MSH6 Pathogenic Variants Research Articles

Founder pathogenic variants in colorectal neoplasia susceptibility genes in Ashkenazi Jews undergoing colonoscopy

BackgroundColorectal neoplasia is one of the most common tumors affecting Western populations.MethodsIn this study we used a custom amplicon sequencing platform and an in-house bioinformatic pipeline to study constitutional DNA from two different case series of Ashkenazi Jews undergoing colonoscopy (n = 765). The first series all had pathologically confirmed colorectal adenomas and/or carcinoma. The second series consisted of persons who had undergone a colonoscopy within the five years prior to ascertainment, regardless of findings. Ninety-one percent of all patients were asymptomatic at the time of colonoscopy.ResultsIn the first group (n = 438), we identified 65 founder variants (56 in APC, 2 in GREM1, 3 in MSH2 and 4 in BLM). In the second group (n = 327), the findings were 30, nothing, 1 and 1, respectively, as well as 2 MSH6 variants.ConclusionsOverall, we found that 10 to 15% of Ashkenazi Jewish persons undergoing colonoscopy harbor variants of interest in colorectal and/or polyposis predisposition. This includes pathogenic variants in MSH6, which is associated with colorectal cancer but not with polyposis. We identified no pathogenic variants in more recently discovered polyposis predisposition genes (POLE, POLD1 or NTHL1), rendering the presence of such founder variants rare.

Metachronous colorectal cancers in Icelandic MSH6 and PMS2 Lynch syndrome carriers in 1955-2017: A population-based study.

76 Background: The prevalence of Lynch syndrome in Iceland is the highest described so far or 1:226 with three founder mutations, one in MSH6 and two in PMS2, and was first reported in 2017. Lynch syndrome predisposes carriers to colorectal cancer and metachronous primaries. Most data on metachronous colorectal cancer reflects on MLH1 and MSH2 carriers and is not well described in MSH6 and PMS2 carriers. The purpose of this study was to examine the cumulative incidence of metachronous colorectal cancer in Icelandic Lynch syndrome carriers diagnosed with colorectal cancer from 1955-2017. Methods: This retrospective study included all individuals with pathogenic variants in mismatch repair genes identified in a nationwide genotype database and a colorectal cancer diagnosis in the Icelandic Cancer Registry from 1955-2017. DeCODE genetics has collected extensive genotypic information on the Icelandic population sequencing the whole genomes of 49,708 Icelanders and imputing genotypes into 116,573 Icelanders whose DNA had been genotyped with SNP chips. Cancer information was obtained from patient charts and cause of death obtained from the Cause of Death Register. All polyp pathology was accessed in the pathology registry and reassessed by two pathologists. Results: A total of 65 individuals developed colorectal cancer during the study period with 34 (52.3%) PMS2 carriers and 25 (38.5%) MSH6 carriers. The cumulative incidence of metachronous colorectal cancer was low or one case (1.5%) in an MSH2 carrier with a median follow-up time of 58 months (Q1 8.0, Q3 167.0, range 0-365 months) in the cohort. Only two (3.1%) individuals, one with MSH2 and one with MSH6 pathogenic variants, underwent a total colectomy. Median age at first colorectal cancer diagnosis was 63 years (Q1 54.0, Q3 72.5, range 28-94). Thirty-one (47.7%) individuals had polyps resected during the study period with adenomas (67.1%) being the most common. Significantly more MSH6 carriers had a history of advanced adenomas as compared to PMS2 carriers (36.0 % vs 11.8%, p = 0.026). Five-year colorectal cancer survival was 81.4% for PMS2 carriers and 71.5% for MSH6 carriers. Conclusions: The incidence of metachronous colorectal cancer was zero in Lynch syndrome carriers with MSH6 or PMS2 pathogenic variants from 1955-2017 despite these individuals not undergoing rigorous Lynch syndrome screening. This would support performing segmental colectomies and following European screening guidelines for MSH6 and PMS2 carriers in Iceland.

Identification of hereditary breast and ovarian cancer germline variants in Granada (Spain): NGS perspective

