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Title: Germline Mutations in FAF1 Are Associated With Hereditary Colorectal Cancer
Author: Bonjoch Gassol, Laia
Franch Expósito, Sebastià
Garre, Pilar
Belhadj, Sami
Muñoz, Jenifer
Arnau Collell, Coral
Díaz Gay, Marcos
Gratacós Mulleras, Anna
Raimondi, Giulia
Esteban Jurado, Clara
Soares de Lima, Yasmin
Herrera Pariente, Cristina
Cuatrecasas Freixas, Miriam
Ocaña, Teresa
Castells Garangou, Antoni
Fillat i Fonts, Cristina
Capellá, G. (Gabriel)
Balaguer Prunés, Francesc
Caldés, Trinidad
Valle Velasco, Laura
Castellví Bel, Sergi
Keywords: Càncer colorectal
Mort cel·lular
Colorectal cancer
Cell death
Issue Date: Jul-2020
Publisher: Elsevier
Abstract: Background & aims: 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. Methods: 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)-kappa-B activity. Results: 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 beta-catenin in the cytoplasm, and translocate NF-kappa-B to the nucleus. Conclusions: 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 beta-catenin and NF-kappa-B.
Note: Reproducció del document publicat a:
It is part of: Gastroenterology, 2020, vol. 159, num. 1, p. 227-240
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ISSN: 0016-5085
Appears in Collections:Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Publicacions de projectes de recerca finançats per la UE
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Ciències Clíniques)

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