A pleiotropic ATM variant (rs1800057 C>G) is associated with risk of multiple cancers.

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Date

2021-10-13

Authors

Qian, Danwen
Liu, Hongliang
Zhao, Lingling
Luo, Sheng
Walsh, Kyle M
Huang, Jiaoti
Li, Chuan-Yuan
Wei, Qingyi

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Abstract

ATM (ataxia-telangiectasia mutated) is an important cell-cycle checkpoint kinase required for cellular response to DNA damage. Activated by DNA double strand breaks, ATM regulates the activities of many downstream proteins involved in various carcinogenic events. Therefore, ATM or its genetic variants may have a pleiotropic effect in cancer development. We conducted a pleiotropic analysis to evaluate associations between genetic variants of ATM and risk of multiple cancers. With genotyping data extracted from previously published genome-wide association studies of various cancers, we performed multivariate logistic regression analysis, followed by a meta-analysis for each cancer site, to identify cancer risk-associated single-nucleotide polymorphisms (SNPs). In the ASSET two-sided analysis, we found that two ATM SNPs were significantly associated with risk of multiple cancers. One tagging SNP (rs1800057 C>G) was associated with risk of multiple cancers (two-sided P=5.27×10 -7). Because ATM rs1800057 is a missense variant, we also explored the intermediate phenotypes through which this variant may confer risk of multiple cancers and identified a possible immune-mediated effect of this variant. Our findings indicate that genetic variants of ATM may have a pleiotropic effect on cancer risk and thus provide an important insight into common mechanisms of carcinogenesis.

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Journal article

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ATM, genetic susceptibility, multiple cancers risk, pleiotropic association, polymorphism

Citation

Published Version (Please cite this version)

10.1093/carcin/bgab092

Publication Info

Qian, Danwen, Hongliang Liu, Lingling Zhao, Sheng Luo, Kyle M Walsh, Jiaoti Huang, Chuan-Yuan Li, Qingyi Wei, et al. (2021). A pleiotropic ATM variant (rs1800057 C>G) is associated with risk of multiple cancers. Carcinogenesis. 10.1093/carcin/bgab092 Retrieved from https://hdl.handle.net/10161/23955.

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Scholars@Duke

Luo

Sheng Luo

Professor of Biostatistics & Bioinformatics
Walsh

Kyle Walsh

Associate Professor in Neurosurgery

Dr. Walsh is Associate Professor of Neurosurgery and Pathology, Director of the Division of Neuro-epidemiology, and a Senior Fellow in the Duke Center for the Study of Aging and Human Development. He leads Duke’s Neuro-epidemiology Lab, which integrates bench science with statistical methods to study the neurobiology of glial senescence and gliomagenesis. This research interrogates human genomic and epigenomic profiles to identify both heritable and modifiable factors that contribute to neurologic and physical decline, applying these approaches to studying the shared neurobiology of cognition, glial senescence, and gliomagenesis. The lab has a long history studying telomere maintenance in pre-malignant cells and its role in the development of cancer, most notably glioblastoma.


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