Lynch syndrome (LS) is a
hereditary cancer syndrome caused by a germline mutation in
a DNA mismatch repair gene, usually MLH1, MSH2, MSH6, or PMS2. The most common
cancers associated with LS are colorectal
adenocarcinoma and
endometrial carcinoma. Identification of women with LS-associated
endometrial cancer is important, as these women and their affected siblings and children are at-risk of developing these same
cancers. Germline testing of all
endometrial cancer patients is not cost effective, and screening using young age of
cancer diagnosis and/or presence of family history of syndrome-associated is underutilized and ineffective. Therefore, most groups now advocate for
tumor tissue testing to screen for LS, with germline testing targeted to women with abnormal tissue testing results. Immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 is used in many clinical laboratories for this
tumor screening step, as immunohistochemistry is relatively inexpensive and is technically more accessible for smaller clinical labs. PCR-based tissue testing, whereas technically more challenging, does play an important role in the identification of these patients. MLH1 methylation analysis identifies women with
tumor MLH1 loss who likely have sporadic
endometrial cancer and do not need heightened
cancer prevention surveillance. High levels of
microsatellite instability have been identified in
tumors with retained positive expression of mismatch repair
proteins. Somatic sequencing of mismatch repair genes from
tumor DNA, whereas not currently available in most clinical laboratories, is helpful in resolution of cases in which germline sequencing fails to identify a mutation in a mismatch repair gene. The
tumor tissue testing approach can help to identify most women at-risk for germline mutations in a LS gene, but not all patients will be captured using this approach. Clinical suspicion can still play a pivotal role in accurately identifying a subset of these patients.