Hum Pathol. 2018 Apr 30. pii: S0046-8177(18)30146-1. doi: 10.1016/j.humpath.2018.04.017. [Epub ahead of print]
Histology of colorectal adenocarcinoma with double somatic mismatch repair mutations is indistinguishable from those caused by lynch syndrome.
Hemminger JA1, Pearlman R2, Haraldsdottir S3, Knight D1, Jonasson JG4, Pritchard CC5, Hampel H2, Frankel WL6.
Lynch syndrome (LS) is the most common form of hereditary colon cancer (CRC). Germline mutations in the mismatch repair (MMR) genes MLH1, MSH2 (EPCAM), MSH6, and PMS2, followed by a second hit to the remaining allele leads to cancer development. Universal tumor screening for LS is routinely performed on CRC, and screening has identified patients with unexplained MMR deficiency that lack MLH1 methylation and a germline mutation. Tumor sequencing has since identified double somatic (DS) mutations in the MMR gene corresponding with the absent protein in 69% of these patients. We assessed whether histomorphology could distinguish patients with DS mutations from those with LS. Colorectal cancer patients with DS mutations were identified from population-based cohorts from Iceland (2000-2009), Columbus, Ohio (1999-2005), and the state of Ohio (2013-2016). Next-generation sequencing was performed on tumors with unexplained MMR deficiency. Patients with LS from Ohio cohorts were the comparison group. The histologic features associated with MMR deficiency (tumor infiltrating lymphocytes, Crohn's-like reaction, histologic subtype, necrosis) were evaluated. We identified 43 tumors with DS mutations and 48 from patients with LS. There was no significant difference in histologic features between tumors in LS patients and tumors with DS mutations. Since histology of tumors with DS mutations is indistinguishable from those caused by LS, tumor sequencing for evaluation of DS mutations should be considered to help clarify sporadic versus hereditary causes of unexplained MMR deficiency.
Biallelic Mutations; Double Somatic Mutations; Lynch Syndrome; Lynch-Like Syndrome; MMR Deficiency