Indexat a

Llicència i ús

Citacions

Cited 22 times in

Cited 21 times in

Cited 17 times in

Cited 22 times in

Cited 17 times in

Altmetrics

Grant support

Laia Bonjoch was supported by a Juan de la Cierva postdoctoral contract (FJCI-2017-32593). Sebastia Franch-Exposito, Coral Arnau-Collell, Jenifer Munoz, and Cristina Herrera-Pariente were supported by a contract from CIBEREHD. Marcos Diaz-Gay was supported by a contract from Agencia de Gestio d'Ajuts Universitaris i de Recerca-AGAUR-(Generalitat de Catalunya, 2019FI_B2_00203) and Yasmin Soares de Lima was awarded an INPhINIT fellowship (LCF/BQ/DI18/11660058) from la Caixa Foundation (ID 100010434 funded by the EU Horizon 2020 Programme Marie Sklodowska-Curie grant agreement no. 713673). CIBEREHD, CIBERER, and CIBERONC are funded by the Instituto de Salud Carlos III. This research was supported by grants from Fondo de Investigacion Sanitaria/FEDER (16/01292, 17/00878), Fundacion Cientifica de la Asociacion Espanola contra el Cancer (GCB13131592CAST), Spanish Ministry of Science, Innovation and Universities, co-funded by FEDER funds (SAF2016-80888-R, BIO201789754-C2-2R), PERIS (SLT002/16/00398, SLT002/16/0037, Generalitat de Catalunya), CERCA Program (Generalitat de Catalunya), and Agencia de Gestio d'Ajuts Universitaris i de Recerca (Generalitat de Catalunya, GRPRE 2017SGR21, GRC 2017SGR653, 2017SGR723, 2017SGR861, 2017SGR1282). This article is based on work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology). www.cost.eu.

Anàlisi d'autories institucional

Compartir

Germline Mutations in FAF1 Are Associated With Hereditary Colorectal Cancer

Publicat a:Gastroenterology. 159 (1): 227-+ - 2020-07-01 159(1), DOI: 10.1053/j.gastro.2020.03.015

Autors: Bonjoch, Laia; Franch-Exposito, Sebastia; Garre, Pilar; Belhadj, Sami; Munoz, Jenifer; Arnau-Collell, Coral; Diaz-Gay, Marcos; Gratacos-Mulleras, Anna; Raimondi, Giulia; Esteban-Jurado, Clara; Soares de Lima, Yasmin; Herrera-Pariente, Cristina; Cuatrecasas, Miriam; Ocana, Teresa; Castells, Antoni; Fillat, Cristina; Capella, Gabriel; Balaguer, Francesc; Caldes, Trinidad; Valle, Laura; Castellvi-Bel, Sergi

Afiliacions

Resum

A significant proportion of colorectal cancer (CRC) cases have familial aggregation but little is known about the genetic factors that contribute to these cases. We performed an exhaustive functional characterization of genetic variants associated with familial CRC.We performed whole-exome sequencing analyses of 75 patients from 40 families with a history of CRC (including early-onset cases) of an unknown germline basis (discovery cohort). We also sequenced specific genes in DNA from an external replication cohort of 473 families, including 488 patients with colorectal tumors that had normal expression of mismatch repair proteins (validation cohort). We disrupted the Fas-associated factor 1 gene (FAF1) in DLD-1 CRC cells using CRISPR/Cas9 gene editing; some cells were transfected with plasmids that express FAF1 missense variants. Cells were analyzed by immunoblots, quantitative real-time polymerase chain reaction, and functional assays monitoring apoptosis, proliferation, and assays for Wnt signaling or nuclear factor (NF)-?B activity.We identified predicted pathogenic variant in the FAF1 gene (c.1111G>A; p.Asp371Asn) in the discovery cohort; it was present in 4 patients of the same family. We identified a second variant in FAF1 in the validation cohort (c.254G>C; p.Arg85Pro). Both variants encoded unstable FAF1 proteins. Expression of these variants in CRC cells caused them to become resistant to apoptosis, accumulate b-catenin in the cytoplasm, and translocate NF-?B to the nucleus.In whole-exome sequencing analyses of patients from families with a history of CRC, we identified variants in FAF1 that associate with development of CRC. These variants encode unstable forms of FAF1 that increase resistance of CRC cells to apoptosis and increase activity of b-catenin and NF-?B.Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Paraules clau