Germline Mutations in FAF1 Are Associated With Hereditary Colorectal Cancer

Bonjoch, Laia; Franch-Expósito, Sebastià; Garré, Pilar; Belhadj, Sami; Muñoz, Jenifer; Arnau‐Collell, Coral; Díaz‐Gay, Marcos; Gratacós-Mulleras, Anna; Raimondi, Giulia; Esteban-Jurado, Clara; Lima, Yasmin Soares de; Herrera‐Pariente, Cristina; Cuatrecasas, Míriam; Ocaña, Teresa; Castells, Antoni; Fillat, Cristina; Capellà, Gabriel; Balaguer, Francesc; Caldés, Trinidad; Valle, Laura; Castellví–Bel, Sergi

doi:10.1053/j.gastro.2020.03.015

Cited by 19 publications

(31 citation statements)

References 49 publications

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“…Recently, likely pathogenic missense variants in FAF1 were identified in two CRC families [ 80 ]. FAF1 is a likely tumor suppressor gene that encodes a pro-apoptotic scaffolding protein that inhibits NF-κB nuclear translocation and activation, antagonizes the canonical Wnt signaling pathway, participates in DNA replication fork dynamics, and is involved in receptor-dependent and -independent apoptosis.…”

Section: Candidate Causal Genes For Mismatch Repair Proficient Hermentioning

confidence: 99%

“…FAF1 is a likely tumor suppressor gene that encodes a pro-apoptotic scaffolding protein that inhibits NF-κB nuclear translocation and activation, antagonizes the canonical Wnt signaling pathway, participates in DNA replication fork dynamics, and is involved in receptor-dependent and -independent apoptosis. Cosegregation results and functional analyses covering almost all the functions described led the authors to suggest that germline FAF1 mutations are implicated in inherited susceptibility to CRC [ 80 ]. In contrast, exome sequencing data from cases and controls seem to suggest otherwise ( Table S2 ) [ 28 ].…”

Section: Candidate Causal Genes For Mismatch Repair Proficient Hermentioning

confidence: 99%

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Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

Terradas

Capellà

Valle

2020

JCM

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In the past two decades, multiple studies have been undertaken to elucidate the genetic cause of the predisposition to mismatch repair (MMR)-proficient nonpolyposis colorectal cancer (CRC). Here, we present the proposed candidate genes according to their involvement in specific pathways considered relevant in hereditary CRC and/or colorectal carcinogenesis. To date, only pathogenic variants in RPS20 may be convincedly linked to hereditary CRC. Nevertheless, accumulated evidence supports the involvement in the CRC predisposition of other genes, including MRE11, BARD1, POT1, BUB1B, POLE2, BRF1, IL12RB1, PTPN12, or the epigenetic alteration of PTPRJ. The contribution of the identified candidate genes to familial/early onset MMR-proficient nonpolyposis CRC, if any, is extremely small, suggesting that other factors, such as the accumulation of low risk CRC alleles, shared environmental exposures, and/or gene–environmental interactions, may explain the missing heritability in CRC.

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Section: Candidate Causal Genes For Mismatch Repair Proficient Hermentioning

confidence: 99%

Section: Candidate Causal Genes For Mismatch Repair Proficient Hermentioning

confidence: 99%

Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

Terradas

Capellà

Valle

2020

JCM

Self Cite

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“…We reviewed these studies following the general setup of candidate discovery studies, which cover cohort composition, variant discovery and prioritization, and variant validation ( Table 1 , Table S1 ). Six studies based discovery on the same cohort that was enlarged over time [ 53 , 64 , 69 , 72 , 75 , 76 ].…”

