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A cis-eQTL genetic variant of the cancer–testis gene CCDC116 is associated with risk of multiple cancers

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Abstract

Recent studies have found that cancer–testis (CT) genes, which are expressed predominantly in germ and cancer cells, may be candidate cancer drivers. Because of their crucial roles, genetic variants in these genes may contribute to the development of cancer. Here, we systematically evaluated associations of common variants in CT genes and their promoters for the risk of lung cancer in our initial GWAS (2331 cases and 3077 controls), followed by in silico replication using additional 10,512 lung cancer cases and 9562 controls. We found a significant association between rs3747093 located in the CCDC116 promoter and lung cancer risk (OR = 0.91, P meta = 7.81 × 10−6). Although CCDC116 was expressed at lower levels in somatic tissues compared to the testis, the protective allele A of rs3747093 was associated with decreased CCDC116 expression in many normal tissues, including the lung (P = 8.1 × 10−13). We subsequently genotyped this variant in another four commonly diagnosed cancers (gastric, esophageal, colorectal, and breast cancers), as we found expression quantitative trait locus (eQTL) signals for rs3747093 and CCDC116 in their corresponding normal tissues. Interestingly, we observed consistent associations between rs3747093 and multiple cancers (gastric cancer: OR = 0.85, P = 2.21 × 10−4; esophageal cancer: OR = 0.91, P = 2.57 × 10−2; colorectal cancer: OR = 0.80, P = 1.85 × 10−6; and breast cancer: OR = 0.87, P = 1.55 × 10−3). Taken together, the A allele of rs3747093 showed significant protective effects on cancer risk (OR = 0.88, P pool = 6.52 × 10−13) in an Asian population. Moreover, our findings suggest that low abundance expression of CT genes in normal tissues may also contribute to tumorigenesis, providing a new mechanism of CT genes in the development of cancer.

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Abbreviations

CT:

Cancer–testis

GWAS:

Genome-wide association study

eQTL:

Expression quantitative trait locus

SNP:

Single nucleotide polymorphism

QC:

Quality control

FDR:

False discovery rate

ENCODE:

Encyclopedia of DNA elements

GTEx:

The genotype-tissue expression

LD:

Linkage disequilibrium

HWE:

Hardy–Weinberg equilibrium

AICNA:

Allele-imbalanced copy number aberrations

TSS:

Transcription start site

FLCCA:

Female Lung Cancer Consortium in Asia

NCI:

National Cancer Institute

EAGLE:

Environment and genetics in lung cancer etiology

ATBC:

Alpha-tocopherol, beta-carotene cancer prevention study

PLCO:

Prostate, lung, colon, ovary screening trial

CPS-II:

Cancer Prevention Study II Nutrition Cohort

MAF:

Minor allele frequency

PCA:

Principal-component analysis

LUAD:

Lung adenocarcinoma

LUSC:

Lung squamous cell carcinoma

ORs:

Odds ratios

CIs:

Confidence intervals

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Acknowledgements

We would like to thank the GTEx project for the use of individual genotype data and expression data. The Genotype-Tissue Expression (GTEx) Project was supported by the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from dbGaP accession number phs000424.v6.p1. We would like to thank all participants who contributed to this work. Z.H. initiated, conceived, and supervised the study. N.Q. performed bioinformatic and statistical analyses with C.W., M.Z., and J.D., and drafted the manuscript with Z.H., C.W., G.J., H.M., H.S., and D.L. and N.Q. performed the genotyping with Q.L., T.H., L.W., F.Y., and M.H., and Y.J. and C.W. collected the samples. This work was supported by the National Key Basic Research Program Grant (2013CB911400), the National Natural Science Foundation of China (81521004, 81230067), the Cheung Kong Scholars Program of China, National Program for Support of Top-notch Young Professionals from the Organization Department of the CPC Central Committee, Jiangsu Specially-Appointed Professor project, Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (PPZY2015A067), the Science and Technology Development Fund of Nanjing Medical University (2016NJMUZD004), and the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine). The funder agencies had no role in the study design, data collection and analysis, decision to publish, or the preparation of the manuscript.

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Qin, N., Wang, C., Lu, Q. et al. A cis-eQTL genetic variant of the cancer–testis gene CCDC116 is associated with risk of multiple cancers. Hum Genet 136, 987–997 (2017). https://doi.org/10.1007/s00439-017-1827-2

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