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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.

Analysis of institutional authors

Bonjoch Gassol, LaiaAuthorFranch-Expósito SAuthorMuñoz JAuthorArnau-Collell CAuthorDíaz-Gay MAuthorRaimondi GAuthorEsteban-Jurado CAuthorSoares De Lima YAuthorHerrera-Pariente, COthersCuatrecasas MAuthorOcana, TAuthorCastells AAuthorFillat CAuthorBalaguer FAuthorCastellvi-Bel SCorresponding Author

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Article

Germline Mutations in FAF1 Are Associated With Hereditary Colorectal Cancer

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

Authors: 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

Affiliations

Ctr Invest Biomed Red Canc CIBERONC, Catalan Inst Oncol, Inst Invest Biomed Bellvitge IDIBELL, Hereditary Canc Program,Oncobell, Barcelona, Spain - Author
Hosp Clin Barcelona, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Pathol Dept, Barcelona, Spain - Author
Hosp Clin Barcelona, Tumor Bank Biobank, Barcelona, Spain - Author
Hosp Clin San Carlos, Mol Oncol Lab, Ctr Invest Biomed Red Canc CIBERONC, Inst Invest Sanitaria San Carlos IdISSC, Madrid, Spain - Author
Univ Barcelona, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Gene Therapy & Canc, Barcelona, Spain - Author
Univ Barcelona, Hosp Clin, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Inst Invest Biomed August Pi & Sunyer IDIBAP,Gast, Barcelona, Spain - Author
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Abstract

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.

Keywords

apoptosisfunctional genomicsgene editinggenetic-variantsguidelineslymphomapathwaypredispositionprogrammed cell deathproteinrisksubunitAdaptor proteins, signal transducingAgedApoptosisApoptosis regulatory proteinsBeta cateninCancer colorectalCell deathCell line, tumorColorectal cancerColorectal neoplasmsCtnnb1 protein, humanDna mutational analysisExome sequencingFaf1 protein, humanFas-associated factor-1FemaleFunctional genomicsGene editingGene knockout techniquesGenetic predisposition to diseaseGerm-line mutationHumansMaleMiddle agedMort cel·lularMutagenesis, site-directedNeoplastic syndromes, hereditaryNf-kappa bPedigreeProgrammed cell deathWnt signalingWnt signaling pathway

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Gastroenterology due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2020, it was in position 4/92, thus managing to position itself as a Q1 (Primer Cuartil), in the category Gastroenterology & Hepatology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations from Scopus Elsevier, it yields a value for the Field-Weighted Citation Impact from the Scopus agency: 1.16, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Field Citation Ratio (FCR) from Dimensions: 4.81 (source consulted: Dimensions Jun 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-06-17, the following number of citations:

  • WoS: 21
  • Scopus: 22
  • Europe PMC: 17
  • Google Scholar: 22
  • OpenCitations: 17

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-17:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 64.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 64 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 36.4.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 36 (Altmetric).
  • The number of mentions in news outlets: 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Bonjoch L) and Last Author (Castellví Bel, Sergi).

the author responsible for correspondence tasks has been Castellví Bel, Sergi.