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2020-07

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cc-by-nc-nd (c) AGA Institute, 2020
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/176858

Germline Mutations in FAF1 Are Associated With Hereditary Colorectal Cancer

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Recurs relacionat

https://doi.org/10.1053/j.gastro.2020.03.015

Resum

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.

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Càncer colorectal, Mort cel·lular

Matèries (anglès)

Colorectal cancer, Cell death

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Articles publicats en revistes (Ciències Clíniques)
<b>Publicacions de projectes de recerca finançats per la UE</b>
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

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. Germline Mutations in FAF1 Are Associated With Hereditary Colorectal Cancer. _Gastroenterology_. 2020. Vol. 159, núm. 1, pàgs. 227-240. [consulta: 25 de gener de 2026]. ISSN: 0016-5085. [Disponible a: https://hdl.handle.net/2445/176858]

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