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Germline variation in the oxidative DNA repair genes NUDT1 and OGG1 is not associated with hereditary colorectal cancer or polyposis
Author(s) -
Mur Pilar,
Jemth AnnSofie,
Bevc Luka,
Amaral Nuno,
Navarro Matilde,
ValdésMas Rafael,
Pons Tirso,
Aiza Gemma,
Urioste Miguel,
Valencia Alfonso,
Lázaro Conxi,
Moreno Victor,
Puente Xose S.,
Stenmark Pål,
WarpmanBerglund Ulrika,
Capellá Gabriel,
Helleday Thomas,
Valle Laura
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23564
Subject(s) - biology , genetics , germline , colorectal cancer , germline mutation , missense mutation , dna mismatch repair , gene , cancer , mutation , cancer research
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.