DNA Mismatch Repair Deficiency as a Biomarker in Sarcoma

Lynch syndrome (LS) is a cancer predisposition syndrome caused by a germline loss-of-function mutation in a mismatch repair (MMR) gene. While sarcomas are not classically considered LS cancers, we investigated the MMR status and clinical features of sarcomas in LS patients to help inform optimal treatment strategies.

A prospectively maintained institutional clinical cancer genetics database was queried for LS patients (defined by pathogenic germline mutation in a MMR gene) with a documented diagnosis of sarcoma between 1998-2022. Tumor MMR status was determined by immunohistochemistry (IHC) for MMR proteins and secondarily by PCR assay if IHC was normal or intact.

Among the 30 LS patients with sarcoma, germline mutations were most common in MSH2 (50%). The most common sarcoma subtypes were undifferentiated pleomorphic sarcoma (40%) and leiomyosarcoma (27%). Median age at diagnosis was 49.2 years (interquartile range 40.4-62.4). 90% presented with localized disease, and 10% presented with synchronous metastatic disease. Among 10 patients with tissue available for biomarker determination, dMMR was confirmed in 4 (40%), while the remaining (60%) were pMMR. Three patients received immunotherapy. Two of these had confirmed dMMR tumor status: one demonstrated a sustained complete response on pembrolizumab monotherapy for 44 months; the other had a partial response on ipilimumab and nivolumab for 31 months but died from an unrelated cause. In the entire cohort of 30 patients at a median follow-up time of 68.2 months since sarcoma diagnosis (interquartile range 29.0-151.5 months), median overall survival and progression-free survival have not been reached.

While rare, sarcoma can be encountered in patients with LS, particularly those with germline MSH2 mutation. LS-associated sarcomas occur significantly earlier, carry a favorable outcome, and demonstrate the potential for durable response with immunotherapy.