Missed colorectal cancers in a fecal immunochemical test-based screening program: Molecular profiling of interval carcinomas

BACKGROUND For optimizing fecal immunochemical test(FIT)-based screening programs,reducing the rate of missed colorectal cancers(CRCs)by FIT(FIT-interval CRCs)is an important aspect.Knowledge of the molecular make-up of these missed lesions could facilitate more accurate detection of all(precursor)lesions.AIM To compare the molecular make-up of FIT-interval CRCs to lesions that are detected by FIT[screen-detected CRCs(SD-CRCs)].METHODS FIT-interval CRCs observed in a Dutch pilot-program of FIT-based screening were compared to a control group of SD-CRCs in a 1:2 ratio,resulting in 27 FIT-interval CRC and 54 SD-CRCs.Molecular analyses included microsatellite instability(MSI),CpG island methylator phenotype(CIMP),DNA sequence mutations and copy number alterations(CNAs).RESULTS Although no significant differences were reached,FIT-interval CRCs were more often CIMP positive and MSI positive(33%CIMP in FIT-interval CRCs vs 21%in SD-CRCs(P=0.274);19%MSI in FIT-interval CRCs vs 12%in SD-CRCs(P=0.469)),and showed more often serrated pathway associated features such as BRAF(30%vs 12%,P=0.090)and PTEN(15%vs 2.4%,P=0.063)mutations.APC mutations,a classic feature of the adenoma-carcinoma-sequence,were more abundant in SD-CRCs(68%vs 40%in FIT-interval CRCs P=0.035).Regarding CNAs differences between the two groups;FIT-interval CRCs less often showed gains at the regions 8p11.22-q24.3(P=0.009),and more often gains at 20p13-p12.1(P=0.039).CONCLUSION Serrated pathway associated molecular features seem to be more common in FIT-interval CRCs,while classic adenoma carcinoma pathway associated molecular features seem to be more common in SD-CRCs.This indicates that proximal serrated lesions may be overrepresented among FITinterval CRCs.