Is it all Lynch syndrome?: An assessment of family history in individuals with mismatch repair-deficient tumors.

PURPOSE: Mismatch repair-deficient (MMRD) colorectal cancer (CRC) and endometrial cancer (EC) may be suggestive of Lynch syndrome (LS). LS can be confirmed only by positive germ-line testing. It is unclear if individuals with MMRD tumors but no identifiable cause (MMRD+/germ-line-) have LS. Because LS is hereditary, individuals with LS are expected to have family histories of LS-related tumors. Our study compared the family histories of MMRD+/germ-line- CRC and/or EC patients with LS CRC and/or EC patients. METHODS: A total of 253 individuals with an MMRD CRC or EC from one institution were included for analysis in one of four groups: LS; MMRD+/germ-line-; MMRD tumor with variant of uncertain significance (MMRD+/VUS); and sporadic MSI-H (MMRD tumor with MLH1 promoter hypermethylation or BRAF mutation). Family histories were analyzed utilizing MMRpro and PREMM1,2,6. Kruskal-Wallis tests were used to compare family history scores. RESULTS: MMRD+/germ-line- individuals had significantly lower median family history scores (MMRpro = 8.1, PREMM1,2,6 = 7.3) than did LS individuals (MMRpro = 89.8, PREMM1,2,6 = 26.1, P < 0.0001). CONCLUSION: MMRD+/germ-line- individuals have less suggestive family histories of LS than individuals with LS. These results imply that MMRD+/germ-line- individuals may not all have LS. This finding highlights the need to determine other causes of MMRD tumors so that these patients and their families can be accurately counseled regarding screening and management.Genet Med 17 6, 476-484.

Consequences of universal MSI/IHC in screening ENDOMETRIAL cancer patients for Lynch syndrome.

OBJECTIVE: Determine factors impacting the uptake of genetic counseling and results of genetic testing following universal tumor testing for Lynch syndrome in patients with endometrial cancer. METHODS: The study population consisted of two unselected cohorts of endometrial cancer patients, 408 identified retrospectively and 206 identified prospectively. Immunohistochemistry for mismatch repair protein expression and/or microsatellite instability analysis was performed on these tumors. MLH1 methylation analysis was performed on tumors with loss of MLH1 protein. Tumor studies were considered suggestive of Lynch Syndrome if they showed immunohistochemical loss of MSH2, MSH6 or PMS2, loss of MLH1 without MLH1 promoter methylation, and/or microsatellite instability. Participants with suggestive tumor studies were contacted and offered genetic counseling and testing. RESULTS: In the retrospective cohort, 11% had tumor studies suggestive of Lynch syndrome, and 42% was seen for genetic counseling. A germline mutation was detected in 40%, and one had a variant of uncertain significance. In the prospective cohort, 8.7% of patients had tumor testing suggestive of Lynch syndrome; 72% were seen for genetic counseling. Germline mutations were found in 40%, and one had a variant of uncertain significance. Common challenges included timing of re-contact, age, perceived lack of relevance, inability to travel and limited insurance coverage. CONCLUSIONS: There are several barriers to genetic counseling and testing follow-up after universal tumor testing, and uninformative genetic test results present a management challenge. It is important to consider these limitations when implementing an approach to screening endometrial cancer patients for Lynch syndrome.

Outcomes of screening endometrial cancer patients for Lynch syndrome by patient-administered checklist.

OBJECTIVE: The aims of this study were to implement a patient-administered checklist designed to identify endometrial cancer patients at elevated risk for Lynch syndrome; measure subsequent genetic counseling and testing; and identify differences between those who attended genetic counseling and those who did not. METHODS: We developed a 4-item yes/no checklist of personal and family history risk factors for Lynch syndrome-associated endometrial cancer and recommended referral for genetic counseling for patients meeting any of the criteria. Retrospective chart review was performed to determine subsequent genetic counseling and testing outcomes over a 15 month period. RESULTS: 6/387 (1.6%) of endometrial cancer patients tested positive for a Lynch syndrome mutation. 4/24 (17%) of endometrial cancer patients who met referral criteria and attended genetic counseling tested positive. 38/70 (55%) of patients who met referral criteria were not seen for genetic counseling. Patients who were diagnosed with endometrial cancer at younger ages, who had primary surgery at our institution, or who met more than one referral criteria were more likely to be seen for genetic counseling. CONCLUSIONS: Endometrial cancer patients who met referral criteria and attended genetic counseling comprised a population enriched for Lynch syndrome. This approach allowed Lynch syndrome evaluation resources to be targeted to a population of patients that is high risk and interested in the information. The referral rate of at-risk patients needs to be improved, and allocating resources towards this goal could increase the identification of Lynch syndrome while avoiding some of the pitfalls of universal screening.