Germline pathogenic variants in <scp><i>HIC1</i> DNA</scp> binding domains are associated with familial serrated polyposis syndrome

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.

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Publication Details

Journal
International Journal of Cancer
Published
2025-05-30
DOI
https://doi.org/10.1002/ijc.35492
Primary Topic
Genetic factors in colorectal cancer
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Yasmin Soares de Lima, Daniel Rodríguez‐Alcalde, Jenifer Muñoz, Míriam Cuatrecasas et al.
International Journal of Cancer
Genetic factors in colorectal cancer
article

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

Yasmin Soares de Lima, Daniel Rodríguez‐Alcalde, Jenifer Muñoz, Míriam Cuatrecasas, Joaquín Cubiella, Gemma Llargués‐Sistac, Sergi Castellvı́-Bel, Gabriel Capellá, Francesc Balaguer, Cristina Herrera‐Pariente, Antoni Castells, Leticia Moreira, Laia Bonjoch, Guerau Fernández, Sabela Carballal, Coral Arnau‐Collell, Anael López‐Novo, Laura Valle, Clara Ruíz-Ponte, Luís Bujanda, Marcos Díaz‐Gay, Xavier Domínguez‐Rovira, Teresa Ocaña, Gemma Gonfaus‐Ortiz, Ainara Llopis
article en

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.

International Journal of CancerVol. 157(6)
Hospital Sant Joan de Déu Barcelona (ES), University of the Basque Country (ES), Universidade de Santiago de Compostela (ES), University of California San Diego (US), Institut d'Investigació Biomédica de Bellvitge (ES), Institut Català d'Oncologia (ES), Centre for Biomedical Network Research on Rare Diseases (ES), Hospital Clínic de Barcelona (ES), Fundación Pública Galega de Medicina Xenómica (ES), La Jolla Bioengineering Institute (US), Biomedical Research Institute (US), Hospital Universitario de Móstoles (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Complejo Hospitalario de Ourense (ES), Universitat de Barcelona (ES)
Fundació la Marató de TV3, Centres de Recerca de Catalunya, Fundación Científica Asociación Española Contra el Cáncer, HORIZON EUROPE Framework Programme, Instituto de Salud Carlos III
Good health and well-being
Openalex Percentile: Top 83%
Genetic factors in colorectal cancer
DOIOpen Access PDFOpenAlex
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