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Background & Aims Hereditary factors play a role in the development of colorectal cancer (CRC). Identification of germline predisposition can have implications on treatment and cancer prevention. This study aimed to determine the prevalence of pathogenic germline variants (PGVs) in CRC patients using a universal testing approach, association with clinical outcomes, and the uptake of family variant testing. Methods We performed a prospective multisite study of germline sequencing using a more than 80-gene next-generation sequencing platform among CRC patients (not selected for age or family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020. Results Of 361 patients, the median age was 57 years (SD, 12.4 y), 43.5% were female, 82% were white, and 38.2% had stage IV disease. PGVs were found in 15.5% (n = 56) of patients, including 44 in moderate- and high-penetrance cancer susceptibility genes. Thirty-four (9.4%) patients had incremental clinically actionable findings that would not have been detected by practice guideline criteria or a CRC-specific gene panel. Only younger age at diagnosis was associated with the presence of PGVs (odds ratio, 1.99; 95% CI, 1.12–3.56). After a median follow-up period of 20.7 months, no differences in overall survival were seen between those with or without a PGV (P = .2). Eleven percent of patients had modifications in their treatment based on genetic findings. Family cascade testing was low (16%). Conclusions Universal multigene panel testing in CRC was associated with a modest, but significant, detection of heritable mutations over guideline-based testing. One in 10 patients had changes in their management based on test results. Uptake of cascade family testing was low, which is a concerning observation that warrants further study.

Cutaneous findings are commonly associated with underlying gastrointestinal disorders and, in many instances, may be the first manifestation. Many such syndromes have incomplete penetrance and variable expressivity, making them difficult to recognise. Skin manifestations may be an easily recognised feature of the underlying disorder. Most of these syndromes are hereditary but not all are associated with malignancies; either benign or premalignant extraintestinal lesions can be the initial manifestation. Some involve a single organ system, while others involve multiple organs of the gastrointestinal tract. In this review, we have focused on Lynch syndrome (hereditary nonpolyposis colon cancer and Muir-Torre syndrome), familial adenomatous polyposis, the hamartomatous polyposis syndromes that include Peutz-Jeghers syndrome and the PTEN hamartoma syndromes, which include Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome and, lastly, Cronkhite-Canada syndrome, which is not heritable. Some of these are associated with colorectal cancer, of which 15% are heritable. The majority are inherited in an autosomal dominant fashion. These syndromes are uncommon. However, because of the strong association with the cutaneous findings, early detection and screening may be possible and are key to decreasing the morbidity and mortality associated with them, for both the patient and family members. The clinical findings, epidemiological findings, underlying genetic alterations and pathological findings are reviewed.

Mismatch repair-deficient (MMRD) brain tumors are rare among primary brain tumors and can be induced by germline or sporadic mutations. Here, we report 13 MMRD-associated (9 sporadic and 4 Lynch syndrome) primary brain tumors to determine clinicopathological and molecular characteristics and biological behavior. Our 13 MMRD brain tumors included glioblastoma (GBM) IDH-wildtype (n = 9) including 1 gliosarcoma, astrocytoma IDH-mutant WHO grade 4 (n = 2), diffuse midline glioma (DMG) H3 K27M-mutant (n = 1), and pleomorphic xanthoastrocytoma (PXA) (n = 1). Next-generation sequencing using a brain tumor-targeted gene panel, microsatellite instability (MSI) testing, Sanger sequencing for germline MMR gene mutation, immunohistochemistry of MMR proteins, and clinicopathological and survival analysis were performed. There were many accompanying mutations, suggesting a high tumor mutational burden (TMB) in 77%, but TMB was absent in one case of GBM, IDH-wildtype, DMG, and PXA, respectively. MSH2, MLH1, MSH6, and PMS2 mutations were found in 31%, 31%, 31% and 7% of patients, respectively. MSI-high and MSI-low were found in 50% and 8% of these gliomas, respectively and 34% was MSI-stable. All Lynch syndrome-associated GBMs had MSI-high. In addition, 77% (10/13) had histopathologically multinucleated giant cells. The progression-free survival tended to be poorer than the patients with no MMRD gliomas, but the number and follow-up duration of our patients were insufficient to get statistical significance. In the present study, we found that the most common MMRD primary brain tumor was GBM IDH-wildtype. The genetic profile of MMRD GBM was different from that of conventional GBM. MMRD gliomas with TMB and MSI-H may be sensitive to immunotherapy but resistant to temozolomide. Our findings can help develop better treatment options., The authors examined 13 mismatch repair-deficient (MMRD)-associated primary brain tumors to determine molecular characteristics and biological behavior. MMRD occurred after chemotherapy and radiotherapy in two cases. The genetic profile of MMRD glioblastoma was different from that of conventional glioblastoma. Half of the MMRD-gliomas and all Lynch syndrome-associated GBMs were high in microsatellite instability. These tumors had high mutational burdens and tended to have shorter progression-free survival than glioma without MMRD.

Universal screening of endometrial cancer for underlying Lynch syndrome (LS) using DNA mismatch repair immunohistochemistry (MMR IHC) has been recommended. The objective of this study was to assess the feasibility and outcomes of using office endometrial samplings in a community LS screening program.A community laboratory adopted Cancer Care Ontario's LS screening recommendations. All new endometrial cancers in women aged70 years were screened for LS using MMR IHC and MLH1 promoter methylation testing cascade for MLH1/PMS2-deficient cases. This retrospective validation study analyzes the first year's results.Of 693 new endometrial cancers, 467 (67.4%) were eligible for LS screening. Both MMR IHC and MLH1 promoter methylation testing were conclusive in98% of cases. MMR deficiency (MMRd), which includes LS screen-positive cases, was identified in 25.9% of patients (121/467). LS screen-positive tumours comprised 5.9% (27/467) of all cases.Endometrial samplings from community practice are suitable for pre-operative LS screening. This testing can identify MMRd endometrial cancers with significant prognostic implications. Approximately 1 in 20 Ontario women70 years of age with endometrial cancer screen positive for LS. Pre-operative and/or operative assessment for co-existent colonic neoplasms needs to be considered in this high-risk group. In addition, these women should be referred to genetic counselling.

Screening for colorectal cancer (CRC) in Lynch syndrome enables early detection and likely cancer prevention. CRC screening guidelines have evolved from universal to gene-specific recommendations based on lifetime neoplasia risks. Regular screening for Lynch syndrome reduces CRC-related mortality; however, high CRC incidence during regular colonoscopy screening suggests the possibility of nonpolypoid carcinogenesis. Colonoscopy is the primary modality for screening for Lynch syndrome with mixed and emerging data on quality metrics, chromoendoscopy, artificial intelligence, and nonendoscopic modalities. Screening adherence varies across studies. In this review, we present the current state of CRC screening recommendations, outcomes, and modalities in Lynch syndrome.

Secondary prevention of colorectal neoplasia with chemoprevention is long-studied area of research and clinical use in patients with the 2 most common hereditary colorectal cancer syndromes including Lynch syndrome and familial adenomatous polyposis. No medication is currently approved for use for the prevention of colorectal polyps or cancer in either the general population or individuals with the hereditary colorectal cancer syndromes. Emerging data in animal models and limited data in humans suggest vaccines may be the next breakthrough for neoplasia prevention in patients with hereditary colorectal cancer. Clinicians must acknowledge chemoprevention is an adjunct and does not supplant endoscopic surveillance.

Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome caused by pathogenic germline variants (PGV) in any of the 4 DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, or deletions in EPCAM. LS leads to an increased risk of intestinal and extraintestinal cancers, of which colorectal and endometrial cancers are the most common. Individuals at risk for LS can be identified by using clinical criteria, prediction models, and universal tumor testing. Understanding each of these tools, including limitations and mimics of LS, is essential to the early identification of at-risk individuals.

Although environmental factors such as Helicobacter pylori, tobacco, and diet are major contributors to the development of gastric cancer (GC) worldwide, it is estimated that up to 5% to 10% of GC cases are due to an underlying hereditary susceptibility caused by germline pathogenic variants. Hereditary diffuse gastric cancer (HDGC) caused by germline pathogenic variants in the CDH1 gene is the principal familial GC syndrome. However, other well-established hereditary gastrointestinal syndromes have been associated with an increased risk of GC. In this review, we will discuss the latest insights and advances in our understanding of GC associated with Lynch syndrome (LS), familial adenomatous polyposis (FAP), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), Li-Fraumeni syndrome (LFS), Peutz-Jeghers syndrome (PJS), and juvenile polyposis syndrome (JPS). We will also discuss the emergence of new associations of the homologous recombination pathway genes (BRCA1, BRCA2) with GC.

