Abstract 2121: Genetic correlation between lung cancer and environmental exposures
Authors: Pettit Rowland West , Byun Jinyoung , Han Younghun , Edelson Jacob , Ostrom Quinn , Walsh Kyle , Bondy Melissa , McKay James , Amos Christopher ,   INTEGRAL Consortium
Published: September 2020

Abstract
Introduction: Lung cancer is the leading cause of cancer-related deaths. 10% of never-smokers develop lung cancer. Currently, no genetic-based lung cancer screening tool exists. As a substitute, phenotypic traits can serve as surrogate markers for lung cancer risk. Our study focuses on identifying novel phenotypes associated with lung cancer. Genome-wide association studies (GWAS) are useful in elucidating complex inheritance patterns and genetic architecture. Cross-trait linkage disequilibrium score regression (LDSC) specifically allows for use of GWAS summary statistics to identify genetic correlations between phenotypes of interest. This method allows for accurate calculations of genetic correlation, as it neutralizes effects from population stratification or cryptic relatedness.
Methods: We used LDSC to (1) confirm prior phenotypic trait associations with lung cancer and to (2) identify novel associations. We measured pairwise genetic correlation (rg) and SNP heritability (h2) (the proportion of phenotypic variance observed in a population that can be explained genetically) between multiple phenotypes and lung cancer using summary statistics from the UK Biobank and OncoArray lung consortium. In addition, we conducted analysis after removal of genome regions related to smoking effects that enables us to correct the potential confounding effect in lung cancer.
Results: Significant negative genetic correlations were found to exist between lung cancer and environmental factors. Overall alcohol use was significantly correlated with lung cancers. The effect observed was split, with a positive correlation for beer and cider intake (rg = 0.2957, p = 3.936 × 10-8) and a negative correlation with wine intake (rg = -0.3281, p = 2.251 × 10-14) for overall lung. Significant correlations existed between lung cancer and health metrics. A positive correlation was found between lung cancer and increased BMI (rg = 0.1986, p = 3.57 × 10-9). This finding was consistent across other BMI related metrics and within histological subtypes of lung cancer, including for lung adenocarcinoma (rg = 0.1059, p = 3.688 × 10-3) and lung small cell carcinoma (rg = 0.2393, p = 6.463 × 10-7). In comparison, physical conditioning metrics such as cycling to work had a negative correlation with lung cancer (rg = -0.2714, p = 5.690 × 10-5). Further, negative correlations were observed between being breastfed as a baby and lung cancer (rg = -0.320, p = 1.554 × 10-6). Each of these associations maintained its significance even after the removal of smoking-related SNPs.
Conclusions: This analysis demonstrates a genetic basis for the shared genetic architecture between environmental factors and lung oncogenesis. We identify several novel associations, including a correlation between breastfeeding and lung cancer. Further studies are necessary in order to confirm these associations and investigate driving genetic mechanisms.
Citation Format: Rowland West Pettit, Jinyoung Byun, Younghun Han, Jacob Edelson, Quinn Ostrom, Kyle Walsh, Melissa Bondy, James McKay, Christopher Amos, INTEGRAL Consortium. Genetic correlation between lung cancer and environmental exposures [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2121.