Section: Strategies For Identification Of Rare High-penetrant Riskmentioning

confidence: 99%

“…We noted that among the 37 candidate gene discovery studies, FH-based inclusion criteria varied from study to study. Some studies used a relatively broad inclusion criterion such as “one first-degree relative or second-degree relative with CRC” while others applied more stringent criteria “the presence of at least three relatives with CRC, of which at least two in consecutive affected generations and at least one case diagnosed with CRC before the age of 60” ( Table 1 : Inclusion criteria FH) [ 42 , 43 , 48 , 50 , 53 , 56 , 59 , 64 , 69 , 70 , 72 , 75 , 76 ]. Furthermore, phenotypic characteristics strongly associated with hereditary CRC and polyposis syndromes, such as tumor types and age-of-onset strongly varied between, but also within cohorts ( Table 1 : Inclusion criteria index phenotype; Table 1 : Inclusion criteria age).…”

Section: Strategies For Identification Of Rare High-penetrant Riskmentioning

confidence: 99%

“…Age-based inclusion criteria were applied in twelve out of the 32 unique discovery cohorts [ 13 , 43 , 47 , 49 , 53 , 54 , 56 , 59 , 64 , 65 , 67 , 69 , 70 , 71 , 72 , 75 , 76 ]. However, this age-based inclusion criterion was heterogeneous ranging from an age at diagnosis ≤35 years [ 47 ] to diagnosis <60 years [ 43 ], to at least one relative diagnosed <60 years [ 53 , 64 , 69 , 72 , 75 , 76 ]. The observed heterogeneity within these NGS study cohorts is in contrast with the discovery studies that were performed before the NGS-era, as discovery studies before the NGS-era were directed to families with multiple affected members and a strong phenotype of hCRC and/or polyposis.…”

Section: Strategies For Identification Of Rare High-penetrant Riskmentioning

confidence: 99%

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Candidate Gene Discovery in Hereditary Colorectal Cancer and Polyposis Syndromes–Considerations for Future Studies

Paske

Ligtenberg

Hoogerbrugge

et al. 2020

IJMS

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To discover novel high-penetrant risk loci for hereditary colorectal cancer (hCRC) and polyposis syndromes many whole-exome and whole-genome sequencing (WES/WGS) studies have been performed. Remarkably, these studies resulted in only a few novel high-penetrant risk genes. Given this observation, the possibility and strategy to identify high-penetrant risk genes for hCRC and polyposis needs reconsideration. Therefore, we reviewed the study design of WES/WGS-based hCRC and polyposis gene discovery studies (n = 37) and provide recommendations to optimize discovery and validation strategies. The group of genetically unresolved patients is phenotypically heterogeneous, and likely composed of distinct molecular subtypes. This knowledge advocates for the screening of a homogeneous, stringently preselected discovery cohort and obtaining multi-level evidence for variant pathogenicity. This evidence can be collected by characterizing the molecular landscape of tumors from individuals with the same affected gene or by functional validation in cell-based models. Together, the combined approach of a phenotype-driven, tumor-based candidate gene search might elucidate the potential contribution of novel genetic predispositions in genetically unresolved hCRC and polyposis.

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A protein‐lipid complex that detoxifies free fatty acids

Cui

2022

BioEssays

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Fatty acids (FAs) are well known to serve as substrates for reactions that provide cells with membranes and energy. In contrast to these metabolic reactions, the physiological importance of FAs themselves known as free FAs (FFAs) in cells remains obscure. Since accumulation of FFAs in cells is toxic, cells must develop mechanisms to detoxify FFAs. One such mechanism is to sequester free polyunsaturated FAs (PUFAs) into a droplet‐like structure assembled by Fas‐Associated Factor 1 (FAF1), a cytosolic protein. This sequestration limits access of PUFAs to Fe2+, thereby preventing Fe2+‐catalyzed PUFA peroxidation. Consequently, assembly of the FAF1‐FFA complex is critical to protect cells from ferroptosis, a cell death pathway triggered by PUFA peroxidation. The observations that free PUFAs in cytosol are not randomly diffused but rather sequestered into a membraneless complex should open new directions to explore signaling pathways by which FFAs regulate cellular physiology.

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Germline Mutations in FAF1 Are Associated With Hereditary Colorectal Cancer

Cited by 19 publications

References 49 publications

Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

Candidate Gene Discovery in Hereditary Colorectal Cancer and Polyposis Syndromes–Considerations for Future Studies

A protein‐lipid complex that detoxifies free fatty acids

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