Serrated polyposis associated with a family history of colorectal cancer and/or polyps: The preferential location of polyps in the colon and rectum defines two molecular entities.

Serrated polyposis (SPP) is characterized by the development of multiple serrated polyps and an increased predisposition to colorectal cancer (CRC). In the present study, we aimed to characterize, at a clinical and molecular level, a cohort of SPP patients with or without a family history of SPP and/or polyps/CRC (SPP-FHP/CRC). Sixty-two lesions from 12 patients with SPP-FHP/CRC and 6 patients with sporadic SPP were included. The patients with SPP-FHP/CRC presented with an older mean age at diagnosis (p=0.027) and a more heterogeneous histological pattern of lesions (p=0.032) than the patients with sporadic SPP. We identified two molecular forms of SPP-FHP/CRC, according to the preferential location of the lesions: proximal/whole-colon or distal colon. Mismatch repair (MMR) gene methylation [mutS homolog 6 (MSH6)/mutS homolog 3 (MSH3)] or loss of heterozygosity (LOH) of D2S123 (flanking MSH6) were detected exclusively in the former (p=3.0x10-7), in most early lesions. Proximal/whole‑colon SPP-FHP/CRC presented a higher frequency of O-6-methylguanine-DNA methyltransferase (MGMT) methylation/LOH, microsatellite instability (MSI) and Wnt mutations (19/29 vs. 7/17; 16/23 vs. 1/14, p=2.2x10-4; 15/26 vs. 2/15, p=0.006; 14/26 vs. 4/20, p=0.02) but a lower frequency of B-raf proto-oncogene, serine/threonine kinase (BRAF) mutations (7/30 vs. 12/20, p=0.0089) than the distal form. CRC was more frequent in cases of Kirsten rat sarcoma viral oncogene homolog (KRAS)-associated proximal/whole-colon SPP-FHP/CRC than in the remaining cases (4/4 vs. 1/8, p=0.01). Thus, SPP-FHP/CRC appears to be a specific entity, presenting two forms, proximal/whole-colon and distal, which differ in the underlying tumor initiation pathways. Early MGMT and MMR gene deficiency in the former may underlie an inherited susceptibility to genotoxic stress.