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Expand universal mismatch repair immunohistochemistry testing for all brain & small bowel tumors?

Updated: May 30

Catie Neumann – CGA-IGC Research Committee

Mismatch repair (MMR) immunohistochemistry (IHC) has historically been utilized to screen for Lynch syndrome in colorectal and endometrial tumors. When the immunotherapy Pembrolizumab became FDA-approved for treatment in multiple cancer types showing MMR deficiency, the spectrum of tumors identified with MMR deficiency expanded.

Dr. Daniel Chung and his colleagues at Massachusetts General Hospital (MGH) attempted to quantify how many patients at their institution with MMR deficient tumors harbored germline pathogenic variants associated with Lynch syndrome. Their findings were presented at the Collaborative Group of the Americas on Inherited Gastrointestinal Cancers (CGA-IGC) Annual Meeting on November 12th, 2022 in Nashville, TN.

In their study, entitled “Genetic Testing Outcomes in a Program of Pan-Cancer Testing for Mismatch Repair Deficiency,” MGH screened 1939 non-colorectal and non-endometrial cancer tumors for MMR deficiency between 2017 and 2021, and 115 (5.9%) of those tumors demonstrated MMR deficiency. Ten tumors came from patients who had known Lynch syndrome. From the 49 additional patients who underwent germline testing, 9 (18%) were found to carry pathogenic germline variants. Four of these patients carried pathogenic germline variants in corresponding mismatch repair genes resulting in a 0.72% Lynch syndrome identification rate in their overall cohort. The additional 5 patients carried pathogenic germline mutations in unrelated genes. Brain tumors and small bowel tumors were the most common tumor types to be associated with patients who had underlying Lynch syndrome.

The authors concluded that their Lynch syndrome identification rate in their pan-cancer cohort is similar to colorectal and endometrial cancer screening programs and argue that MMR testing should be prioritized in patients with small bowel and brain cancers. As over half of the patients tested were found to carry pathogenic germline variants in non-MMR genes, the authors also recommended offering multigene panels to these patients.

Teresa Chai, a genetic counseling assistant at MGH who reviewed MMR IHC reports and is first author on the abstract, provided suggestions for other institutions who have pan-cancer MMR IHC screening programs: “Currently at our institution, a genetic counseling assistant and/or a genetic counselor reviews every MMR IHC case individually. As the number of eligible cancers for MMR deficiency testing expands, we have seen the number of cases to review grow each year, which will eventually become unsustainable. Ideally, the EMR would be able to flag [MMR deficient] results for follow-up. Stakeholders in pathology, medical oncology, and genetics should collaborate to streamline the workflow for MMR testing, results review, and follow-up.” Teresa is now enrolled in University of Pennsylvania’s Master Program in Genetic Counseling and anticipates graduating in the Class of 2024.

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