Mismatch Repair Deficiency (dMMR)

Mismatch repair deficiency is a breakdown in the cellular system that proofreads DNA after it copies itself. When the MMR proteins (most commonly MLH1, MSH2, MSH6, or PMS2) are missing or non-functional, small copying errors accumulate, creating a tumor that is genetically unstable and prone to mutations. Tumors with dMMR often show a feature called microsatellite instability (MSI-High) and tend to respond well to immunotherapy drugs called immune checkpoint inhibitors.

Origin

The mismatch repair system was characterized in bacteria in the 1970s–80s by Paul Modrich and colleagues, work that later earned the 2015 Nobel Prize in Chemistry. The link between germline MMR mutations and cancer was established in the 1990s with the discovery of Lynch syndrome (hereditary non-polyposis colorectal cancer).

Significance in Asbestos Context

For patients with asbestos-related cancers, dMMR status is primarily a treatment-planning tool. In lung cancer and other solid tumors, dMMR or MSI-High status can qualify a patient for FDA-approved immune checkpoint inhibitors such as pembrolizumab, regardless of where the tumor started. dMMR is uncommon in mesothelioma but is sometimes tested for when standard chemotherapy options are exhausted. Identifying dMMR doesn't change the fact that asbestos caused the disease (causation rests on exposure history and the tumor type), but it can open additional treatment doors and may also reveal an inherited cancer syndrome (Lynch syndrome) that has implications for blood relatives.

Example Sentence

"After her mesothelioma progressed on first-line chemotherapy, the oncologist ordered dMMR and PD-L1 testing on the tumor block to see whether she might qualify for immunotherapy."

Related Terms

Microsatellite Instability (MSI-High), Immune Checkpoint Inhibitors, Lynch Syndrome, BAP1, Tumor Mutational Burden, Immunohistochemistry

Notes

• Ask your oncologist whether your tumor has been tested for dMMR (by immunohistochemistry for MLH1, MSH2, MSH6, and PMS2) or for MSI (by PCR or next-generation sequencing). This testing is standard for many cancers but is sometimes overlooked in mesothelioma.
• If dMMR is found, ask whether you qualify for an immune checkpoint inhibitor such as pembrolizumab, and whether genetic counseling is warranted to check for Lynch syndrome, which affects blood relatives.
• Preserve copies of all molecular pathology reports (dMMR/MSI results, BAP1 status, PD-L1 levels) both for ongoing treatment decisions and for your legal team's medical record file.
• Request that your hospital save unused tumor tissue blocks; later treatment decisions or expert reviews may require additional testing on that tissue.