Functional analysis of ATM variants in a high risk cohort provides insight into missing heritability

Baughan, Scott; Darwiche, Fatima; Tainsky, Michael A.

doi:10.1016/j.cancergen.2022.03.003

Cited by 5 publications

(1 citation statement)

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“…Complete ATM loss of function caused by biallelic ATM pathogenic variants results in the disease ataxia telangiectasia (AT), characterized by immunodeficiency, neurological degeneration and predisposition to cancer [7]. Epidemiological studies show that obligate heterozygote parents of individuals with AT reveal an increased risk of cancer, which may be true of ATM heterozygotes in the general population [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

The ATM Ser49Cys Variant Effects ATM Function as a Regulator of Oncogene-Induced Senescence

Atkinson,

McInerney-Leo,

Proctor

et al. 2024

IJMS

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An apical component of the cell cycle checkpoint and DNA damage repair response is the ataxia-telangiectasia mutated (ATM) Ser/Thr protein kinase. A variant of ATM, Ser49Cys (rs1800054; minor allele frequency = 0.011), has been associated with an elevated risk of melanoma development; however, the functional consequence of this variant is not defined. ATM-dependent signalling in response to DNA damage has been assessed in a panel of patient-derived lymphoblastoid lines and primary human melanocytic cell strains heterozygous for the ATM Ser49Cys variant allele. The ATM Ser49Cys allele appears functional for acute p53-dependent signalling in response to DNA damage. Expression of the variant allele did reduce the efficacy of oncogene expression in inducing senescence. These findings demonstrate that the ATM 146C>G Ser49Cys allele has little discernible effect on the acute response to DNA damage but has reduced function observed in the chronic response to oncogene over-expression. Analysis of melanoma, naevus and skin colour genomics and GWAS analyses have demonstrated no association of this variant with any of these outcomes. The modest loss of function detected suggest that the variant may act as a modifier of other variants of ATM/p53-dependent signalling.

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