Uncovering variable neoplasms between ATM protein-truncating and common missense variants using 394 694 UK Biobank exomes.

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Tytuł:: Uncovering variable neoplasms between ATM protein-truncating and common missense variants using 394 694 UK Biobank exomes.
Autorzy:: Jiang X; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
O'Neill A; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Smith KR; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Lai Z; Translational Medicine, Early Oncology R&D, AstraZeneca, Waltham, Massachusetts, USA.
Carss K; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Wang Q; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, Massachusetts, USA.
Petrovski S; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Źródło:: Genes, chromosomes & cancer [Genes Chromosomes Cancer] 2022 Sep; Vol. 61 (9), pp. 523-529. Date of Electronic Publication: 2022 Apr 16.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: New York, NY : Wiley-Liss
Original Publication: New York : A.R. Liss, c1989-
MeSH Terms:: Ataxia Telangiectasia Mutated Proteins*/genetics
Breast Neoplasms*/genetics
Mutation, Missense*
Neoplasms*/genetics
Biological Specimen Banks ; Cell Cycle Proteins/genetics ; DNA-Binding Proteins/genetics ; Exome ; Female ; Genetic Predisposition to Disease ; Humans ; United Kingdom
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Grant Information:: MC_PC_17228 United Kingdom MRC_ Medical Research Council; MC_QA137853 United Kingdom MRC_ Medical Research Council
Contributed Indexing:: Keywords: ATM; UK Biobank; missense variants; neoplasms; protein-truncating variants; whole-exome sequencing
Substance Nomenclature:: 0 (Cell Cycle Proteins)
0 (DNA-Binding Proteins)
EC 2.7.11.1 (ATM protein, human)
EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
Entry Date(s):: Date Created: 20220408 Date Completed: 20220712 Latest Revision: 20230802
Update Code:: 20240105
DOI:: 10.1002/gcc.23042
PMID:: 35394676
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As an essential regulator of DNA damage, ataxia-telangiectasia mutated (ATM) gene has been widely studied in oncology. However, the independent effects of ATM missense variants and protein-truncating variants (PTVs) on neoplasms have not been heavily studied. Whole-exome sequencing data and the clinical health records of 394,694 UK Biobank European participants were used in this analysis. We mined genetic associations from gene-level and variant-level phenome-wide association studies, and conducted a variant-level conditional association study to test whether the effects of ATM missense variants on neoplasms were independent of ATM PTV carrier status. The gene-level PTV collapsing analysis was consistent with established ATM PTV literature showing that the aggregated impact of 286 ATM PTVs significantly (p < 2 × 10 -9 ) associated with 31 malignant neoplasm phenotypes. Of 773 distinct protein-coding variants in ATM, three individual missense variants significantly (p < 2 × 10 -9 ) associated with nine phenotypes. Remarkably, although the nine phenotypes were tumor-related, none overlapped the established ATM PTV-linked malignancies. A subsequent conditional analysis identified that the missense signals were acting independently of the known clinically relevant ATM PTVs.
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