The aim of this study was to assess the prevalence of germline variants in cancer-predisposing genes by either targeted (BRCA1/2) or multigene NGS panel in a high-risk Hereditary Breast and Ovarian Cancer (HBOC) cohort. Samples from 824 Caucasian probands were retrospectively collected and the impact of genetic diagnosis and genetic variants epidemiology in this cohort was evaluated. Performance of risk-reducing prophylactic measures, such as prophylactic mastectomy and/or prophylactic oophorectomy, was assessed through clinical follow-up of patients with a positive genetic result. Pathogenic variants predisposing to HBOC were identified in 11.9% (98/824) individuals at BRCA2 (47/98), BRCA1 (24/98), PALB2 (8/51), ATM (7/51), CHEK2 (6/51) MSH6, (2/51), RAD51C (2/51) and TP53 (2/386). Of them, 11 novel pathogenic variants and 12 VUS were identified, characterized, and submitted to ClinVar. Regarding clinical impact, the risk of developing basal or Her2 breast cancer was increased 15.7 times or 37.5 times for BRCA1 and MSH6 pathogenic variants respectively. On the contrary, the risk of developing basal or luminal A breast cancer was reduced to 81% or 77% for BRCA2 and BRCA1 pathogenic variants, respectively. Finally, 53.2% of individuals testing positive for class IV/V variants underwent prophylactic surgery (mastectomy, oophorectomy or both) being significantly younger at the cancer diagnosis than those undertaking prophylactic measures (p = 0.008). Of them, 8 carried a pathogenic/likely pathogenic variant in other genes different from BRCA1 and BRCA2, and the remaining (46.7%) decided to continue with clinical follow-up. No differences in pathogenicity or risk of developing cancer were found for BRCA1/2 between targeted and multigene sequencing strategies; however, NGS was able to resolve a greater proportion of high-risk patients.

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

SummaryBackgroundLynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants.MethodsThe IMPACT study is an international, prospective study. Men aged 40–69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual.FindingsBetween Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1–2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3–7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0–2·6), MSH6 carriers was 3·0% (four of 135; 0·8–7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0–68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3–46·0).InterpretationAfter the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings.FundingCancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

Reimagining prostate cancer screening: the IMPACT of germline mutations.

Structured prostate-specific antigen (PSA) screening allows for the early detection of prostate cancer in men aged 55–69 years with a reduction in the incidence of metastatic disease at presentation and cancer-specific mortality at 16 year's follow-up. 1 Hugosson J Roobol MJ Månsson M et al. A 16-yr follow-up of the European randomized study of screening for prostate cancer. Eur Urol. 2019; 76: 43-51 Summary Full Text Full Text PDF PubMed Scopus (182) Google Scholar Population-based screening has been associated with a non-negligible risk of overdiagnosis (ie, the detection of cancers that would not have caused symptoms), which can be as high as 40%, and has limited its adoption at a large scale 2 Martin RM Donovan JL Turner EL et al. Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality: the CAP randomized clinical trial. JAMA. 2018; 319: 883-895 Crossref PubMed Scopus (210) Google Scholar such that no national prostate cancer screening programmes exist in the USA and Europe. 3 Van Poppel H Hogenhout R Albers P van den Bergh RCN Barentsz JO Roobol MJ A European model for an organised risk-stratified early detection programme for prostate cancer. Eur Urol Oncol. 2021; (published online Aug 4)https://doi.org/10.1016/j.euo.2021.06.006 Summary Full Text Full Text PDF Scopus (11) Google Scholar Restricting the use of repeated PSA testing to men at risk of early-onset disease because of a family history of prostate cancer or germline mutations has been proposed as a means of improving the effectiveness of screening. 2 Martin RM Donovan JL Turner EL et al. Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality: the CAP randomized clinical trial. JAMA. 2018; 319: 883-895 Crossref PubMed Scopus (210) Google Scholar , 4 Gandaglia G Albers P Abrahamsson PA et al. Structured population-based prostate-specific antigen screening for prostate cancer: the European Association of Urology Position in 2019. Eur Urol. 2019; 76: 142-150 Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar , 5 Page EC Bancroft EK Brook MN et al. Interim results from the IMPACT study: evidence for prostate-specific antigen screening in BRCA2 mutation carriers. Eur Urol. 2019; 76: 831-842 Summary Full Text Full Text PDF PubMed Scopus (89) Google Scholar A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective studyAfter the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. Full-Text PDF Open Access

Gene-Specific Variation in Colorectal Cancer Surveillance Strategies for Lynch Syndrome

