Objectives: Patients with hereditary cancer syndromes are at high risk for a second primary cancer. Early identification of these patients after an initial cancer diagnosis is the key to implementing cancer risk-reducing strategies. Methods: A commercial laboratory database was searched for women with a history of both breast and ovarian or colorectal and endometrial cancer who underwent genetic testing for hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (LS). Results: Among women with both breast and ovarian cancer, 22.4% (2,237/9,982) had a BRCA1 or BRCA2 mutation. Among women with both colorectal and ovarian cancer, 28.1% (264/941) had a mutation associated with LS. In 66.6% of BRCA1 or BRCA2 mutation carriers and in 58.3% of LS mutation carriers, >5 years passed between the cancer diagnoses. Of patients with HBOC and LS, 56 and 65.2%, respectively, met the National Comprehensive Cancer Network guidelines for hereditary cancer testing after their initial diagnosis based on their personal cancer history alone. Conclusions: A substantial number of women tested for LS or HBOC after being diagnosed with two successive primary cancers were diagnosed with a hereditary cancer syndrome. In many cases, the time interval between the diagnoses was long enough to allow for the implementation of surveillance and/or prophylactic measures. © 2014 S. Karger AG, Basel

MUTYH-associated polyposis (MAP) is an autosomal recessive syndrome caused by biallelic mutations in the base excision repair gene MUTYH. Owing to potential limitations in the MAP testing strategy and testing criteria, it is possible that MAP is being under-identified both genotypically and phenotypically. To determine whether full sequencing of MUTYH would increase clinical sensitivity over a founder mutation (FM) strategy, a retrospective analysis of two datasets from a commercial clinical laboratory was performed. The first cohort contained 1522 individuals who received MUTYH analysis for two FMs with subsequent full-gene sequencing. Eighty-five biallelic individuals were identified; 47 carried two FMs, 17 carried one FM and one mutation identified on full sequencing, and 21 carried biallelic mutations identified only on full sequencing. The second cohort contained 921 patients with colorectal cancer <50 years and <10 reported colorectal adenomas who had undergone MUTYH mutation testing. In this cohort, 19 of 921 (2.1%) individuals were identified as biallelic MUTYH carriers. Of these, 13 did not have a personal or family history of polyps and would not have met guidelines for MUTYH testing. These results suggest that individuals with biallelic MUTYH mutations are under-ascertained based on both genotype and phenotype under current standard testing practices.

Background and AimsTumor immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins is often used to guide germline genetic testing and variant classification for patients with suspected Lynch syndrome. This analysis examined the spectrum of germline findings in a cohort of individuals showing abnormal tumor IHC.MethodsWe assessed individuals with reported abnormal IHC findings and referred for testing with a six-gene syndrome-specific panel (n=703). Pathogenic variants (PVs) and variants of uncertain significance (VUS) in MMR genes were designated expected/unexpected relative to IHC results.ResultsThe PV positive rate was 23.2% (163/703; 95% confidence interval [CI], 20.1%-26.5%); 8.0% (13/163; 95% CI, 4.3%-13.3%) of PV carriers had a PV in an unexpected MMR gene. Overall, 121 individuals carried VUS in MMR genes expected to be mutated based on IHC results. Based on independent evidence, in 47.1% (57/121; 95% CI, 38.0%-56.4%) of these individuals the VUSs were later reclassified as benign and in 14.0% (17/121; 95% CI, 8.4%-21.5%) of these individuals the VUSs were reclassified as pathogenic.ConclusionsAmong patients with abnormal IHC findings, IHC-guided single-gene genetic testing may miss 8% of individuals with Lynch syndrome. In addition, in patients with VUS identified in MMR genes predicted to be mutated by IHC, extreme caution must be taken when the IHC results are considered in variant classification.

402 Background: Lynch syndrome is a well-described cause of hereditary colon cancer. A point of the Amsterdam II criteria, which defines Lynch syndrome, is to exclude familial adenomatous polyposis (FAP). FAP is caused by mutations in the APC gene and is defined as the presence of 100+ adenomas. The attenuated form of familial adenomatous polyposis (AFAP) can be considered when an individual has 10-99 adenomas. While adenomatous polyps may be a part of the Lynch syndrome phenotype (as a precursor to carcinoma), the assumption is that Lynch syndrome and APC-associated polyposis do not have overlapping phenotypes. Methods: A retrospective analysis was performed on 8,202 individuals with a personal history of adenomatous polyps that had clinical genetic testing for Lynch syndrome (including genes MLH1, MSH2, MSH6, PMS2, and EPCAM) between January 2006 and July 2013. Patient adenoma history was collected on the test request form. The inclusion criterion was limited to personal history of adenomatous polyps and did not depend on personal or family history of cancer. Patients were excluded if the test performed was either targeted mutation testing or single gene testing, presumably based on prior immunohistochemistry tumor testing. Results: Of 8,202 patients with a personal history of adenomatous polyps that underwent Lynch syndrome testing, 610 (7.4%) were positive for a mutation. Mutations were detected in patients with a wide distribution of cumulative adenomas (Table). Seventy-five of the patients with a Lynch syndrome mutation had an adenomatous polyp phenotype suggestive of either FAP (100+ adenomas) or AFAP (10-99 adenomas). Of these 75 patients, 19 underwent APCtesting, all of whom were negative for a mutation. Conclusions: Individuals with an adenoma history, who were tested for Lynch syndrome, had an overall 7.4% mutation positive rate, indicating an overlapping phenotype between Lynch syndrome and FAP/AFAP. This overlap supports consideration of a gene panel test approach. [Table: see text]

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Objective: Patients diagnosed with colorectal cancer before the age of 50 years are recommended for Lynch syndrome (LS) testing according to current clinical guidelines. However, many patients are not identified because of the stringent guidelines on existing diagnostic criteria. The aim of this analysis was to evaluate the ability of existing criteria to adequately ascertain patients appropriate for LS genetic testing. Method: To determine whether existing clinical diagnostic criteria underascertain individuals who would be appropriate candidates for hereditary cancer risk assessment, we stratified the detection rate of deleterious mismatch repair (MMR) mutations in 9,109 patients with a personal history of colorectal cancer who were diagnosed between the ages of 30 and 74 years with little or no family history suggestive of LS by 5-year age-at-detection intervals. Results: There was little difference in the aggregate positive mutation rate in individuals diagnosed between the ages of 50 and 59 years compared to the positive mutation rate in patients diagnosed before the age of 50 years. Conclusion: These results suggest that cancer diagnosis under the age of 50 years is an insufficiently sensitive predictor of hereditary cancer susceptibility.

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