Purpose: How primary care providers (PCPs) respond to genomic secondary findings (SFs) of varying clinical significance (pathogenic, uncertain significance (VUS), or benign) is unknown. Methods: We randomized 148 American Academy of Family Physicians members to review three reports with varying significance for Lynch syndrome. Participants provided open-ended responses about the follow-up they would address and organized the SF reports and five other topics in the order they would prioritize responding to them (1=highest priority, 6=lowest priority). Results: PCPs suggested referrals more often for pathogenic variants or VUSs than benign variants (72% vs 16%, p0.46). SF reports were prioritized highest for pathogenic variants (2.7 for pathogenic variants, 3.6 for VUSs, 4.3 for benign variants, all p≤0.014). Conclusions: Results suggest that while PCPs appreciated the differences in clinical significance, disclosure of VUSs as SFs would substantially increase downstream health care utilization.

In the absence of an effective screening test, women with a high genetic predisposition for ovarian cancer are recommended to undergo risk-reducing bilateral salpingo-oophorectomy (RRBSO) once childbearing is complete. This reduces the risk of ovarian cancer by up to 96%, but can result in undesirable side effects, including menopausal symptoms and sexual dysfunction. We have performed a systematic review and meta-analysis to investigate the effect of RRBSO on sexual function in women at high risk of breast/and or ovarian cancer.A literature search of the AMED (Allied and complementary medicine), Embase and Medline databases was performed, using search terms including sexual function, risk reducing and oophorectomy. Results were filtered according to the PRISMA protocol. Quality assessment of studies was performed using the Newcastle-Ottawa scale. Data were pooled in meta-analysis.There were 21 eligible studies, 10 of which reported sufficient data for meta-analysis. Most studies were retrospective cohort or observational studies. Fifteen of the 21 studies (71%) reported a negative impact of RRBSO on sexual function. Participant numbers ranged from 37 to 1522. Meta-analysis was performed with studies including 3201 patients. This demonstrated that RRBSO has a statistically significant negative impact on sexual function (SMD -0.63, [-0.82, -0.44], p = 0.03). There was a trend towards reduced sexual pleasure and increased discomfort but this did not reach statistical significance. There was minimal change in the frequency of sex. There was a significant increase in vaginal dryness post-RRBSO (SMD 9.25, [3.66, 14.83], p 0.00001). There was no significant difference in sexual function between pre-menopausal and post-menopausal RRBSO. Hormone replacement therapy (HRT) did not abolish this negative impact.Sexual function declines post RRBSO, independent of menopausal status. Comprehensive pre-operative counselling regarding anticipated menopausal and sexual symptoms is key to setting realistic patient expectations and minimising post-operative distress. Information and support regarding management of these side effects should be available to all patients.

Objective To improve prostate cancer screening for high-risk men, we developed an early detection clinic for patients at high genetic risk of developing prostate cancer. Despite the rapidly growing understanding of germline variants in driving aggressive prostate cancer and the increased availability of genetic testing, there is little evidence surrounding how best to screen these men. Methods We are reporting on the first 45 patients enrolled, men between the ages of 35–75, primarily with known pathogenic germline variants in prostate cancer susceptibility genes. Screening consists of an intake lifestyle survey, PSA, DRE, and SelectMDx urine assay. A biopsy was recommended for any of the following indications: 1) abnormal DRE, 2) PSA above threshold, or 3) SelectMDx above threshold. The primary outcomes were number needed to screen, and number needed to biopsy to diagnose a patient with prostate cancer. Results Patients enrolled in the clinic included those with BRCA1 (n=7), BRCA2 (n=16), Lynch Syndrome (n=6), and CHEK2 (n = 4) known pathogenic germline variants. The median age and PSA were 58 (range 35–71) and 1.4 ng/ml (range 0.1–11.4 ng/ml), respectively. 12 patients underwent a prostate needle biopsy and there were 4positive biopsies for prostate cancer. Conclusion These early data support the feasibility of opening a dedicated clinic for men at high genetic risk of prostate cancer. This early report on the initial enrollment of our long-term study will help optimize early detection protocols and provide evidence for personalized prostate cancer screening in men with key pathogenic germline variants.

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and 30% of all cases of CRC are believed to have a familial component and up to one-third of these (10%) are hereditary. Pathogenic germline variants in multiple genes have been associated with predisposition to hereditary CRC or polyposis. Lynch syndrome (LS) is the most common hereditary CRC syndrome, caused by variants in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 and is inherited in a dominant manner. Heritable conditions associated with colonic polyposis include familial adenomatous polyposis (FAP) associated with APC pathogenic variants, MUTYH-associated polyposis (MAP) caused by biallelic MUTYH pathogenic variants, and polymerase proofreading-associated polyposis (PPAP) caused by POLE or POLD1 pathogenic variants. Given the overlapping phenotypes of the cancer syndromes along with the limited sensitivity of using clinical criteria alone, a multigene panel testing approach to diagnose these conditions using next-generation sequencing (NGS) is effective and efficient. This technical standard is not recommended for use in the clinic for patient evaluation. Please refer to National Comprehensive Cancer Network (NCCN) clinical practice guidelines to determine an appropriate testing strategy and guide medical screening and management. This 2021 edition of the American College of Medical Genetics and Genomics (ACMG) technical standard supersedes the 2013 edition on this topic.

Colorectal carcinoma is one of the most common cancer types in men and women, responsible for both the third highest incidence of new cancer cases and the third highest cause of cancer deaths. In the last several decades, the molecular mechanisms surrounding colorectal carcinoma's tumorigenesis have become clearer through research, providing new avenues for diagnostic testing and novel approaches to therapeutics. Laboratories are tasked with providing the most current information to help guide clinical decisions. In this review, we summarize the current knowledge surrounding colorectal carcinoma tumorigenesis and highlight clinically relevant molecular testing.

Importance Thymic carcinoma (TC) is a rare aggressive tumour occurring in adults characterised by one of the lowest tumor mutational burdens (TMB). Microsatellite instability (MSI) is a mutational signature, caused by defects in the DNA MisMatch Repair (MMR) system, that predicts benefit from immunotherapy and causes high TMB. Fragmentary and unstructured evidence of these conditions co-occurring are reported in literature. Objective Review available data on the co-occurrence of these two conditions and determine its frequency in our institute case series. Design We performed a systematic analysis of literature and a retrospective evaluation of all the cases of TET treated at our institution from 2000 to 2020, selecting patients with a medical history of multiple tumours to enhance a priori probability of identifying cases with underlying predisposition. Results Literature yielded 3 cases of patients with MSI TC, for which MMR gene alteration was reported. None of them received immunotherapy. Of 366 patients with TETs treated in our institute, 32 had a medical history of multiple tumours and 25 of 32 (19 thymomas and 6 TCs) had available tissue for MMR analysis. One patient with TC showed a high TMB, and MSI due to MLH1 mutation and was treated in a phase II study with avelumab and axitinib combination obtaining a long-lasting partial response. MLH1 alterations are shared across MSI TC cases. Conclusions and relevance This analysis highlights the usefulness of MSI testing in patients with TC. The observation of cases of TC occurring in patients with Lynch syndrome and the unexpected homogeneity of gene alterations support further investigation.

Approximately 10% of patients with gastric cancer show familial aggregation and up to 3% are related to an inherited cancer syndrome. There are multiple germline pathogenic variants and cancer syndromes associated with an increased risk of gastric cancer. Appropriate assessment of familial and genetic risk may allow a personalized approach to gastric cancer prevention through screening and risk-reducing surgeries. The ability to better identify carriers with pathogenic genetic variants associated with gastric cancer before a diagnosis of cancer requires effective genetic risk assessment and testing, followed by optimal screening and surveillance recommendations to further reduce the morbidity and mortality.