Lynch syndrome is associated with pathogenic variants in 4 mismatch repair (MMR) genes that increase lifetime risk of colorectal cancer. Guidelines recommend intensive colorectal cancer surveillance with colonoscopy every 1-2 years starting at age 25 years for all carriers of Lynch syndrome-associated variants, regardless of gene product. We constructed a simulation model to analyze the effects of different ages of colonoscopy initiation and surveillance intervals for each MMR gene (MLH1, MSH2, MSH6, and PMS2) on colorectal cancer incidence and mortality, quality-adjusted life-years, and cost. Using published literature, we developed a Markov simulation model of Lynch syndrome progression for patients with each MMR variant. The model simulated clinical trials of Lynch syndrome carriers, varying age of colonoscopy initiation (5-year increments from 25-40 years), and surveillance intervals (1-5 years). We assessed the optimal strategy for each gene, defined as the strategy with the highest quality-adjusted life-years and incremental cost-effectiveness ratio below a $100,000 willingness-to-pay threshold. Optimal surveillance for patients with pathogenic variants in the MLH1 and MSH2 genes was colonoscopy starting at age 25 years, with 1- to 2-year surveillance intervals. Initiating colonoscopy at age 35 and 40 years, with 3-year intervals, was cost-effective for patients with pathogenic variants in MSH6 or PMS2, respectively. We developed a simulation model to select optimal surveillance starting ages and intervals for patients with Lynch syndrome based on MMR variant. The model supports recommendations for intensive surveillance of patients with Lynch syndrome-associated variants in MLH1 or MSH2. However, for patients with Lynch syndrome-associated variants of MSH6 or PMS2, later initiation of surveillance at 35 and 40 years, respectively, and at 3-year intervals, can be considered.

MSH6 gene pathogenic variant identified in familial pancreatic cancer in the absence of colon cancer.

Lynch syndrome is characterized by pathogenetic variants in the mismatch repair genes and autosomal dominant inheritance with incomplete penetrance. Lynch syndrome is characterized by colorectal and, with lesser and variable extent, extracolonic cancers. We describe a family with MSH6-dependent Lynch syndrome and familial pancreatic cancer and other tumours (gastric and endometrial), in the absence of colorectal neoplasia. Patients were analysed by sequencing, Next Generation or Sanger, to identify germinal pathogenic variants in hereditary cancer genes. We identified the MSH6 gene pathogenic variant c.2194C>T, p.(Arg732Ter) in a family with hereditary pancreatic cancer without diagnosed cases of colorectal adenocarcinoma. Seven family members were affected by the MSH6 pathogenic variant. Three had pancreatic adenocarcinoma at 65, 57 and 44 years; one had endometrial cancer at 36 years. None of the remaining three subjects (75, 45 and 17 years old) had developed any cancer yet. Lynch syndrome should be suspected in families with familial pancreatic cancer, even in the absence of colon cancers. Specifically, our observation supports the association between the MSH6 c.2194C>T pathogenic variant and extracolonic tumours and it suggests that MSH6 pathogenic variants are associated with familial pancreatic cancer more frequently than assumed.

Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome

Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P= .001 and P= .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P= .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P= .002). Noneof the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.

Yield of Lynch Syndrome Surveillance for Patients With Pathogenic Variants in DNA Mismatch Repair Genes

Patients with Lynch syndrome are offered the same colorectal cancer (CRC) surveillance programs (colonoscopy every 2 years), regardless of the pathogenic DNA mismatch repair gene variant the patient carries. We aimed to assess the yield of surveillance for patients with these variants in MLH1, MSH2, MSH6, and PMS2. We analyzed data on colonoscopy surveillance, including histopathology analysis, from all patients diagnosed with Lynch syndrome (n = 264) at a single center. We compared the development of (advanced) adenomas and CRC among patients with pathogenic variants in the DNA mismatch repair genes MLH1 (n = 55), MSH2 (n = 44), MSH6 (n = 143), or PMS2 (n = 22) over 1836 years of follow-up (median follow-up of 6 years per patient). At first colonoscopy, CRC was found in 8 patients. During 916 follow-up colonoscopies, CRC was found in 9 patients. No CRC was found in patients with variants in MSH6 or PMS2 over the entire follow-up period. There were no significant differences in the number of colonoscopies with adenomas or advanced adenomas among the groups. The median time of adenoma development was 3 years (IQR, 2-6 years). There were no significant differences in time to development of adenoma. However, patients with variants in MSH6 had a significant longer time to development of advanced neoplasia (advanced adenoma or CRC) than patients in the other groups. Six carriers died during follow up (5 from cancer, of which 3 from pancreatic cancer). No CRC was found during follow-up of patients with Lynch syndrome carrying pathogenic variants in MSH6; advanced neoplasia developed over shorter follow-up time periods in patients with pathogenic variants in MLH1 or MSH2. The colonoscopy interval for patients with pathogenic variants in MSH6 might be increased to 3 years from the regular 2-year interval.

Impact of gene-specific germline pathogenic variants on presentation of endometrial cancer in Lynch syndrome.

