Systematic identification of pathogenic variants of non-small cell lung cancer in the promoters of DNA-damage repair genesResearch in context
Mingxing An,
Congcong Chen,
Jun Xiang,
Yang Li,
Pinyu Qiu,
Yiru Tang,
Xinyue Liu,
Yayun Gu,
Na Qin,
Yuanlin He,
Meng Zhu,
Yue Jiang,
Juncheng Dai,
Guangfu Jin,
Hongxia Ma,
Cheng Wang,
Zhibin Hu,
Hongbing Shen
Affiliations
Mingxing An
Department of Epidemiology, School of Public Health, Southeast University, Nanjing, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Congcong Chen
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou 213003, China
Jun Xiang
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Yang Li
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Pinyu Qiu
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Yiru Tang
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Xinyue Liu
State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Yayun Gu
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Na Qin
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Yuanlin He
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Meng Zhu
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Yue Jiang
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Juncheng Dai
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Guangfu Jin
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Hongxia Ma
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Research Units of Cohort Study on Cardiovascular Diseases and Cancers, Chinese Academy of Medical Sciences, Beijing 100730, China
Cheng Wang
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou 213003, China; Corresponding author. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Zhibin Hu
Department of Epidemiology, School of Public Health, Southeast University, Nanjing, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Corresponding author. Department of Epidemiology, School of Public Health, Southeast University, Nanjing, Jiangsu 210009, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Hongbing Shen
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Research Units of Cohort Study on Cardiovascular Diseases and Cancers, Chinese Academy of Medical Sciences, Beijing 100730, China; Corresponding author. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Summary: Background: Deficiency in DNA-damage repair (DDR) genes, often due to disruptive coding variants, is linked to higher cancer risk. Our previous study has revealed the association between rare loss-of-function variants in DDR genes and the risk of lung cancer. However, it is still challenging to study the predisposing role of rare regulatory variants of these genes. Methods: Based on whole-genome sequencing data from 2984 patients with non-small cell lung cancer (NSCLC) and 3020 controls, we performed massively parallel reporter assays on 1818 rare variants located in the promoters of DDR genes. Pathway- or gene-level burden analyses were performed using Firth’s logistic regression or generalized linear model. Findings: We identified 750 rare functional regulatory variants (frVars) that showed allelic differences in transcriptional activity within the promoter regions of DDR genes. Interestingly, the burden of frVars was significantly elevated in cases (odds ratio [OR] = 1.17, p = 0.026), whereas the burden of variants prioritized solely based on bioinformatics annotation was comparable between cases and controls (OR = 1.04, p = 0.549). Among the frVars, 297 were down-regulated transcriptional activity (dr-frVars) and 453 were up-regulated transcriptional activity (ur-frVars); especially, dr-frVars (OR = 1.30, p = 0.008) rather than ur-frVars (OR = 1.06, p = 0.495) were significantly associated with risk of NSCLC. Individuals with NSCLC carried more dr-frVars from Fanconi anemia, homologous recombination, and nucleotide excision repair pathways. In addition, we identified seven genes (i.e., BRCA2, GTF2H1, DDB2, BLM, ALKBH2, APEX1, and RAD51B) with promoter dr-frVars that were associated with lung cancer susceptibility. Interpretation: Our findings indicate that functional promoter variants in DDR genes, in addition to protein-truncating variants, can be pathogenic and contribute to lung cancer susceptibility. Funding: National Natural Science Foundation of China, Youth Foundation of Jiangsu Province, Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancer of Chinese Academy of Medical Sciences, and Natural Science Foundation of Jiangsu Province.