Lynch syndrome (LS), is the most common hereditary colorectal cancer syndrome. However, it is poorly characterized in Brazil. Therefore, we aimed to determine the spectrum of pathogenic variants in Mismatch Repair (MMR) genes and investigate the MLH1 promotor methylation role as a second hit in LS tumors. Tumor screening through microsatellite instability and immunohistochemistry for MMR proteins was performed in 323 cases who met clinical criteria. BRAF-V600E and MLH1 promoter methylation were analyzed for all MLH1-deficient tumors. Patients with MMR deficient tumor proceeded to germline genetic testing. MMR deficient tumors were detected in 41% of patients recruited. About half of patients carried a pathogenic germline variant. Two recurrent variants in MLH1 and three novel pathogenic variants were identified. Furthermore, pathogenic germline variants with concomitant somatic MLH1 hypermethylation were found in 6% of cases. Predictive genetic testing was offered to 387 relatives. Overall, 127 tumors were diagnosed in 100 LS patients, from 62 unrelated families. Our molecular data provide new information about the spectrum of MMR mutations, which contributes to a better characterization of LS in Brazil. Furthermore, we call attention to the possibility of failure in the diagnosis of germline MLH1 mutation carriers when somatic MLH1 hypermethylation is used to rule out LS.

A MSH6 3'UTR variant (c.*23_26dup) was found in 13 unrelated families consulted for Lynch/Muir-Torre Syndrome. This variant, which is very rare in the genomic databases, was absent in healthy controls and strongly segregated with the disease in the studied pedigrees. All tumors were defective for MSH2/MSH6/MSH3 proteins expression, but only MSH2 somatic pathogenic mutations were found in 5 of the 12 sequenced tumors. Moreover, we had no evidence of MSH6 transcript decrease in carriers, whereas MSH2 transcript was downregulated. Additional evaluations performed in representative carriers, including karyotype, arrayCGH and Linked-Reads whole genome sequencing, failed to evidence any MSH2 germline pathogenic variant. Posterior probability of pathogenicity for MSH6 c.*23_26dup was obtained from a multifactorial analysis incorporating segregation and phenotypic data and resulted >0.999, allowing to classify the variant as pathogenic (InSiGHT Class 5). Carriers shared a common haplotype involving MSH2/MSH6 loci, then a cryptic disease-associated variant, linked with MSH6 c.*23_26dup, cannot be completely excluded. Even if it is not clear whether the MSH6 variant is pathogenic per se or simply a marker of a disease-associated MSH2/MSH6 haplotype, all data collected on patients and pedigrees prompted us to manage the variant as pathogenic and to offer predictive testing within these families.

Sporadic synchronous endometrial (ECs) and ovarian cancers (OCs), although clinically considered to be independent primaries, have been shown to be clonally related and likely constitute metastases from each other. We sought to define whether synchronous ECs/OCs in patients with DNA mismatch repair (MMR)-deficiency syndromes would be clonally-related. We subjected synchronous ECs/OCs from four patients (LS3-LS6) with clinically confirmed Lynch syndrome (LS) and one patient with constitutional mismatch repair deficiency syndrome (CMMRD) to massively parallel sequencing targeting 468 cancer-related genes. Somatic mutations, copy number alterations (CNAs), clonal relatedness and clonal decomposition analyses were performed using previously described bioinformatics methods. All synchronous ECs/OCs analyzed were considered independent primaries based on clinicopathologic criteria. Sequencing analysis revealed that the ECs/OCs of three cases (LS2-CMMRD, L3, L4) harbored similar repertoires of somatic mutations and CNAs and were clonally-related. In these three cases, a subset of subclonal mutations in the EC became clonal in the OC, suggesting that the EC was likely the substrate from which the OC developed. LS5’s EC/OC had distinct mutational profiles but shared specific CNAs. In contrast, LS6’s EC/OC harbored distinct somatic mutation and lacked CNAs, consistent with each tumor constituting an independent primary lesion. In LS5 and LS6, PTEN mutations and PTEN loss of protein expression were found to be restricted to the EC. Finally, re-analysis of sequencing data of sporadic synchronous ECs/OCs supported the observations made in the current study that the directionality of progression is likely from the endometrium to the ovary. In conclusion, contrary to sporadic synchronous ECs/OCs, which are almost invariably clonally-related, ECs/OCs simultaneously involving the uterus and ovary in LS patients may represent distinct primary tumors. A subset of MMR-deficiency syndrome-related synchronous ECs/OCs, however, may originate from a single primary tumor at variance with their clinical diagnosis, with the endometrium being the likeliest site of origin. JSR-F was funded in part by a Breast Cancer Research Foundation grant, BW in part by Breast Cancer Research Foundation, Cycle for Survival and Stand Up To Cancer grants, F.P. partially by a National Institutes of Health/ National Cancer Institute K12 CA184746 grant, XM-G by AECC (grupos estables) and GC and MP by the Spanish Ministry of Economy and Competitiveness and co-funded by FEDER funds -a way to build Europe- (grant SAF2015-68016-R), CIBERONC and the Government of Catalonia (grant 2017SGR1282). XM-G, GC and MP thank CERCA Programme for institutional support. Research reported in this publication was supported in part by a Cancer Center Support Grant of the NIH/NCI (Grant No. P30CA008748).

Patients in whom mismatch repair (MMR)-deficient cancer develops in the absence of pathogenic variants of germline MMR genes or somatic hypermethylation of the MLH1 gene promoter are classified as having suspected Lynch syndrome (SLS). Germline whole-genome sequencing (WGS) and targeted and genome-wide tumor sequencing were applied to identify the underlying cause of tumor MMR deficiency in SLS. Germline WGS was performed on samples from 14 cancer-affected patients with SLS, including two sets of first-degree relatives. MMR genes were assessed for germline pathogenic variants, including complex structural rearrangements and noncoding variants. Tumor tissue was assessed for somatic MMR gene mutations using targeted, whole-exome sequencing or WGS. Germline WGS identified pathogenic MMR variants in 3 of the 14 cases (21.4%), including a 9.5-megabase inversion disrupting MSH2 in a mother and daughter. Excluding these 3 MMR carriers, tumor sequencing identified at least two somatic MMR gene mutations in 8 of 11 tumors tested (72.7%). In a second mother–daughter pair, a somatic cause of tumor MMR deficiency was supported by the presence of double somatic MSH2 mutations in their respective tumors. More than 70% of SLS cases had double somatic MMR mutations in the absence of germline pathogenic variants in the MMR or other DNA repair–related genes on WGS, and, therefore, were confidently assigned a noninherited cause of tumor MMR deficiency.

Context This systematic review aims to (1) characterize strategies used to identify individuals at increased risk for hereditary breast and ovarian cancer syndrome and Lynch syndrome outside of oncology and clinical genetic settings, (2) describe the extent to which these strategies have extended the reach of genetic services to underserved target populations, and (3) summarize indicators of the potential scalability of these strategies. Evidence acquisition Investigators searched PubMed, EMBASE, and PsycINFO for manuscripts published from October 2005 to August 2019. Eligible manuscripts were those published in English, those that described strategies to identify those at risk for hereditary breast and ovarian cancer syndrome or Lynch syndrome, those implemented outside of an oncology or genetic specialty clinic, and those that included measures of cancer genetic services uptake. This study assessed strategies used to increase the reach of genetic risk screening and counseling services. Each study was evaluated using the 16-item quality assessment tool, and results were reported according to the PRISMA guidelines. Evidence synthesis Of the 16 eligible studies, 11 were conducted in clinical settings and 5 in public health settings. Regardless of setting, most (63%, 10/16) used brief screening tools to identify people with a family history suggestive of hereditary breast and ovarian cancer syndrome or Lynch syndrome. When reported, genetic risk screening reach (range =11%–100%) and genetic counseling reach (range =11%–100%) varied widely across studies. Strategies implemented in public health settings appeared to be more successful (median counseling reach=65%) than those implemented in clinical settings (median counseling reach=26%). Most studies did not describe fundamental components relevant for broad scalability. Conclusions Efforts to expand cancer genomic services are limited outside of traditional oncology and genetic clinics. This is a missed opportunity because evidence thus far suggests that these efforts can be successful in expanding the reach of genetic services with the potential to reduce health inequities in access. This review highlights the need for accelerating research that applies evidence-based implementation strategies and frameworks along with process evaluation to understand barriers and facilitators to scalability of strategies with high reach.

