Evidence suggests that germline <i>RNF43</i> mutations are a rare cause of serrated polyposis

Quintana, Isabel; Mejías-Luque, Raquel; Terradas, Mariona; Navarro, Matilde; Piñol, Virgı́nia; Mur, Pilar; Belhadj, Sami; Grau, Èlia; Darder, Esther; Solanes, Ares; Brunet, Joan; Capellà, Gabriel; Gerhard, Markus; Valle, Laura

doi:10.1136/gutjnl-2017-315733

Cited by 50 publications

(45 citation statements)

References 6 publications

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“…Despite recent developments in sequencing technologies, the genetic aetiology of SPS remains largely unknown. The only proposed gene for germline SPS predisposition is RNF43 , which would explain a small proportion of SPS cases 12–15…”

Section: Introductionmentioning

confidence: 99%

Colorectal cancer genetic variants are also associated with serrated polyposis syndrome susceptibility

et al. 2020

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BackgroundSerrated polyposis syndrome (SPS) is a clinical entity characterised by large and/ormultiple serrated polyps throughout the colon and increased risk for colorectal cancer (CRC). The basis for SPS genetic predisposition is largely unknown. Common, low-penetrance genetic variants have been consistently associated with CRC susceptibility, however, their role in SPS genetic predisposition has not been yet explored.ObjectiveThe aim of this study was to evaluate if common, low-penetrance genetic variants for CRC risk are also implicated in SPS genetic susceptibility.MethodsA case-control study was performed in 219 SPS patients and 548 asymptomatic controls analysing 65 CRC susceptibility variants. A risk prediction model for SPS predisposition was developed.ResultsStatistically significant associations with SPS were found for seven genetic variants (rs4779584-GREM1, rs16892766-EIF3H, rs3217810-CCND2, rs992157-PNKD1/TMBIM1, rs704017-ZMIZ1, rs11196172-TCF7L2, rs6061231-LAMA5). The GREM1 risk allele was remarkably over-represented in SPS cases compared with controls (OR=1.573, 1.21–2.04, p value=0.0006). A fourfold increase in SPS risk was observed when comparing subjects within the highest decile of variants (≥65) with those in the first decile (≤50).ConclusionsGenetic variants for CRC risk are also involved in SPS susceptibility, being the most relevant ones rs4779584-GREM1, rs16892766-EIF3H and rs3217810-CCND2.

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Section: Introductionmentioning

confidence: 99%

Colorectal cancer genetic variants are also associated with serrated polyposis syndrome susceptibility

et al. 2020

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“…Pathogenic germline variants of RNF43 gene have been described in about 2% of SPS patients. 52,53 It is important to reiterate that serrated polyps may also occur in other polyposis syndromes, commonly in MUTYH polyposis and hereditary mixed polyposis syndrome associated with GREM1 germline mutations. 54 These possibilities must be excluded before rendering a diagnosis of SPS.…”

Section: Serrated Polyposis Syndromementioning

confidence: 99%

Adenomatous and serrated polyposis syndromes

Srivastava

2020

Diagnostic Histopathology

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“… g Results from functional assays performed by Quintana et al () were considered to classify this variant using InterVar.…”

Section: Rnf43 Mutations Do Not Cause Nonserrated Polyposismentioning

confidence: 99%

“…Although known to be rare, some of the newly described polyposis genes, such as MSH3 (Adam et al, ), lack of reported data on their actual frequency among polyposis cases without mutations in the classically associated polyposis genes (i.e., APC and MUTYH ), or as NTHL1 , this information is scarce in the literature (Grolleman et al, ). On the contrary, five of the 13 reported carriers of RNF43 mutations, in addition to the serrated/hyperplastic polyps, had developed several adenomas, suggesting a potential implication of RNF43 in the predisposition to adenomatous polyposis and/or polyposis of multiple polyp types (reviewed by Quintana et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…A detailed description of the evidence used for variant classification is shown inTable S2. Ad., and 1 rectal cancer) from c.953−1G>A mutation carriers studied had either somatic LOH or mutations in RNF43.Results from functional assays performed byQuintana et al (2018) were considered to classify this variant using InterVar.CIMP assessed using the ME042-C1 CIMP MS-MLPA kit (MRC-Holland, Amsterdam, the Netherlands). Methylated gene promoters (>20% methylation): IGF2, RUNX3, NEURO, CDKN2A, CRABP1.…”

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Contribution to colonic polyposis of recently proposed predisposing genes and assessment of the prevalence of NTHL1 ‐ and MSH3 ‐associated polyposes

et al. 2019

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Technological advances have allowed the identification of new adenomatous and serrated polyposis genes, and of several candidate genes that require additional supporting evidence of causality. Through an exhaustive literature review and mutational screening of 177 unrelated polyposis patients, we assessed the involvement of MCM9, FOCAD, POLQ, and RNF43 in the predisposition to (nonserrated) colonic polyposis, as well as the prevalence of NTHL1 and MSH3 mutations among genetically unexplained polyposis patients. Our results, together with previously reported data and mutation frequency in controls, indicate that: MCM9 and POLQ mutations are not associated with polyposis; germline RNF43 mutations, with a prevalence of 1.5–2.5% among serrated polyposis patients, do not cause nonserrated polyposis; MSH3 biallelic mutations are highly infrequent among European polyposis patients, and the prevalence of NTHL1 biallelic mutations among unexplained polyposes is ~2%. Although nonsignificant, FOCAD predicted deleterious variants are overrepresented in polyposis patients compared to controls, warranting larger studies to provide definite evidence in favor or against their causal association with polyposis predisposition.

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Evidence suggests that germline RNF43 mutations are a rare cause of serrated polyposis

Cited by 50 publications

References 6 publications

Colorectal cancer genetic variants are also associated with serrated polyposis syndrome susceptibility

Colorectal cancer genetic variants are also associated with serrated polyposis syndrome susceptibility

Adenomatous and serrated polyposis syndromes

Contribution to colonic polyposis of recently proposed predisposing genes and assessment of the prevalence of NTHL1 ‐ and MSH3 ‐associated polyposes

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