Germline pathogenic variants in HIC1 DNA binding domains are associated with familial serrated polyposis syndrome.
Por:
Domínguez-Rovira X, Arnau-Collell C, Gonfaus-Ortiz G, Llargués-Sistac G, Muñoz J, Llopis A, Soares de Lima Y, Herrera-Pariente C, Moreira L, Ocaña T, Díaz-Gay M, Cuatrecasas M, Carballal S, López-Novo A, Fernandez-Isern G, Castells A, Bujanda L, Capellà G, Cubiella J, Rodríguez-Alcalde D, Valle L, Balaguer F, Ruiz-Ponte C, Bonjoch L and Castellví-Bel S
Publicada:
15 sep 2025
Ahead of Print:
30 may 2025
Resumen:
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.
Filiaciones:
Domínguez-Rovira X:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Arnau-Collell C:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Gonfaus-Ortiz G:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Llargués-Sistac G:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Muñoz J:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Llopis A:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Soares de Lima Y:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Herrera-Pariente C:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Moreira L:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Ocaña T:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Díaz-Gay M:
Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, California, USA
Department of Bioengineering and Moores Cancer Center, UC San Diego, La Jolla, California, USA
Cuatrecasas M:
Department of Pathology, Hospital Clínic Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Carballal S:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
López-Novo A:
Galician Public Foundation of Genomic Medicine (FPGMX), Foundation Health Research Institute of Santiago de Compostela, Genomic Medicine Group, University of Santiago de Compostela, Santiago de Compostela, Spain
Fernandez-Isern G:
Hospital Sant Joan de Deu, CIBERER, Barcelona, Spain
Castells A:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Bujanda L:
Gastroenterology, Biogipuzkoa Health Research Institute, CIBEREHD. University of the Basque Country (UPV/EHU), San Sebastián, Spain
Capellà G:
Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell Program, IDIBELL, CIBERONC, Barcelona, Spain
Cubiella J:
Department of Gastroenterology, Ourense Hospital, CIBEREHD, Ourense, Spain
Rodríguez-Alcalde D:
Digestive Diseases Section, Móstoles University Hospital, Madrid, Spain
Valle L:
Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell Program, IDIBELL, CIBERONC, Barcelona, Spain
Balaguer F:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Ruiz-Ponte C:
Galician Public Foundation of Genomic Medicine (FPGMX), Foundation Health Research Institute of Santiago de Compostela, Genomic Medicine Group, University of Santiago de Compostela, Santiago de Compostela, Spain
Bonjoch L:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Castellví-Bel S:
Gastroenterology, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), CIBEREHD, Hospital Clínic Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain
Green Submitted, hybrid
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