Prostate cancer plays an undeniably prominent role in public health in our days and health systems. Its epidemiological impact is quantitatively very close to that of other tumors such as colon cancer and breast cancer, in which genetic counseling is part of their routine clinical practice, both in the initial evaluation and in the selection of therapeutic strategies. Hereditary cancer syndromes, breast/ovarian and Lynch syndrome are part of genetic counseling in these tumors. Currently, we also know that they can be associated to prostate cancer. The time has come to implement genetic counseling in prostate cancer from the earliest stages of its approach, from initial suspicion to the most advanced tumors. We present an updated review carried out by our interdisciplinary working group on scientific literature, clinical practice guidelines and consensus documents, aimed at the creation and drafting of a'Protocol for genetic counseling in prostate cancer' for the study of germline, with easy application in different healthcare settings. This protocol is currently being implemented in our routine practice and provides answers to 3 specific questions: Who should receive genetic counseling for prostate cancer? Which gene panel should be analyzed? How should counseling be done according to the results obtained? Other aspects about who should perform genetic counseling, ethical considerations and regulations are also collected.

Background\ud Lynch syndrome is an inherited genetic condition that is associated with an increased risk of cancer, including endometrial and colorectal cancer. We assessed the test accuracy of immunohistochemistry and microsatellite instability-based testing (with or without MLH1 promoter methylation testing) for Lynch syndrome in women with endometrial cancer.\ud \ud Methods\ud We conducted a systematic review of literature published up to August 2019. We searched bibliographic databases, contacted experts and checked reference lists of relevant studies. Two reviewers conducted each stage of the review.\ud \ud Results\ud Thirteen studies were identified that included approximately 3500 participants. None of the studies was at low risk of bias in all domains. Data could not be pooled due to the small number of heterogeneous studies. Sensitivity ranged from 60.7–100% for immunohistochemistry, 41.7–100% for microsatellite instability-based testing, and 90.5–100% for studies combining immunohistochemistry, microsatellite instability-based testing, and MLH1 promoter methylation testing. Specificity ranged from 60.9–83.3% (excluding 1 study with highly selective inclusion criteria) for immunohistochemistry, 69.2–89.9% for microsatellite instability-based testing, and 72.4–92.3% (excluding 1 study with highly selective inclusion criteria) for testing strategies that included immunohistochemistry, microsatellite instability-based testing, and MLH1 promoter methylation. We found no statistically significant differences in test accuracy estimates (sensitivity, specificity) in head-to-head studies of immunohistochemistry versus microsatellite instability-based testing. Reported test failures were rare.\ud \ud Conclusions\ud Sensitivity of the index tests were generally high, though most studies had much lower specificity. We found no evidence that test accuracy differed between IHC and MSI based strategies. The evidence base is currently small and at high risk of bias.

Objective Lynch syndrome is the most common cause of inherited endometrial cancer, attributable to germline pathogenic variants (PV) in mismatch repair (MMR) genes. Tumor microsatellite instability (MSI-high) and MMR IHC abnormalities are characteristics of Lynch syndrome. Double somatic MMR gene PV also cause MSI-high endometrial cancers. The aim of this study was to determine the relative frequency of Lynch syndrome and double somatic MMR PV. Methods 341 endometrial cancer patients enrolled in the Ohio Colorectal Cancer Prevention Initiative at The Ohio State University Comprehensive Cancer Center from 1/1/13–12/31/16. All tumors underwent immunohistochemical (IHC) staining for the four MMR proteins, MSI testing, and MLH1 methylation testing if the tumor was MMR-deficient (dMMR). Germline genetic testing for Lynch syndrome was undertaken for all cases with dMMR tumors lacking MLH1 methylation. Tumor sequencing followed if a germline MMR gene PV was not identified. Results Twenty-seven percent (91/341) of tumors were either MSI-high or had abnormal IHC indicating dMMR. As expected, most dMMR tumors had MLH1 methylation; (69, 75.8% of the dMMR cases; 20.2% of total). Among the 22 (6.5%) cases with dMMR not explained by methylation, 10 (2.9% of total) were found to have Lynch syndrome (6 MSH6, 3 MSH2, 1 PMS2). Double somatic MMR PV accounted for the remaining 12 dMMR cases (3.5% of total). Conclusions Since double somatic MMR gene PV are as common as Lynch syndrome among endometrial cancer patients, paired tumor and germline testing for patients with non-methylated dMMR tumor may be the most efficient approach for LS screening.

Introduction Identifying carriers of genetic mutations that increase the risk of developing cancer allows to adopt timely risk-reducing strategies. However, due to the elevated cost of genetic testing, few oncogenetics services are available in the Brazilian public health care system, especially in economically disadvantaged areas. Objective To describe the implementation of an oncogenetics service for patients suspected of hereditary cancer syndromes (HBOC and HNPCC) at a philanthropic referral oncology hospital in Northeastern Brazil, funded by the Ministry of Health's National Oncology Care Support Program (PRONON). Methods The service was implemented with the PDCA method (Plan, Do, Check and Act). Results During the first year of operation (starting in August 2018), 675 individuals were examined, of whom 272 patients and 98 family members were submitted to genetic testing. This included the collection of 338 DNA samples of which 300 were sequenced. The analysis identified 48 (17.1%) mutations for HBOC and 19 (6.8%) for HNPCC. Conclusion In one year, the oncogenetics service was able to benefit over 300 families by generating advanced molecular data which may be used for tailoring cancer prevention and management.

Objective To determine the feasibility and effectiveness of a quality improvement initiative (QI) to adopt universal screening for Lynch syndrome in uterine cancer patients at an institution that previously employed age-based screening. Methods Prior to the initiative, tumors of patients with uterine cancer diagnosed at age ≤ 60 years were screened for mismatch repair deficiency (MMR) and microsatellite instability (MSI). The QI process change model adopted universal testing of all uterine cancer specimens and implemented provider training, standardized documentation, and enhanced use of the electronic medical record (EMR). We compared screening rates, results of screening, follow up of abnormal results, and final diagnoses from the pre- and post-implementation periods. Results Pre- and post-implementation screening rates for women age ≤ 60 years at the time of diagnosis were 45/78 (57.7%) and 64/68 (94.5%), respectively. The screening rate for all patients with uterine cancer increased from 73/190 (38.4%) to 172/182 (94.5%). The rate of abnormal screening results increased from 15/190 (7.9%) to 44/182 (24.0%) cases. Genetics referral rates among screen positives increased from 3/15 (20.0%) to 16/44 (36.4%). Germline diagnoses increased from 2/190 (1.1%) with two Lynch syndrome diagnoses to 4/182 (2.2%) including three Lynch syndrome diagnoses and one BRCA1 germline diagnosis. The number of patients errantly not screened decreased from at least 32 patients to 3 patients after the intervention. Conclusions Adherence to screening guidelines significantly improved after interventions involving provider education, optimal use of the EMR, and simplification of screening indications. These interventions are feasible at other institutions and translatable to other screening indications., Highlights • Compliance with Lynch syndrome screening guidelines can be dramatically improved with straightforward interventions. • Universal screening for Lynch syndrome in uterine cancer patients is feasible. • Universal screening for Lynch syndrome identifies substantially more patients eligible for targeted treatments.

Summary The lack of functional evidence for the majority of missense variants limits their clinical interpretability and poses a key barrier to the broad utility of carrier screening. In Lynch syndrome (LS), one of the most highly prevalent cancer syndromes, nearly 90% of clinically observed missense variants are deemed “variants of uncertain significance” (VUS). To systematically resolve their functional status, we performed a massively parallel screen in human cells to identify loss-of-function missense variants in the key DNA mismatch repair factor MSH2. The resulting functional effect map is substantially complete, covering 94% of the 17,746 possible variants, and is highly concordant (96%) with existing functional data and expert clinicians’ interpretations. The large majority (89%) of missense variants were functionally neutral, perhaps unexpectedly in light of its evolutionary conservation. These data provide ready-to-use functional evidence to resolve the ∼1,300 extant missense VUSs in MSH2 and may facilitate the prospective classification of newly discovered variants in the clinic.

