Deciphering associations between three RNA splicing-related genetic variants and lung cancer risk.

Journal Article (Journal Article)

Limited efforts have been made in assessing the effect of genome-wide profiling of RNA splicing-related variation on lung cancer risk. In the present study, we first identified RNA splicing-related genetic variants linked to lung cancer in a genome-wide profiling analysis and then conducted a two-stage (discovery and replication) association study in populations of European ancestry. Discovery and validation were conducted sequentially with a total of 29,266 cases and 56,450 controls from both the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium as well as the OncoArray database. For those variants identified as significant in the two datasets, we further performed stratified analyses by smoking status and histological type and investigated their effects on gene expression and potential regulatory mechanisms. We identified three genetic variants significantly associated with lung cancer risk: rs329118 in JADE2 (P = 8.80E-09), rs2285521 in GGA2 (P = 4.43E-08), and rs198459 in MYRF (P = 1.60E-06). The combined effects of all three SNPs were more evident in lung squamous cell carcinomas (P = 1.81E-08, P = 6.21E-08, and P = 7.93E-04, respectively) than in lung adenocarcinomas and in ever smokers (P = 9.80E-05, P = 2.70E-04, and P = 2.90E-05, respectively) than in never smokers. Gene expression quantitative trait analysis suggested a role for the SNPs in regulating transcriptional expression of the corresponding target genes. In conclusion, we report that three RNA splicing-related genetic variants contribute to lung cancer susceptibility in European populations. However, additional validation is needed, and specific splicing mechanisms of the target genes underlying the observed associations also warrants further exploration.

Full Text

Duke Authors

Cited Authors

  • Yang, W; Liu, H; Zhang, R; Freedman, JA; Han, Y; Hung, RJ; Brhane, Y; McLaughlin, J; Brennan, P; Bickeboeller, H; Rosenberger, A; Houlston, RS; Caporaso, NE; Landi, MT; Brueske, I; Risch, A; Christiani, DC; Amos, CI; Chen, X; Patierno, SR; Wei, Q

Published Date

  • June 30, 2022

Published In

Volume / Issue

  • 6 / 1

Start / End Page

  • 48 -

PubMed ID

  • 35773316

Pubmed Central ID

  • PMC9247007

International Standard Serial Number (ISSN)

  • 2397-768X

Digital Object Identifier (DOI)

  • 10.1038/s41698-022-00281-9

Language

  • eng

Conference Location

  • England