T32 DK007202 NIH HHS
• R01 DK083762 NIDDK NIH HHS
• DK083762 NIH HHS
• RT2-01985 California Institute for Regenerative Medicine
• R01 CA72851 NIH CA
• Ludwig Institute for Cancer Research
• NIH
• California Institute for Regenerative Medicine
• Ludwig Institute for Cancer Research

• Lynch syndrome
• colorectal cancer
• mismatch repair
• physical activity

• Adult
• Cohort Studies
• Colorectal Neoplasms/etiology
• Colorectal Neoplasms, Hereditary Nonpolyposis/complications
• Colorectal Neoplasms, Hereditary Nonpolyposis/rehabilitation
• DNA Repair Enzymes/genetics
• Exercise Therapy/adverse effects
• Female
• Follow-Up Studies
• Humans
• Male
• Middle Aged
• Mutation
• Prognosis
• Registries
• Risk Factors
• Young Adult

• P30 CA016672 NCI NIH HHS
• U01 CA074799 NCI NIH HHS
• R25 CA056452 NCI NIH HHS
• U24 CA074794 NCI NIH HHS
• N01PC35137 NCI NIH HHS
• U24 CA074806 NCI NIH HHS
• U01 CA167551 NCI NIH HHS
• HHSN261201300012I NCI NIH HHS
• K07 CA160753 NCI NIH HHS
• N01PC35142 NCI NIH HHS
• K07 CA222060 NCI NIH HHS
• U01 CA097735 NCI NIH HHS
• U01 CA074783 NCI NIH HHS
• U24 CA074799 NCI NIH HHS
• U24 CA074783 NCI NIH HHS
• N01 CN067009 NCI NIH HHS
• U24 CA097735 NCI NIH HHS
• U01 CA074794 NCI NIH HHS
• K05 CA152715 NCI NIH HHS
• UM1 CA167551 NCI NIH HHS
• U01 CA074806 NCI NIH HHS
• U24 CA074800 NCI NIH HHS
• P30 CA071789 NCI NIH HHS
• U01 CA074800 NCI NIH HHS

• Choice Behavior
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/psychology
• Female
• Genetic Testing
• Humans
• Male
• Middle Aged
• Patient Preference
• Exome Sequencing

• U01 AG047109 NIA NIH HHS
• U01 HG006507 NHGRI NIH HHS
• U01 HG007307 NHGRI NIH HHS
• U01 HG010233 NHGRI NIH HHS

Lynch syndrome is an autosomal dominant disorder that predisposes individuals affected to certain malignancies. Colon and endometrial cancers are the malignancies most highly associated with Lynch syndrome. However, growing body of evidence links Lynch syndrome to urological cancers.

This review aims to clarify the type of urological malignancies that fall under the Lynch-associated cancer spectrum.

Using PRISMA guidelines, a systematic search between January 1990 to February 2018, was conducted using the MEDLINE database with the application of the following MESH terms: colorectal neoplasms, hereditary nonpolyposis; DNA mismatch repair; urologic neoplasms; kidney pelvis; ureteral neoplasms; urinary bladder; carcinoma, transitional cell; prostatic neoplasms; testicular neoplasms.

Upper tract urothelial cancers are well established under the Lynch spectrum. Increasing evidence supports its association with prostate cancer. However, there is, inconclusive and limited evidence for an association with bladder and testicular cancer.

The evidence underpinning certain urological malignancies associated with Lynch syndrome has expanded in recent years. Our review may assist in providing a summary of the current standing in literature. However, we recommend further investigations to better clarify associations, particularly with prostate, bladder and testicular cancer.

• -testicular neoplasms
• Colorectal neoplasms
• DNA mismatch repair
• carcinoma
• hereditary nonpolyposis
• kidney pelvis
• prostatic neoplasms
• transitional cell
• ureteral neoplasms
• urinary bladder
• urologic neoplasms

Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in one of the major genes involved in mismatch repair (MMR): MLH1,MSH2,MSH6 and more rarely, PMS2. Recently, germline deletions in EPCAM have been also associated to the syndrome. Most of the pathogenic MMR mutations found in LS families occur in MLH1 or MSH2. Gene variants include missense, nonsense, frameshift mutations, large genomic rearrangements and splice‐site variants and most of the studies reporting the molecular characterization of LS families have been conducted outside South America. In this study, we analyzed 60 unrelated probands diagnosed with colorectal cancer and LS criteria. Testing for germline mutations and/or rearrangements in the most commonly affected MMR genes (MLH1, MSH2, EPCAM and MSH6) was done by Sanger sequencing and MLPA. Pathogenic or likely pathogenic variants were identified in MLH1 or MSH2 in 21 probands (35.0%). Of these, approximately one‐third were gene rearrangements. In addition, nine variants of uncertain significance (VUS) were identified in 10 (16.6%) of the sixty probands analyzed. Other four novel variants were identified, only in MLH1. Our results suggest that MSH6 pathogenic variants are not common among Brazilian LS probands diagnosed with CRC and that MMR gene rearrangements account for a significant proportion of the germline variants in this population underscoring the need to include rearrangement analysis in the molecular testing of Brazilian individuals with suspected Lynch syndrome.

• Colorectal cancer
• Lynch syndrome
• MMR genes

• Adult
• Aged
• Aged, 80 and over
• Brazil
• Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
• DNA-Binding Proteins/genetics
• Epithelial Cell Adhesion Molecule/genetics
• Female
• Gene Frequency/genetics
• Genetic Predisposition to Disease/genetics
• Genetic Testing
• Germ-Line Mutation/genetics
• High-Throughput Nucleotide Sequencing
• Humans
• Male
• Middle Aged
• MutL Protein Homolog 1/genetics
• MutS Homolog 2 Protein/genetics
• Young Adult