Germline pathogenic variants in HIC1 DNA binding domains are associated with familial serrated polyposis syndrome

Abstract Serrated polyposis syndrome (SPS) is characterized by multiple and/or large serrated polyps and increased colorectal cancer (CRC) risk. Germline predisposition to SPS is mostly undetermined. We aimed to identify a new inherited SPS predisposition component by functionally evaluating a candidate gene replicated in two independent SPS cohorts. Exome sequencing was performed in a discovery cohort of 39 patients from 16 SPS families, and validation of relevant results was performed by multi‐gene panel sequencing in 211 independent SPS patients. Considering the discovery and validation cohorts, three predicted pathogenic missense variants were identified in HIC1 (Hypermethylated in cancer 1): c.110C>T (p.Ala37Val), c.1295A>G (p.Gln432Arg), and c.1411G>A (p.Gly471Arg). HIC1 is a tumor suppressor gene which encodes a transcriptional repressor involved in the DNA damage response, and it is commonly silenced in several cancers and serrated polyps. Two cellular models for HIC1 , a CRISPR/Cas9 knockout model and an overexpression model, were produced. In these in vitro models, we assessed DNA damage levels and the SIRT1 regulatory pathway in the presence and absence of the identified variants. Compared to HIC1 wild‐type, models harboring the HIC1 variants identified in SPS patients showed higher p‐H2AX levels (marker of DNA damage) and impaired HIC1 binding to the SIRT1 promoter. Our results indicate that HIC1 genetic variants located in the zinc finger region affected its transcriptional repressor role. We can conclude that HIC1 may be involved in germline predisposition to SPS through an alteration of its repressor capacity and a faulty DNA damage response, as a molecular mechanism.