espanolEl adenocarcinoma ductal de pancreas es el mas comun de los tumores pancreaticos y, a pesar de ocupar la octava posicion en incidencia en Espana, representa la tercera causa de muerte por cancer. Entre los factores de riesgo para su aparicion se encuentran factores ambientales como el tabaco o el alcohol, patologias como la diabetes o factores geneticos como el sindrome de Lynch o las mutaciones en BRCA1 y BRCA2. Los pacientes con sospecha de cancer de pancreas deben ser rapidamente valorados, y es necesaria la coordinacion multidisciplinar para realizar un correcto diagnostico y abordaje terapeutico. La tomografia computadorizada (TC) establece la sospecha diagnostica y estadificacion. La ecoendoscopia con toma de muestra por puncion es el procedimiento de eleccion para la confirmacion histologica. Los tumores de pancreas se clasifican en cuatro subgrupos que definen el abordaje terapeutico: resecables, borderline resecables, irresecables y metastasicos. La cirugia es el tratamiento de eleccion siempre que sea posible. El tratamiento adyuvante con quimioterapia esta indicado en todos los casos. El abordaje de los tumores borderline resecable e irresecables es mas controvertido y se acepta el empleo de la terapia sistemica primaria seguido de tratamiento local. La enfermedad metastasica se trata con distintos esquemas de quimioterapia como FOLFIRINOX o gemcitabina con nab-paclitaxel. EnglishPancreatic ductal adenocarcinoma is the most common pancreatic tumor and, despite being in eighth in incidence in Spain, it is the third cause of death due to cancer. Risk factors for its onset include environmental factors such as tobacco or alcohol use, diseases such as diabetes, and genetic factors such as Lynch syndrome or BRCA1 and BRCA2 mutations. Patients who are suspected of having pancreatic cancer must be evaluated promptly. Multidisciplinary coordination is necessary in order to make a correct diagnosis and decide on a proper therapeutic approach. A computerized tomography (CT) scan can confirm a diagnostic suspicion and stage the disease. An echoendoscopy with a needle biopsy sample is the procedure of choice for histological confirmation. Pancreatic tumors are classified in four subgroups that determine the therapeutic approach: resectable, borderline resectable, unresectable, and metastatic. Surgery is the treatment of choice so long it is possible. Adjuvant treatment with chemotherapy is indicated in all cases. The approach to borderline resectable and unresectable tumors is more controversial. The use of a primary systemic therapy followed by local treatment is accepted. Metastatic disease is treated with different chemotherapy regimens such as FOLFIRINOX or gemcitabine with nab-paclitaxel.

Hereditary nonpolyposis colorectal cancer or Lynch syndrome is autosomal dominant cancer predisposition syndrome characterized by early onset of colorectal cancer and neoplasia in other organs. This condition typically caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. To date, a considerable number of MLH1 gene mutations have been found to be associated with Lynch syndrome. We were aimed at identifying a genetic mutation in an extended Iranian family affected by Lynch syndrome-related cancers. Here, we applied whole-exome sequencing to identifying mutation in the proband. Furthermore, we applied Sanger sequencing to validate the candidate variant. We found a heterozygous novel single nucleotide deletion (c.206delG) in the exon two of the MLH1 gene in the proband. Also, Sanger sequencing analysis showed that this mutation has segregated in all affected family members. The mutation (c.206delG:p.R69fs) may create a premature stop codon followed by the formation of a truncated (p.R69fs) Mlh1 protein. Our findings expand the mutational spectra of MLH1 gene related Lynch syndrome which is vital for screening and genetic diagnosis of the disease.

To evaluate clinicopathologic characteristics and survival impact associated with mismatch repair (MMR) deficient subgroups of endometrial cancer (EC) in patients undergoing universal screening for Lynch Syndrome.A retrospective cohort study using a prospectively maintained gynecologic oncology registry of patients who underwent surgery for EC was conducted. All pathology specimens underwent tumor testing using immunohistochemistry for MMR deficiency with reflex MLH1 promotor methylation testing. Tumors were classified as MMR-I (intact MMR expression), MMR-DM (MMR deficient due to MLH1 methylation), and MMR-DU (MMR deficient without MLH1 methylation). Univariate and multivariate analysis performed to determine factors associated with MMR-DM. Progression-free survival (PFS) and overall survival (OS) analyzed by stage and endometrioid subgroup.From 2012 to 2016, 1018 EC patients were identified and screened. Overall, 71.6% were classified as MMR-I, 23.8% MMR-DM, and 4.6% MMR-DU. In comparison to MMR-DU, MMR-DM tumors were associated with older age, postmenopausal status, lymphovascular space invasion, and pure endometrioid histology. Compared to MMR-I, MMR-DM tumors were associated with older age, endometrioid histology, lymphovascular space invasion, and higher grade on multivariable analysis. There was no difference in PFS and OS between the three groups overall. In patients with endometrioid EC, MMR-DM tumors were associated with lower PFS vs. MMR-I (HR:2.51, CI:1.54, 4.10, P 0.001). This effect persisted for stage I/II endometrioid EC (HR 2.66, CI:1.34, 5.26 p = 0.005). No difference in PFS or OS was noted among stage III/IV endometrioid tumors.MMR deficiency is associated with adverse prognostic factors and worse PFS among endometrioid tumors, particularly in early stage EC. MMR testing outside of LS screening has prognostic value, warranting consideration for inclusion as a biomarker in prospective clinical trials.

PURPOSE: To measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals. METHODS: We used targeted sequencing to detect pathogenic or likely pathogenic variants in 55 genes associated with autosomal dominant medically actionable conditions, among a population of 13,131 individuals aged 70 or older (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no previous diagnosis or current symptoms of cardiovascular disease, physical disability or dementia, and no current diagnosis of life-threatening cancer. Variant curation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards. RESULTS: One in 75 (1.3%) healthy elderly individuals carried a PV. This was lower than rates reported from population-based studies, which have ranged from 1.8% to 3.4%. We detected 20 PV carriers for Lynch syndrome (MSH6/MLH1/MSH2/PMS2) and 13 for familial hypercholesterolemia (LDLR/APOB/PCSK9). Among 7056 female participants, we detected 15 BRCA1/BRCA2 PV carriers (1 in 470 females). We detected 86 carriers of PVs in lower-penetrance genes associated with inherited cardiac disorders. CONCLUSION: Medically actionable PVs are carried in a healthy elderly population. Our findings raise questions about the actionability of lower-penetrance genes, especially when PVs are detected in the absence of symptoms and/or family history of disease.

Background & Aims Lynch syndrome is the most common inherited cause of colorectal cancer (CRC). Contemporary and mutation-specific estimates of CRC-risk in patients undergoing colonoscopy would optimize surveillance strategies. We performed a prospective national cohort study, using data from New Zealand, to assess overall and mutation-specific risk of CRC in patients with Lynch syndrome undergoing surveillance. Methods We performed a prospective study of 381 persons with Lynch syndrome in New Zealand (98 with Lynch-syndrome associated variants in MLH1, 159 in MSH2, 103 in MSH6, and 21 in PMS2). Participants were offered annual colonoscopy starting at age 25 y, and those who underwent 2 or more colonoscopies before December 31, 2017 were included in the final analysis. Patients with previous colonic resection, history of CRC or diagnosis of CRC at index colonoscopy were excluded. Results Study participants underwent 2061 colonoscopies during 2296 person-y; the median observation-period was 4.43 y and mean-age at enrollment was 43 y. Eighteen patients developed CRC (8 with variants in MLH1, 8 in MSH2, and 2 in MSH6) after a median follow-up period of 6.5 y (range 1–16 y). Eighty-three percent of patients had a surveillance colonoscopy in preceding 24 months before diagnosis of CRC; 94% were diagnosed with stage 0–II CRC and there was no CRC-related mortality. The overall-risk of developing CRC in the 5 y after first surveillance colonoscopy was 2.49% (95% CI, 1.18–5.23); cumulative risks for CRC in patients with Lynch syndrome-associated variants in MLH1, MSH2, or MSH6 by age 70 y were 17.7%, 17.8%, and 8.5%, respectively. Age-adjusted CRC-risk in patients with variants in MSH6 was lower than in MLH1 (hazard ratio, 0.2; 95% CI, 0.04–0.94; P = .02). Of patients with CRC, 33% had an adenomatous polyp resected from same segment in which a colorectal tumor later developed. Conclusions The risk of CRC in patients with Lynch syndrome-associated mutations in MSH6 or PMS2 was significantly lower than in patients with mutations in MLH1. Incomplete adenomatous polyp resection might be responsible for one third of surveillance-detected CRCs.

