A Common Variant On 2q31.3 Reduces Lung Cancer Risk Among Light Smokers: Transdisciplinary Research In Lung Cancer Consortium

Summer HAN, Stanford University, United States
CHENG I. 1,2 , HAN Y. 3 , CHRISTIANI D. 4 , HUNG R. 5 , BICKEBOLLER H. 6 , WU X. 7 , BRENNAN P. 8 , AMOS C. 3

1 Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA
2 Stanford Cancer Institute, Stanford, CA, USA
3 Biomedical Data Science, Dartmouth, Hanover, NH, USA
4 Harvard School of Public Health; Boston, MA, USA
5 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
6 Department of Genetic Epidemiology, University Medical Centre Göttingen, Göttingen, Germany
7 Department of Epidemiology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
8 International Agency for Research on Cancer, Lyon, France

Heavy smoking increases the risk of lung cancer(LC) by 50-fold. However, the lifetime risk of LC is between 15-20% even among heavy smokers, raising the question whether there may be protective factors that mitigate the carcinogenic risk of smoking. Previously, we have shown significant gene-smoking interactions on chromosome 15q25.1, with genetic variants in this region associated with minimal increased risks of LC among never smokers, but substantially increased risks among smokers. Studies contrasting LC risk between heavy and light smokers have not been conducted, and little is known about protective factors that may reduce LC risk for certain smokers.

To identify genetic factors that may reduce LC risk by levels of smoking, we conducted a genome-wide case-only analysis to detect gene-smoking interactions for LC, comparing heavy(≥30 cigarette pack-years) versus light smokers(<30 cigarette pack-years). The case-only design provides improved power for detecting interactions provided there is no correlation between the genetic and the environmental factors in the underlying population. Genotype data for 4,639 heavy smoker cases and 1,824 light smoker cases were meta-analyzed from 7 studies within the Transdisciplinary Research in Cancer of the Lung(TRICL) consortium.

The most significant gene-smoking interaction was found on 2q31.3 with rs62180069(P=5x10-8; OR=0.76). This SNP lies between the SCHLAP1 gene encoding the SWI/SNF complex antagonist associated with prostate cancer 1 and the UBE2E3 gene. While this variant showed no association with risk of LC among heavy smokers(OR=1.03; 95% CI:0.94-1.13), it significantly lowered the risk of LC among light smokers(OR=0.85; CI:0.78-0.93). There was no evidence of gene-smoking correlation among controls and no evidence of heterogeneity in the associations across studies.

Our large-scale meta-analysis identified a protective genetic variant for LC that reduces the risk of disease among light smokers. Further studies are needed to characterize the biological mechanism underlying the interaction between rs62180069 and smoking behavior.