Lynch syndrome is a risk factor for developing endometrial carcinoma. Our aim was to evaluate the impact of gene-specific germline pathogenic variants on clinical features of patients affected by endometrial cancer. Patients with a diagnosis of endometrial cancer and with a germline pathogenic variant in mismatch repair genes were reviewed. Patients were classified on the basis of classes of risk according to the ESGO-ESGO-ESTRO (European Society of Medical Oncology/European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology) guidelines. One-way analysis of variance (ANOVA) and Kruskal-Wallis test were performed to compare three groups of continuous parametric and non-parametric variables, respectively. χ2 test was used to analyze proportions. Overall, 68 patients with endometrial cancer and Lynch syndrome were evaluated. Ten (14.7%) patients were excluded because of absence of information about the gene involved in Lynch syndrome, thus leaving 58 (85.3%) patients available for the final analysis. MLH1, MSH2, and MSH6 pathogenic variants were observed in 19 (32.7%), 33 (56.9%), and six (10.3%) patients, respectively. Mean±SD age at endometrial cancer diagnosis was 51±6.4, 43.5±7.4, and 60.3±8.8 years (p=0.0002). Prevalence of non-endometrioid endometrial cancer was 15.7%, 24.2%, and 0% in the MLH1, MSH2, and MSH6 groups, respectively (p=0.345). According to the ESMO-ESGO-ESTRO classification, low, intermediate, and high risk endometrial cancer accounted for 47.3%, 10.5%, and 42.1% of the MLH1 group, 57.6%, 3%, and 39.4% of the MSH2 group, and 50%, 50%m and 0% of the MSH6 group (p=0.009). Patients with MLH1 and MSH2 pathogenic variants are at a higher risk of early onset of endometrial cancer than patients with MSH6 pathogenic variants.

Testing strategies to reduce morbidity and mortality from Lynch syndrome

Objective: Lynch syndrome (LS) has an autosomal dominant inheritance pattern and is associated with increased risk for colorectal cancer (CRC) and other cancers. Various strategies are used to identify patients at risk and offer surveillance and preventive programs, the cost effectiveness of which is much dependent on the prevalence of LS in a population. Universal testing (UT) is proposed as an effective measure, targeting all newly diagnosed CRC patients under a certain age.Materials and methods: LS cases were identified in a cohort of 572 consecutive CRC patients. Immunohistochemistry was performed in 539 cases, using antibodies against mismatch repair proteins MLH1, PMS2, MSH2, and MSH6. Microsatellite instability and gene mutation screening were performed in 57 cases.Results: In total 11 pathogenic variants were detected, identifying LS in 1.9% of new CRC cases. Comparing the results with current clinical methods, 2 pathogenic variants were found with Amsterdam criteria and 9 when using either Bethesda guidelines or our institution’s prior clinical criteria. Pathogenic variants in MSH6 were the most common in our series. We also found different outcomes using different age cut offs.Conclusion: Our study demonstrates that UT of tumors before age on onset at 75 years would most likely be cost-efficient and essentially equivalent to applying the Bethesda guidelines or our institution’s prior clinical criteria on all new CRC.

Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome.

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.

Pan-cancer panel testing in individuals with abnormal immunohistochemistry (IHC) staining of the mismatch-repair (MMR) genes.

e13014 Background: IHC staining of the MMR genes is often used to screen for Lynch syndrome (LS) in patients with newly diagnosed colorectal cancer (CRC) and endometrial cancer (EC). Genetic testing of MMR genes guided by IHC has historically been used to confirm a diagnosis of LS. Given the known genetic heterogeneity of LS-related cancers, we assessed the extent to which IHC results reliably predicted findings with pan-cancer panel testing. Methods: We analyzed results from pan-cancer panel testing of 750 individuals with abnormal IHC results from 2013-2016. The panel included the MMR genes and other genes associated with CRC and/or other cancers. All clinical data, including IHC results, were obtained from provider-completed test request forms. Results: CRC (66.0%) was the most common cancer among tested individuals with abnormal IHC results, followed by EC (35.1%). 236 pathogenic variants (PVs) were identified in 228 (30.4%) individuals, 8 of whom carried two distinct mutations. Overall, 191 (80.9%) PVs occurred in MMR genes that were concordant with IHC results. The remaining 45 (19.1%) PVs were not predicted by IHC results, and included two PVs in MMR genes ( MSH6 PV with MLH1/PMS1 absent in IHC, MSH2 PV with PMS2 absent in IHC). The majority of PVs that were not predicted by IHC results occurred in non-MMR genes associated with CRC and EC (n=27, 60.0%; see Table). Conclusions: In this cohort, PVs were identified in 30% of individuals with abnormal IHC who were tested with a pan-cancer panel. Nearly 20% of PVs occurred in non-MMR genes that would be missed by MMR gene-specific testing based on IHC results. Collectively, this suggests pan-cancer panel testing may increase diagnostic yield among individuals with abnormal IHC. [Table: see text]