Upper tract urothelial carcinoma (UTUC) may arise in the setting of hereditary non-polyposis colorectal cancer (Lynch syndrome [LS]) or sporadically. Variable frequencies of microsatellite instability (MSI) were found in UTUC. For advanced solid MSI tumors, targeted therapy with programmed death-ligand 1 inhibitors is available. Therefore, we aimed to determine the prevalence of mismatch repair (MMR) protein loss and MSI in UTUC using a tissue microarray approach and further molecular and correlation analysis.We studied the immunohistochemical expression of MLH1, MSH2, MSH6, and PMS2 on tissue microarrays containing formalin-fixed, paraffin-embedded samples of 128 patients with UTUC. MSI analysis was performed in 79 cases with deficient MMR protein expression, and/or in patients aged 60 years and below, and/or other tumors possibly related to LS.Loss of MMR protein expression was seen in 24 (18.8%) of 128 cases. MSI analysis revealed MSI-high in 29, MSI-low in 7 cases. The Fisher exact test demonstrated significant differences between MSI and loss of MMR protein expression, clinically possible LS, tumor growth pattern, inverted growth pattern, and death (P .001, P .001, P = .002, P = .003, and P = .033, respectively). MSI does not appear to influence survival (overall and progression-free), but there was a significant shorter progression-free survival in MSI-high versus MSS patients who had received chemotherapy.The frequency of MSI in UTUC was 36 (28.1%) of 128 patients with a good accuracy of immunohistochemistry. In daily practice, MSI screening especially is recommended in patients with advanced UTUC and inverted papillary tumor growth pattern with the aim of screening patients for possible targeted therapy.

The objectives of this expert review are: (1) to prepare clinicians to recognize the presentation and evidence-based risk factors for young adult-onset colorectal cancer (CRC), defined as CRC diagnosed in individuals 18 -50 years of age; (2) to improve management for patients with young onset CRC. This review will focus on the following topics relevant to young adult-onset CRC: epidemiology and risk factors; clinical presentation; diagnostic and therapeutic management including options for colorectal and extra-colonic surgical intervention, chemotherapy and immune-oncology therapies; genetic testing and its potential impact on preimplantation genetics; fertility preservation; and cancer surveillance recommendations for these individuals and their family members.The evidence reviewed in this manuscript is a summation of relevant scientific publications, expert opinion statements, and current practice guidelines. BEST PRACTICE ADVICE 1: With the rising incidence of people developing CRC before 50 years of age, diagnostic evaluation of the colon and rectum is encouraged for all patients, irrespective of age, who present with symptoms that may be consistent with CRC, including but not limited to: rectal bleeding, weight loss, change in bowel habit, abdominal pain, iron deficiency anemia. BEST PRACTICE ADVICE 2: Clinicians should obtain family history of colorectal and other cancers in first and second degree relatives of patients with young adult-onset CRC and discuss genetic evaluation with germline genetic testing either in targeted genes based on phenotypic presentation or in multiplex gene panels regardless of family history. BEST PRACTICE ADVICE 3: Clinicians should present the role of fertility preservation prior to cancer-directed therapy including surgery, pelvic radiation, or chemotherapy BEST PRACTICE ADVICE 4: Clinicians should counsel patients on the benefit of germline genetic testing and familial cancer panel testing in the pre-surgical period to inform which surgical options may be available to the patient with young adult-onset CRC BEST PRACTICE ADVICE 5: Clinicians should consider utilizing germline and somatic genetic testing results to inform chemotherapeutic strategies BEST PRACTICE ADVICE 6: Clinicians should offer hereditary CRC syndrome specific screening for CRC and extra-colonic cancers only to young adult-onset CRC patients who have a genetically or clinically diagnosed hereditary CRC syndrome. For patients with sporadic young adult-onset CRC, extra-colonic screening and CRC surveillance intervals are the same as for patients with older adult-onset CRC.

Objective To report the frequency of Lynch syndrome (LS) in a cohort of patients from Southeast Brazil bearing endometrial cancer (EC), using a tumor screening universal approach. Methods A total of 242 endometrial carcinomas were screened by immunohistochemistry (IHC) and microsatellite instability (MSI) for detection of DNA mismatch repair deficiency (dMMR). MLH1 methylation was assessed to identify sporadic cases. Patients with dMMR tumors were recruited for germline variant analysis by next-generation sequencing of the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. Results Ninety-three out of 242 tumors (38.5%) were classified as dMMR based on MSI and IHC results. Of these, 54 cases were selected for germline analysis, and 37/54 (68.5%) were available for sequencing. Ten patients (10/37, 27%) harbored germline pathogenic or likely pathogenic variants, most of them in the MSH6 gene (4/10, 40%). Seven variants of uncertain significance were found. Eight novel germline variants were identified. The LS prevalence in our cohort was of at least 4.1%. LS patients presented lower mean age at cancer diagnosis compared with patients diagnosed with sporadic EC. Individuals with dMMR tumors, without germline pathogenic variants detected in LS-genes (“Lynch-like” syndrome), had an intermediate mean age at cancer diagnosis between LS and sporadic cases. Conclusion This is the first report of the LS prevalence in EC screened by a universal approach in Brazil. Our findings contribute to a better understanding of the mutational landscape of this syndrome in Brazil, which is relevant for improved identification, genetic counseling, prevention and control of cancer in LS.

Compare detection of Lynch syndrome in endometrial cancer between regions of a health care system with different screening strategies.A retrospective study of endometrial cancer (EC) cases from 2 regions of an integrated health care system (Kaiser Permanente Northern (KPNC) and Southern (KPSC) California). Within KPNC, immunohistochemistry tumor screening (IHC) was physician ordered and risk-based; within KPSC, IHC was universal and automated. Clinical risk factors associated with abnormal IHC and Lynch Syndrome (LS) were identified.During the study, there were 2045 endometrial cancers: 1399 in the physician-order group and 646 in the universal testing group. In the physician-order group: among womenage 60, 34% underwent IHC; 9.6% were abnormal, and 3% were possible LS after methylation testing; among women ≥60, 11% underwent IHC, 3% were abnormal and1% were possible LS. In the universal group, 87% of women age60 had IHC, 19.4% were abnormal, and 6% were possible LS; Among women age ≥60, 82% underwent IHC, 26% were abnormal, and 2% were possible LS. There were no differences in LS cases between the physician-order group and the universal group in either age strata (60: 3% vs. 3.6%, p=0.62; ≥60:1% vs. 1%, p=0.63) Factors associated with LS were younger age (odds ratio (OR) 0.11, 95% confidence interval (CI) 0.04-0.29) and lower body mass index (BMI), (OR 0.38 95% CI 0.18-0.80).Universal IHC screening did not result in increased LS detection in EC.

The pathogenesis of DNA mismatch repair (MMR)-deficient endometrial carcinoma (EC) is driven by inactivating methylation or less frequently mutation of an MMR gene (MLH1, PMS2, MSH2, or MSH6). This study evaluated the prognostic and clinicopathologic differences between methylation-linked and nonmethylated MMR-deficient endometrioid ECs. We performed MMR immunohistochemistry and methylation-specific multiplex ligation-dependent probe amplification, and classified 682 unselected endometrioid ECs as MMR proficient (MMRp, n = 438) and MMR deficient (MMRd, n = 244), with the latter subcategorized as methylated (MMRd Met) and nonmethylated tumors. Loss of MMR protein expression was detected in 35.8% of the tumors as follows: MLH1 + PMS2 in 29.8%, PMS2 in 0.9%, MSH2 + MSH6 in 1.3%, MSH6 in 2.8%, and multiple abnormalities in 0.9%. Of the 244 MMRd cases, 76% were methylation-linked. MMR deficiency was associated with older age, high grade of differentiation (G3), advanced stage (II-IV), larger tumor size, abundant tumor-infiltrating lymphocytes, PD-L1 positivity in immune cells and combined positive score, wild-type p53, negative L1CAM, ARID1A loss, and type of adjuvant therapy. MMRd-Met phenotype correlated with older age and larger tumor size, and predicted diminished disease-specific survival in the whole cohort. In the MMRd subgroup, univariate analysis demonstrated an association between disease-specific survival and disease stage II-IV, high grade (G3), deep myometrial invasion, lymphovascular invasion, ER negativity, and L1CAM positivity. In conclusion, MMR methylation profile correlates with clinicopathologic characteristics of endometrioid EC, and MMRd-Met phenotype predicts lower disease-specific survival. MMR deficiency, but not MLH1 methylation status, correlates with T-cell inflammation and PD-L1 expression.

