Distinct mutational profile of Lynch syndrome colorectal cancers diagnosed under regular colonoscopy surveillance

ABSTRACT Background Regular colonoscopy even with short intervals does not prevent all colorectal cancers (CRC) in Lynch syndrome (LS). In the present study, we asked whether cancers detected under regular colonoscopy surveillance (incident cancers) are phenotypically different from cancers detected at first colonoscopy (prevalent cancers). Methods We analyzed clinical, histological, immunological and mutational characteristics, including panel sequencing and high through-put coding microsatellite (cMS) analysis, in 28 incident and 67 prevalent LS CRCs. Results Incident cancers presented with lower UICC and T stage compared to prevalent cancers (p< 0.0005). The majority of incident cancers (21/28) were detected after previous colonoscopy without any pathological findings. On the molecular level, incident cancers presented with a significantly lower KRAS codon 12/13 (1/23, 4.3% vs. 11/21, 52%; p = 0.0005) and pathogenic TP53 mutation frequency (0/17, 0% vs. 7/21, 33.3%; p = 0.0108,) compared to prevalent cancers; 10/17 (58.8%) incident cancers harbored one or more truncating APC mutations, all showing mutational signatures of mismatch repair (MMR) deficiency. The proportion of MMR deficiency-related mutational events was significantly higher in incident compared to prevalent CRC (p = 0.018). Conclusions LS CRC diagnosed under regular colonoscopy surveillance are biologically distinct, suggesting that the preventive effectiveness of colonoscopy in LS depends on the molecular subtypes of tumors.