Germline variation in the oxidative DNA repair genes NUDT1 and OGG1 is not associated with hereditary colorectal cancer or polyposis. Issue 9 (4th July 2018)

• Record Type: Journal Article
• Authors: Mur, Pilar; Jemth, Ann‐Sofie; Bevc, Luka; Amaral, Nuno; Navarro, Matilde; Valdés‐Mas, Rafael; Pons, Tirso; Aiza, Gemma; Urioste, Miguel; Valencia, Alfonso; Lázaro, Conxi; Moreno, Victor; Puente, Xose S.; Stenmark, Pål; Warpman‐Berglund, Ulrika; Capellá, Gabriel; Helleday, Thomas; Valle, Laura
• Is Part Of: Human mutation. Volume 39:Issue 9(2018)
• Page Start: 1214
• Page End: 1225
• Publication Date: 2018-07-04
• Subjects: base excision repair -- colorectal cancer predisposition -- genetic testing -- germline mutation -- hereditary cancer -- MTH1 -- NUDT1 -- OGG1 -- oxidative DNA repair; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23564
• Languages: English
• ISSNs: 1059-7794

Abstract

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 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. Abstract : The evidence supporting a causal association of germline mutations in NUDT1 and OGG1 with hereditary colorectal cancer (CRC) or polyposis is currently insufficient/contradictory. We performed the mutational screening of the two genes in 529 families with unexplained mismatch repair‐proficient familial nonpolyposis CRC or polyposis, followed by co‐segregation analyses and extensive functional assays. Heterozygous NUDT1 and OGG1 germline variants are not a relevant cause of hereditary CRC or polyposis, therefore, their screening is not recommended in routine genetic testing.