Description The purpose of this American Gastroenterological Association Institute Clinical Practice Update is to describe the indications for screening for pancreas cancer in high-risk individuals. Methods The evidence reviewed in this work is based on reports of pancreas cancer screening studies in high-risk individuals and expert opinion. Best Practice Advice 1 Pancreas cancer screening should be considered in patients determined to be at high risk, including first-degree relatives of patients with pancreas cancer with at least 2 affected genetically related relatives. Best Practice Advice 2 Pancreas cancer screening should be considered in patients with genetic syndromes associated with an increased risk of pancreas cancer, including all patients with Peutz–Jeghers syndrome, hereditary pancreatitis, patients with CDKN2A gene mutation, and patients with 1 or more first-degree relatives with pancreas cancer with Lynch syndrome, and mutations in BRCA1, BRCA2, PALB2, and ATM genes. Best Practice Advice 3 Genetic testing and counseling should be considered for familial pancreas cancer relatives who are eligible for surveillance. A positive germline mutation is associated with an increased risk of neoplastic progression and may also lead to screening for other relevant associated cancers. Best Practice Advice 4 Participation in a registry or referral to a pancreas Center of Excellence should be pursued when possible for high-risk patients undergoing pancreas cancer screening. Best Practice Advice 5 Clinicians should not screen average-risk individuals for pancreas cancer. Best Practice Advice 6 Pancreas cancer screening in high-risk individuals should begin at age 50 years, or 10 years younger than the initial age of familial onset. Screening should be initiated at age 40 years in CKDN2A and PRSS1 mutation carriers with hereditary pancreatitis and at age 35 years in the setting of Peutz–Jeghers syndrome. Best Practice Advice 7 Magnetic resonance imaging and endoscopic ultrasonography (EUS) should be used in combination as the preferred screening modalities in individuals undergoing pancreas cancer screening. Best Practice Advice 8 The target detectable pancreatic neoplasms are resectable stage I pancreatic ductal adenocarcinoma and high-risk precursor neoplasms, such as intraductal papillary mucinous neoplasms with high-grade dysplasia and some enlarged pancreatic intraepithelial neoplasias. Best Practice Advice 9 Screening intervals of 12 months should be considered when there are no concerning pancreas lesions, with shortened intervals and/or the performance of EUS in 6–12 months directed towards lesions determined to be low risk (by a multidisciplinary team). EUS evaluation should be performed within 3–6 months for indeterminate lesions and within 3 months for high-risk lesions, if surgical resection is not planned. New-onset diabetes in a high-risk individual should lead to additional diagnostic studies or change in surveillance interval. Best Practice Advice 10 Decisions regarding therapy directed towards abnormal findings detected during screening should be made by a dedicated multidisciplinary team together with the high-risk individual and their family. Best Practice Advice 11 Surgical resection should be performed at high-volume centers. Best Practice Advice 12 Clinicians should consider discontinuing pancreas cancer screening in high-risk individuals when they are more likely to die of non-pancreas cancer–related causes due to comorbidity and/or are not candidates for pancreas resection. Best Practice Advice 13 The limitations and potential risks of pancreas cancer screening should be discussed with patients before initiating a screening program.

Early onset colorectal cancer (EOCRC) refers to colorectal cancer (CRC) in individuals under age 50. Although the incidence and mortality due to later onset CRC (≥50 years) has been declining over several decades, both are increasing in those under 50. EOCRC is more likely to occur in the distal colon and rectum. There are some unique pathologic and genetic features to these tumors; they are not usually associated with a germline mutation in a gene that predisposes to cancer, and at least some may have a distinct pathogenesis. Initiating CRC screening at an earlier age (40-45 years of age) would presumably detect more early stage and asymptomatic EOCRCs, but this would imply a major additional health care burden. The understanding of EOCRC and the optimal management approach to this problem are unsolved problems.

Lynch syndrome is most often caused by a germline mutation in one of four DNA mismatch repair (MMR) genes (MLH1, PMS2, MSH2, or MSH6) or EPCAM and is associated with a significantly increased risk of endometrial cancer in affected women. Although universal screening of endometrial cancer for Lynch syndrome is becoming increasingly common by various algorithms using MMR immunohistochemistry and/or microsatellite instability testing by PCR, establishing the diagnosis of Lynch syndrome can be still challenging. MMR-deficient nonneoplastic colonic crypts have been recently described in Lynch syndrome patients with colorectal carcinoma, and have been proposed to be a novel indicator of Lynch syndrome. Presence of MMR-deficient nonneoplastic endometrial glands have not yet been systematically evaluated in Lynch syndrome patients. We performed MMR protein immunohistochemistry in prophylactic hysterectomies and endometrial curettings/biopsies from 27 patients with known Lynch syndrome confirmed by germline mutation analysis. A total of 56 control benign endometrial tissues were also analyzed, and included benign endometrium adjacent to MMR-deficient sporadic (MLH1 promoter hypermethylated) endometrial carcinoma (n = 9), adjacent to MMR-intact sporadic endometrial carcinoma (n = 27), and normal endometrium from hysterectomies performed for benign disease (n = 20). MMR protein deficient nonneoplastic endometrial glands were identified in 70% (19 of 27) of Lynch syndrome patients. In all 19 cases the MMR protein loss was specific for the patients' known germline mutation. None of the control cases showed loss of MMR protein expression in nonneoplastic endometrium. Our findings suggest that MMR-deficient nonneoplastic endometrial glands may be a unique, specific marker of Lynch syndrome, and may provide an important insight into the pathogenesis of Lynch syndrome-associated endometrial cancer. Evaluation of MMR protein expression of benign background endometrium in endometrial cancer patients may be further explored as a possible useful addition to the Lynch syndrome screening algorithm.

Due largely to the rise in obesity and prolonged life expectancy, endometrial cancer (EC) rates have increased by 56% since the early 90s. Women at high risk (Lynch Syndrome) have a 12-47% lifetime risk of developing EC and professional societies recommend annual surveillance using transvaginal ultrasound (TVS) and endometrial biopsy (outpatients hysteroscopy) from the age of 30-35 years with hysterectomy from the age of 40 years. In women at low risk, screening is not currently advocated. The emerging data from Genome Wide Association studies (GWAS) in combination with epidemiological data may refine risk stratification in the future. In addition to screening, preventative approaches such as intrauterine progesterone may help reduce disease burden in those identified at 'higher risk'.

NTRK gene rearrangements are important to identify as predictors of response to targeted therapy in many malignancies. Only 0.16–0.3% of colorectal carcinomas (CRCs) harbor these fusions making universal screening difficult. We therefore investigated whether pan-Trk immunohistochemistry (IHC), mismatch repair deficiency (MMRd), and BRAFV600E mutation status could be used to triage molecular testing for NTRK gene rearrangements in CRC. CRCs from 4569 unselected patients underwent IHC in TMA format with two different anti-pan-Trk rabbit monoclonal antibodies. All positive cases were confirmed on whole sections and underwent RNA-sequencing. Pan-Trk IHC was positive in 0.2% of CRCs (9/4569). Both antibodies demonstrated similar staining characteristics with diffuse positive staining in all neoplastic cells. Of note 8/9 (89%) IHC positive cases were both MMRd (all showing MLH1/PMS2 loss) and lacked BRAFV600E mutation. That is, IHC was positive in 5.3% (8/152) MLH1/PMS2/BRAFV600E triple negative CRCs, but only 0.02% (1/4417) not showing this phenotype. All nine IHC positive CRCs demonstrated gene rearrangements (LMNA-NTRK1 in 5 CRCs, TPR-NTRK1, STRM-NTRK1, MUC2-NTRK2, and NTRK1 with an unknown partner in one each), suggesting close to 100% specificity for IHC in this sub-population. NTRK fusions were associated with right sided (p = 0.02), larger tumors (p = 0.029) with infiltrative growth (p = 0.021). As a part of universal Lynch syndrome screening many institutions routinely test all CRCs for MMRd, and then proceed to reflex BRAFV600E mutation testing in MLH1/PMS2 negative CRCs. We conclude that performing pan-Trk IHC on this preselected subgroup of MLH1/PMS2/BRAFV600E triple negative CRCs (only 3.3% of all CRC patients) is a resource effective approach to identify the overwhelming majority of CRC patients with NTRK gene fusions.

