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 21% in SD-CRCs ( = 0.274); 19% MSI in FIT-interval CRCs 12% in SD-CRCs ( = 0.469)), and showed more often serrated pathway associated features such as (30% 12%, = 0.090) and (15% 2.4%, = 0.063) mutations. mutations, a classic feature of the adenoma-carcinoma-sequence, were more abundant in SD-CRCs (68% 40% in FIT-interval CRCs = 0.035). Regarding CNAs differences between the two groups; FIT-interval CRCs less often showed gains at the regions 8p11.22-q24.3 ( = 0.009), and more often gains at 20p13-p12.1 ( = 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 FIT-interval CRCs.