DNA Mismatch Repair Deficiency as a Biomarker in Sarcoma

Area of Science:

• Oncology
• Genetics
• Cancer Research

Background:

• Lynch syndrome (LS) is an inherited cancer predisposition caused by mismatch repair (MMR) gene mutations.
• Sarcomas are not typically considered LS-associated cancers, but their occurrence in LS patients warrants investigation.

Purpose of the Study:

• To investigate the MMR status and clinical characteristics of sarcomas in patients with Lynch syndrome.
• To inform optimal treatment strategies for sarcomas in the context of LS.

Main Methods:

• A database of LS patients with sarcoma diagnoses (1998-2022) was queried.
• Tumor MMR status was assessed using immunohistochemistry (IHC) and PCR assays.

Main Results:

• Of 30 LS patients with sarcoma, 50% had MSH2 mutations. Common subtypes included undifferentiated pleomorphic sarcoma and leiomyosarcoma.
• 40% of evaluable tumors showed deficient MMR (dMMR); 60% showed proficient MMR (pMMR).
• Two patients with dMMR tumors experienced durable responses to immunotherapy (pembrolizumab or ipilimumab/nivolumab).

Conclusions:

• Sarcomas, though rare, can occur in LS patients, particularly those with MSH2 mutations.
• LS-associated sarcomas tend to present earlier and have a favorable prognosis.
• Immunotherapy shows potential for durable responses in LS-associated sarcomas with dMMR status.