Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer

Yanhong Liu, Christine M. Lusk, Michael H. Cho, Edwin K. Silverman, Dandi Qiao, Ruyang Zhang, Michael E. Scheurer, Farrah Kheradmand, David A. Wheeler, Spiridon Tsavachidis, Georgina Armstrong, Dakai Zhu, Ignacio I. Wistuba, Chi Wan B. Chow, Carmen Behrens, Claudio W. Pikielny, Christine Neslund-Dudas, Susan M. Pinney, Marshall Anderson, Elena KupertJoan Bailey-Wilson, Colette Gaba, Diptasri Mandal, Ming You, Mariza De Andrade, Ping Yang, John K. Field, Triantafillos Liloglou, Michael Davies, Jolanta Lissowska, Beata Swiatkowska, David Zaridze, Anush Mukeriya, Vladimir Janout, Ivana Holcatova, Dana Mates, Sasa Milosavljevic, Ghislaine Scelo, Paul Brennan, James McKay, Geoffrey Liu, Rayjean J. Hung, David C. Christiani, Ann G. Schwartz, Christopher I. Amos, Margaret R. Spitz

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Background: Genome-wide association studies are widely used to map genomic regions contributing to lung cancer (LC) susceptibility, but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited genetic variants that cause LC, we performed focused exome-sequencing analyses on genes located in 121 genome-wide association study–identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior. Methods: Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single-variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1773 case patients and 1123 controls. Results: We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant, namely, BRCA2, DNA repair associated gene (BRCA2) K3326X (OR = 2.36, 95% confidence interval [CI]: 1.38–3.99), and three newly identified variations, namely, lymphotoxin beta gene (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01–16.56), prolyl 3-hydroxylase 2 gene (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75–15.43), and dishevelled associated activator of morphogenesis 2 gene (DAAM2) p.Asp762Gly (OR = 0.25, 95% CI: 0.10–0.79). Burden tests revealed strong associations between zinc finger protein 93 gene (ZNF93), DAAM2, bromodomain containing 9 gene (BRD9), and the gene LTB and LC susceptibility. Conclusion: Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.

Original languageEnglish (US)
Pages (from-to)1483-1495
Number of pages13
JournalJournal of Thoracic Oncology
Volume13
Issue number10
DOIs
StatePublished - Oct 1 2018

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Keywords

  • Exome sequencing
  • Lung cancer
  • Rare variants
  • Susceptibility loci

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Liu, Y., Lusk, C. M., Cho, M. H., Silverman, E. K., Qiao, D., Zhang, R., Scheurer, M. E., Kheradmand, F., Wheeler, D. A., Tsavachidis, S., Armstrong, G., Zhu, D., Wistuba, I. I., Chow, C. W. B., Behrens, C., Pikielny, C. W., Neslund-Dudas, C., Pinney, S. M., Anderson, M., ... Spitz, M. R. (2018). Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer. Journal of Thoracic Oncology, 13(10), 1483-1495. https://doi.org/10.1016/j.jtho.2018.06.016