Germline variation in the oxidative DNA repair genes<i>NUDT1</i>and<i>OGG1</i>is not associated with hereditary colorectal cancer or polyposis

Mur, Pilar; Jemth, Ann-Sofie; Bevc, Luka; Amaral, Nuno; Navarro, Matilde; Valdés-Mas, Rafael; Pons, Tirso; Aiza, Gemma; Urioste, Miguel; Valencia, Alfonso; Lázaro, Conxi; Puente, Xosé S.; Stenmark, Pål; Berglund, Ulrika Warpman; Capellà, Gabriel; Helleday, Thomas; Valle, Laura

doi:10.1002/humu.23564

Cited by 10 publications

(14 citation statements)

References 43 publications

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“…Polygenic inheritance has been shown to explain up to ∼15% of the familial CRC risk (Frampton et al, 2016) and at least two cases with CRC and possible digenic and oligogenic inheritance have been reported; these patients had variants in MUTYH and OGG1 (both involved in the base excision repair pathway) and in APC, OGG1, EXO1 and POLQ, respectively (Morak et al, 2011;Ciavarella et al, 2018). OGG1 was not part of our gene panel, and its role in hereditary CRC/polyposis is controversial (Smith et al, 2013;Mur et al, 2018). Intriguingly, we identified the same EXO1 variant in a patient with rectal cancer 31-yearsold (no.…”

Section: Discussionmentioning

confidence: 99%

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

et al. 2020

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A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as APC, POLE, MSH2 or PMS2. The MSH2 variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The POLE variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be de novo. One pathogenic PMS2 variant was novel. We also identified a number of highly interesting variants of unknown significance in APC, BUB1, TP53 and RPS20. The RPS20 variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple in silico tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in RPS20 expands the phenotypic spectrum of RPS20-related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels.

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Section: Discussionmentioning

confidence: 99%

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

et al. 2020

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“…Finally, MUTYH -null mice showed increased intestinal tumorigenesis and C:G>A:T transversion mutations (Sakamoto et al 2007). To date, germline variation in OGG1 and NUDT1 has not been associated with a Mendelian hereditary cancer predisposition, and MUTYH remains the only validated cancer predisposition gene linked to the SBS18/SBS36 signatures with a strong phenotype of C:G>A:T transversions (Mur et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Base excision repair deficiency signatures implicate germline and somatic MUTYH aberrations in pancreatic ductal adenocarcinoma and breast cancer oncogenesis

Thibodeau

Zhao

Reisle

et al. 2019

Cold Spring Harb Mol Case Stud

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We report a case of early-onset pancreatic ductal adenocarcinoma in a patient harboring biallelic MUTYH germline mutations, whose tumor featured somatic mutational signatures consistent with defective MUTYH -mediated base excision repair and the associated driver KRAS transversion mutation p.Gly12Cys. Analysis of an additional 730 advanced cancer cases ( N = 731) was undertaken to determine whether the mutational signatures were also present in tumors from germline MUTYH heterozygote carriers or if instead the signatures were only seen in those with biallelic loss of function. We identified two patients with breast cancer each carrying a pathogenic germline MUTYH variant with a somatic MUTYH copy loss leading to the germline variant being homozygous in the tumor and demonstrating the same somatic signatures. Our results suggest that monoallelic inactivation of MUTYH is not sufficient for C:G>A:T transversion signatures previously linked to MUTYH deficiency to arise ( N = 9), but that biallelic complete loss of MUTYH function can cause such signatures to arise even in tumors not classically seen in MUTYH -associated polyposis ( N = 3). Although defective MUTYH is not the only determinant of these signatures, MUTYH germline variants may be present in a subset of patients with tumors demonstrating elevated somatic signatures possibly suggestive of MUTYH deficiency (e.g., COSMIC Signature 18, SigProfiler SBS18/SBS36, SignatureAnalyzer SBS18/SBS36).

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“…For years, several groups undertook the study of OGG1 and NUDT1 (= MTH1 ) variants as potential causal factors of CRC predisposition. Several studies have been published, and what seemed to be promising mostly in the first years [ 22 , 23 , 24 , 25 , 26 ], reduced their degree of interest, at least as high- or moderate-risk genes, when subsequent larger studies suggested no causal association [ 27 , 28 , 29 ].…”

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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Germline variation in the oxidative DNA repair genesNUDT1andOGG1is not associated with hereditary colorectal cancer or polyposis

Cited by 10 publications

References 43 publications

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

Base excision repair deficiency signatures implicate germline and somatic MUTYH aberrations in pancreatic ductal adenocarcinoma and breast cancer oncogenesis

Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

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