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Germline variation in the oxidative DNA repair genes NUDT1 and OGG1 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 and Valencia, Alfonso , et al. (2018) In Human Mutation 39(9). p.1214-1225
Abstract

The causal association of NUDT1 (=MTH1) and OGG1 with hereditary colorectal cancer (CRC) remains unclear. Here, we sought to provide additional evidence for or against the causal contribution of NUDT1 and OGG1 mutations to hereditary CRC and/or polyposis. Mutational screening was performed using pooled DNA amplification and targeted next-generation sequencing in 529 families (441 uncharacterized MMR-proficient familial nonpolyposis CRC and 88 polyposis cases). Cosegregation, in silico analyses, in vitro functional assays, and case-control associations were carried out to characterize the identified variants. Five heterozygous carriers of novel (n = 1) or rare (n = 4) NUDT1 variants were identified. In vitro deleterious effects were... (More)

The causal association of NUDT1 (=MTH1) and OGG1 with hereditary colorectal cancer (CRC) remains unclear. Here, we sought to provide additional evidence for or against the causal contribution of NUDT1 and OGG1 mutations to hereditary CRC and/or polyposis. Mutational screening was performed using pooled DNA amplification and targeted next-generation sequencing in 529 families (441 uncharacterized MMR-proficient familial nonpolyposis CRC and 88 polyposis cases). Cosegregation, in silico analyses, in vitro functional assays, and case-control associations were carried out to characterize the identified variants. Five heterozygous carriers of novel (n = 1) or rare (n = 4) NUDT1 variants were identified. In vitro deleterious effects were demonstrated for c.143G>A p.G48E (catalytic activity and protein stability) and c.403G>T p.G135W (protein stability), although cosegregation data in the carrier families were inconclusive or nonsupportive. The frequency of missense, loss-of-function, and splice-site NUDT1 variants in our familial CRC cohort was similar to the one observed in cancer-free individuals, suggesting lack of association with CRC predisposition. No OGG1 pathogenic mutations were identified. Our results suggest that the contribution of NUDT1 and OGG1 germline mutations to hereditary CRC and to polyposis is inexistent or, at most, negligible. The inclusion of these genes in routine genetic testing is not recommended.

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published
in
Human Mutation
volume
39
issue
9
pages
1214 - 1225
publisher
John Wiley & Sons
external identifiers
  • pmid:29900613
  • scopus:85050653312
ISSN
1059-7794
DOI
10.1002/humu.23564
language
English
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no
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© 2018 Wiley Periodicals, Inc.
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c3187e9c-9059-4640-839d-e15cbb0f74f4
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2019-04-30 07:46:06
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2020-02-12 10:00:19
@article{c3187e9c-9059-4640-839d-e15cbb0f74f4,
  abstract     = {<p>The causal association of NUDT1 (=MTH1) and OGG1 with hereditary colorectal cancer (CRC) remains unclear. Here, we sought to provide additional evidence for or against the causal contribution of NUDT1 and OGG1 mutations to hereditary CRC and/or polyposis. Mutational screening was performed using pooled DNA amplification and targeted next-generation sequencing in 529 families (441 uncharacterized MMR-proficient familial nonpolyposis CRC and 88 polyposis cases). Cosegregation, in silico analyses, in vitro functional assays, and case-control associations were carried out to characterize the identified variants. Five heterozygous carriers of novel (n = 1) or rare (n = 4) NUDT1 variants were identified. In vitro deleterious effects were demonstrated for c.143G&gt;A p.G48E (catalytic activity and protein stability) and c.403G&gt;T p.G135W (protein stability), although cosegregation data in the carrier families were inconclusive or nonsupportive. The frequency of missense, loss-of-function, and splice-site NUDT1 variants in our familial CRC cohort was similar to the one observed in cancer-free individuals, suggesting lack of association with CRC predisposition. No OGG1 pathogenic mutations were identified. Our results suggest that the contribution of NUDT1 and OGG1 germline mutations to hereditary CRC and to polyposis is inexistent or, at most, negligible. The inclusion of these genes in routine genetic testing is not recommended.</p>},
  author       = {Mur, Pilar and Jemth, Ann-Sofie and Bevc, Luka and Amaral, Nuno and Navarro, Matilde and Valdés-Mas, Rafael and Pons, Tirso and Aiza, Gemma and Urioste, Miguel and Valencia, Alfonso and Lázaro, Conxi and Moreno, Victor and Puente, Xose S and Stenmark, Pål and Warpman-Berglund, Ulrika and Capellá, Gabriel and Helleday, Thomas and Valle, Laura},
  issn         = {1059-7794},
  language     = {eng},
  number       = {9},
  pages        = {1214--1225},
  publisher    = {John Wiley & Sons},
  series       = {Human Mutation},
  title        = {Germline variation in the oxidative DNA repair genes NUDT1 and OGG1 is not associated with hereditary colorectal cancer or polyposis},
  url          = {http://dx.doi.org/10.1002/humu.23564},
  doi          = {10.1002/humu.23564},
  volume       = {39},
  year         = {2018},
}