Correspondence: SEMA4A variation and risk of colorectal cancer

Kinnersley, Ben; Chubb, Daniel; Dobbins, Sara E.; Frampton, Matthew; Buch, Stephan; Timofeeva, Maria; Castellví–Bel, Sergi; Farrington, Susan M.; Försti, Asta; Hampe, Jochen; Hemminki, Kari; Hofstra, Robert M.W.; Northwood, Emma; Palles, Claire; Pinheiro, Manuela; Ruíz-Ponte, Clara; Schafmayer, Clemens; Teixeira, Manuel R.; Westers, Helga; Wezel, Tom van; Bishop, D. Timothy; Tomlinson, Ian; Dunlop, Malcolm G.; Houlston, Richard S.

doi:10.1038/ncomms10611

Cited by 7 publications

(8 citation statements)

References 4 publications

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“…Considering all three studies together (Kinnersley et al, 2016; Schulz et al, 2014; current study), while no enrichment of Type‐A variants was found in cases ( p = 1), Type‐B variants were identified more frequently in cases (10/3,066; 0.33%) than in controls (229/118,190; 0.19%), although the difference did not reach statistical significance ( p = 0.1) (Table 3; Figure 1). In this context, two potential scenarios may have occurred: (a) Missense variants, probably affecting a specific domain of the protein, are the ones increasing CRC risk; or (b) the (nonsignificant) association detected for Type‐B variants is not real and will disappear when analyzing larger cohorts.…”

Section: Resultsmentioning

confidence: 99%

“…Despite this knowledge, much of the genetic predisposition to CRC is still unexplained. In the last years, by using genome‐wide approaches such as whole‐genome and whole‐exome sequencing, or copy number variation (CNV) analysis, multiple candidate genes for CRC predisposition have been proposed, including RPS20 (MIM# 603682), IL12RB1 (MIM# 601604), LIMK2 (MIM# 601988), POLE2 (MIM# 602670), MRE11 (MIM# 600814), POT1 (MIM# 606478), FAN1 (MIM# 613534), WIF1 (MIM# 605186), HNRNPA0 (MIM# 609409), SEMA4A (MIM# 607292), FOCAD (MIM# 614606), PTPN12 (MIM# 600079), LRP6 (MIM# 603507), POLQ (MIM# 604419), BLM (MIM# 604610), MCM9 (MIM# 610098), and the epigenetic inactivation of PTPRJ (MIM# 600925), among others (Chubb, Broderick, Dobbins, Frampton et al, 2016; de Voer et al, 2015; de Voer et al, 2016; Goldberg et al, 2015; Kinnersley et al, 2016; Nieminen et al, 2014; Raskin et al, 2017; Schulz et al, 2014; Segui et al, 2015; Sill, Schulz, Steinke‐Lange, & Boland, 2016; Spier et al, 2015; Valle, 2017; Venkatachalam et al, 2010; Venkatachalam et al, 2011; Wei et al, 2015; Weren et al, 2015). The reported supporting evidence varies considerably among candidate genes: while some studies provide evidence of co‐segregation, somatic second hits, functional effects and/or higher mutational frequency in cases versus controls, other reports are inconclusive.…”

Section: Introductionmentioning

confidence: 99%

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Candidate genes for hereditary colorectal cancer: Mutational screening and systematic review

et al. 2020

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Genome‐wide approaches applied for the identification of new hereditary colorectal cancer (CRC) genes, identified several potential causal genes, including RPS20, IL12RB1, LIMK2, POLE2, MRE11, POT1, FAN1, WIF1, HNRNPA0, SEMA4A, FOCAD, PTPN12, LRP6, POLQ, BLM, MCM9, and the epigenetic inactivation of PTPRJ. Here we attempted to validate the association between variants in these genes and nonpolyposis CRC by performing a mutational screening of the genes and PTPRJ promoter methylation analysis in 473 familial/early‐onset CRC cases, a systematic review of the published cases, and assessment of allele frequencies in control population. In the studied cohort, 24 (5%) carriers of (predicted) deleterious variants in the studied genes and no constitutional PTPRJ epimutations were identified. Assessment of allele frequencies in controls compared with familial/early‐onset patients with CRC showed association with increased nonpolyposis CRC risk of disruptive variants in RPS20, IL12RB1, POLE2, MRE11 and POT1, and of FAN1 c.149T>G (p.Met50Arg). Lack of association was demonstrated for LIMK2, PTPN12, LRP6, PTPRJ, POLQ, BLM, MCM9 and FOCAD variants. Additional studies are required to provide conclusive evidence for SEMA4A, WIF1, HNRNPA0 c.−110G>C, and FOCAD large deletions.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Candidate genes for hereditary colorectal cancer: Mutational screening and systematic review

et al. 2020

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“…SEMA4A , a gene coding for the membrane-bound signaling protein Semaphorin 4A, was first associated with CRC predisposition by Schulz et al (2014), who estimated a 6.8-fold increased CRC risk for the variant p.Pro682Ser [ 87 ]. Subsequently, Kinnersley et al (2015) assessed the presence of p.Pro682Ser and p.Gly484Ala in ~7000 CRC cases and 10,000 controls, finding no association with CRC [ 88 ]. We performed a mutational screening of the gene in 473 familial/early onset CRC cases, finding one rare predicted pathogenic missense variant.…”

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

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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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“…For the SEMA4A gene, first described as a strong candidate for hereditary nonpolyposis CRC, 79 a subsequent study failed to validate the variation in SEMA4A as a determinant of CRC risk. 80 In conclusion, the confirmation of the diagnostic value of all these candidate genes depends on the publication of additional supporting and conclusive evidence.…”

Section: Genes Identified Through Agnostic Approachesmentioning

confidence: 97%

Recent Discoveries in the Genetics of Familial Colorectal Cancer and Polyposis

Valle

2017

Clinical Gastroenterology and Hepatology

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The development of genome-wide massively parallel sequencing, ie, whole-genome and whole-exome sequencing, and copy number approaches has raised high expectations for the identification of novel hereditary colorectal cancer genes. Although relatively successful for genes causing adenomatous polyposis syndromes, both autosomal dominant and recessive, the identification of genes associated with hereditary non-polyposis colorectal cancer has proven extremely challenging, mainly because of the absence of major high-penetrance genes and the difficulty in demonstrating the functional impact of the identified variants and their causal association with tumor development. Indeed, most, if not all, novel candidate non-polyposis colorectal cancer genes identified so far lack corroborative data in independent studies. Here we review the novel hereditary colorectal cancer genes and syndromes identified and the candidate genes proposed in recent years as well as discuss the challenges we face.

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Correspondence: SEMA4A variation and risk of colorectal cancer

Cited by 7 publications

References 4 publications

Candidate genes for hereditary colorectal cancer: Mutational screening and systematic review

Candidate genes for hereditary colorectal cancer: Mutational screening and systematic review

Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

Recent Discoveries in the Genetics of Familial Colorectal Cancer and Polyposis

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