Somatic tumor profiling of DNA mismatch repair deficient (MMR-D) colorectal cancers (CRC).

Abstract

1528Background: MMR-D in CRC may be caused by a somatic event, characterized by presence of BRAF V600E/MLH1-promoter hypermethylation (BRAF/HM+), or by a germline mutation in an MMR gene, diagnostic of Lynch syndrome (LS). In patients with Lynch-like syndrome (LLS), the etiology of the MMR-D remains unclear (LS germline-, BRAF/HM-) and these patients receive LS cancer screening recommendations. We sought to determine whether somatic tumor profiling of 1) BRAF/HM+, 2) LS and 3) LLS tumors may illuminate inherent biologic differences among MMR-D CRCs. Methods: We sequenced 410 genes in tumor and normal samples of 53 MMR-D patients who had undergone germline evaluation. Somatic mutation profiles were compared among subgroups. Results: Among 15 BRAF/HM+, 25 LS and 13 LLS cases, mean numbers of mutations were equivalent. Comparison of BRAF/HM+ and LS cases revealed differentially mutated genes with LS cases more frequently mutated in APC (80% vs 27%, p = 0.009), KRAS (60% vs 13%, p = 0.004) and MSH6 (36% vs 7%...