Importance of PCR-based Tumor Testing in the Evaluation of Lynch Syndrome-associated Endometrial Cancer

Lynch Syndrome 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 Lynch Syndrome are colorectal adenocarcinoma and endometrial carcinoma. Identification of women with Lynch Syndrome-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 Lynch Syndrome, 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, while 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, while 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 Lynch Syndrome 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.