Latham A, et al. - In order to determine the degree to which Lynch syndrome (LS) is responsible for high-frequency microsatellite instability (MSI) (MSI-H) across heterogeneous tumor types, researchers assessed the prevalence of LS across solid tumors according to MSI status. Findings revealed that LS was predicted by MSI-H/mismatch repair deficiency (MMR-D) across a considerably wider tumor spectrum than currently thought. Based on the findings, germline genetic assessment for LS was supported for patients with an MSI-H/MMR-D tumor, irrespective of cancer type or family cancer history.

Methods

• Researchers used targeted next-generation sequencing to determine MSI status, based on which tumors were classified as MSI-H, MSI-indeterminate, or microsatellite-stable.
• They analyzed matched germline DNA for mutations in LS-associated mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM).
• They also evaluated immunohistochemical staining for MMR-D in patients with LS with MSI-H/I tumors.

Results

• Among 15,045 unique patients (more than 50 cancer types), the percentage of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors who were detected to have LS was 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020), respectively (P < .001).
• Tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors, were detected in 50% (33 of 66) of patients with LS with MSI-H/I tumors.
• LS genetic testing criteria was not met by 45% (15 of 33) of these patients with non-CRC/EC tumors, on the basis of personal/family history.
• In 98.2% (56 of 57) of available cases, MMR-D was shown in immunohistochemical staining of LS-positive MSI-H/I tumors.