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 FIT-interval CRCs.