Discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected Lynch syndrome.

Background and Aims: Tumor 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. Methods: We 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. Results: The 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. Conclusions: Among 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.

Lynch Syndrome Patients with Limited Family History Identified in a Laboratory Setting: A Descriptive Study.

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.

Hereditary cancer-associated mutations in women diagnosed with two primary cancers: an opportunity to identify hereditary cancer syndromes after the first cancer diagnosis.

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.