Germline mutations in cancer-susceptibility-genes (CSG) can dramatically increase womens' lifetime risk of ovarian, endometrial, breast and bowel cancers. Identification of unaffected carriers is important to enable proactive engagement with highly effective screening and preventive options to minimise cancer risk. Currently, a family-history model is used to identify individuals with CSGs. Complex regional referral guidelines specify the family-history criteria required before an individual is eligible for genetic-testing. This model is ineffective, resource intense, misses >50% CSG carriers, is associated with underutilisation of genetic-testing services and delays detection of mutation carriers. Although awareness and detection of CSG-carriers has improved, over 97% carriers remain unidentified. This reflects significant missed opportunities for precision-prevention. Population-based genetic-testing (PBGT) represents a novel healthcare strategy with the potential to dramatically improve detection of unaffected CSG-carriers along with enabling population risk-stratification for cancer precision-prevention. Several research studies have assessed the impact, feasibility, acceptability, long-term psychological outcomes and cost-effectiveness of population-based BRCA-testing in the Ashkenazi-Jewish population. Initial data on PBGT in the general-population is beginning to emerge and large implementation studies investigating PBGT in the general-population are needed. This review will summarise the current research into the clinical, psycho-social, health-economic, societal and ethical consequences of a PBGT model for women's cancer precision-prevention.

About 23% of adnexal tumors are related to a hereditary syndrome, most often hereditary breast and ovarian cancer syndrome or Lynch syndrome, responsible of epithelial tumors. However, the pathologist should be aware of rare hereditary syndromes responsible of non-epithelial ovarian tumors. Ovarian tumors associated with germline mutation of BRCA genes are essentially high-grade serous carcinomas of tubal origin, while those seen in Lynch syndrome are most often endometrioid or clear cell carcinomas. Sex-cord tumors associated with a familial predisposition are Sertoli-Leydig cell tumors in DICER syndrome and sex-cord tumors with annular tubules in Peutz-Jeghers syndrome. Small cell carcinoma of hypercalcemic type may be associated with a rhabdoid tumor predisposition syndrome 2. Finally, rare germ cell tumors have been reported related to ataxia telangiectasia. The recognition of these entities by pathologists is crucial. Even though the morphologic features pointing toward an inherited mutation may vary depending on the syndrome, the diagnosis may contribute to refer the patient for genetic counselling, modifying the management and follow-up of the patient and her family.

International audience; IntroductionPerioperative chemotherapy is the standard strategy for localized gastric cancers. Nevertheless, this strategy seems to be inefficient, if not deleterious, for patients with tumors harboring microsatellite instability (MSI) and/or mismatch repair deficiency (dMMR), a tumor phenotype predictive for the efficacy of immune checkpoint inhibitors (ICKi).AimThe GERCOR NEONIPIGA single-arm phase II study (NCT04006262; EUDRACT 2018-004712-22) aims at evaluating the efficacy of a peri-operative strategy with nivolumab and ipilimumab in neoadjuvant setting, then nivolumab alone after surgery for patients with resectable MSI/dMMR gastric cancer.Material and methodsMain inclusion criteria are: gastric and oesogastric junction adenocarcinoma (GOA), T2-T4, all N stage and M0, MSI/dMMR. Patients will be treated with nivolumab 240 mg Q2 W, 6 infusions, and ipilimumab 1 mg/kg Q6 W, 2 infusions in neoadjuvant setting. Following surgery, patients with TRG 1-2-3 (Mandard tumor regression grade), acceptable tolerance of neoadjuvant treatment and postoperative ECOG performance status 0–1, will be treated with adjuvant nivolumab 480 mg Q4 W, 9 infusions.ResultsThe primary endpoint is pathological complete response rate (pCR-R). Based on a Fleming design, with α = 5% and β = 20%, 27 patients have to be evaluated (H0 = 5%; H1 = 20%). Secondary endpoints include disease-free survival, overall survival and safety.ConclusionThis study is planned to include 32 patients to evaluate the pCR-R with the combination of nivolumab and ipilimumab in neoadjuvant setting for MSI/dMMR localized GOA. The MSI/MMR status should be systematically assessed on diagnostic biopsies of all GOA. If it meets its primary endpoint, the GERCOR NEONIPIGA study might mark a turning point in the management of localized MSI/dMMR GOA patients.; IntroductionLa chimiothérapie périopératoire est la stratégie de référence pour les cancers gastriques (CG) localisés, mais semble inefficace voire délétère pour les patients avec un cancer MSI/dMMR (microsatellites instables/MMR-déficient), biomarqueur prédictif de l’efficacité de l’immunothérapie.ObjectifL’essai de phase 2 mono-bras GERCOR NEONIPIGA (NCT04006262; EUDRACT 2018-004712-22) évalue l’efficacité du nivolumab plus ipilimumab en néo-adjuvant puis nivolumab seul en adjuvant pour les CG ou de la jonction œsogastrique (JOG) MSI/dMMR résécables.Matériel et méthodesLes principaux critères d’inclusion sont : CG/JOG, T2-4 tout N M0, MSI/dMMR. Les patients sont traités en néo-adjuvant par nivolumab 240 mg Q2 W, 6 perfusions, et ipilimumab 1 mg/kg Q6 W, deux injections. Les patients avec un degré de régression tumorale 1-3 selon Mandard, une tolérance acceptable du traitement néo-adjuvant et un indice de performance postopératoire ECOG 0-1 recevront neuf perfusions mensuelles de nivolumab 480 mg en adjuvant.RésultatsL’objectif principal est le taux de réponse complète pathologique (pCR). Selon un design de Fleming avec α = 5 % et β = 20 %, 27 patients évaluables sont à analyser (H0 = 5 % ; H1 = 20 %). Les critères secondaires de jugement sont la survie sans maladie, la survie globale et le profil de tolérance.ConclusionIl est prévu d’inclure 32 patients pour évaluer le taux de pCR pour les CG/JOG MSI/dMMR traités par nivolumab et ipilimumab néo-adjuvant. Le statut MSI/MMR doit être systématiquement analysé sur les biopsies diagnostiques de tout CG/JOG. L’étude NEONIPIGA pourrait marquer un tournant dans la prise en charge des CG/JOG MSI/dMMR si elle atteint son objectif principal.

Purpose Despite the rapid uptake of multigene panel testing (MGPT) for hereditary cancer predisposition, there is limited guidance surrounding indications for testing and genes to include. Methods To inform the clinical approach to hereditary cancer MGPT, we comprehensively evaluated 32 cancer predisposition genes by assessing phenotype-specific pathogenic variant (PV) frequencies, cancer risk associations, and performance of genetic testing criteria in a cohort of 165,000 patients referred for MGPT. Results We identified extensive genetic heterogeneity surrounding predisposition to cancer types commonly referred for germline testing (breast, ovarian, colorectal, uterine/endometrial, pancreatic, and melanoma). PV frequencies were highest among patients with ovarian cancer (13.8%) and lowest among patients with melanoma (8.1%). Fewer than half of PVs identified in patients meeting testing criteria for only BRCA1/2 or only Lynch syndrome occurred in the respective genes (33.1% and 46.2%). In addition, 5.8% of patients with PVs in BRCA1/2 and 26.9% of patients with PVs in Lynch syndrome genes did not meet respective testing criteria. Conclusion Opportunities to improve upon identification of patients at risk for hereditary cancer predisposition include revising BRCA1/2 and Lynch syndrome testing criteria to include additional clinically actionable genes with overlapping phenotypes and relaxing testing criteria for associated cancers.

Mismatch repair protein (MMR) immunohistochemistry is an important tool in screening for Lynch syndrome in colorectal cancer patients. Unusual staining patterns such as heterogeneous MSH6 staining have been reported in colorectal and endometrial cancers. We aim to better understand MSH6 staining heterogeneity in colorectal cancer by comparative sequencing of different tumor areas for MMR and DNA polymerase mutations. Whole-section slides of 1754 colorectal cancers were reviewed for heterogeneous MSH6 staining, defined as discrete tumor areas with abrupt loss of staining juxtaposed to tumor areas with retained staining. Nine cases (0.05%) demonstrated heterogeneous MSH6 staining; none received neoadjuvant therapy prior to the specimen collection. The area of tumor with loss of MSH6 expression ranged from 5% to 60% (average 22%). Four cases had enough tissue remaining in both retained and lost MSH6 areas to perform tumor sequencing on both areas. All 9 cases were negative for MSH6 germline mutation; MSH6 heterogeneous staining was seen in tumors with MLH1 or PMS2 abnormalities (6 cases of MLH1 methylation, 2 PMS2 germline mutation, 1 MLH1 germline mutation). In addition, case 1 also had a somatic POLD1 exonuclease domain mutation (p.Y405C) in the MSH6 loss area but not in the intact area. We recommend reporting MSH6 heterogeneous pattern as MSH6 staining is present with a comment stating that the heterogeneous pattern typically does not indicate germline mutation in MSH6 but is commonly associated with abnormality in another MMR gene such as MLH1 or PMS2, or even other DNA repair genes such as DNA polymerase.