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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. |
