ArticleEBioMedicine2024
Systematic identification of pathogenic variants of non-small cell lung cancer in the promoters of DNA-damage repair genes.
Article in EBioMedicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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- Studying the Impact of the DDB2 T338M Missense Mutation on the Development of Equine Squamous Cell Carcinoma and Sarcoid.Animals : an open access journal from MDPI · 2025Article
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Abstract
backgroundDeficiency 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.
methodsBased 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.
findingsWe 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.
interpretationOur findings indicate that functional promoter variants in DDR genes, in addition to protein-truncating variants, can be pathogenic and contribute to lung cancer susceptibility.
fundingNational 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.
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