Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Abstract

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

Polygenic Risk Score, Environmental Tobacco Smoke, and Risk of Lung Adenocarcinoma in Never-Smoking Women in Taiwan

“…Environmental tobacco smoke contains genotoxic and carcinogenic byproducts of cigarette smoke, which are the main cause of lung adenocarcinoma (LUAD), the most common histologic subtype among never-smokers . In addition to environmental carcinogens, several authors of the present study recently conducted the largest multi-ancestry genome-wide association study (GWAS) of lung cancer among East Asian and European populations and identified 25 single nucleotide variants (SNVs) associated with LUAD among East Asian individuals, which highlights the importance of genetic susceptibility to the etiology of LUAD …”

“…Data analysis was conducted from January 17 to July 15, 2022. We derived a polygenic risk score (PRS) using 25 independent SNVs that have previously reached genome-wide significance (ie, P = 5 × 10 −8 ) in a recently conducted 2-stage GWAS with 21 658 cases of histologically confirmed LUAD in East Asian populations from Taiwan, Mainland China, Japan, Singapore, and Korea . The PRS was calculated for each individual (i) as the following linear combination:…”

“…7,8 In addition to environmental carcinogens, several authors of the present study recently conducted the largest multi-ancestry genome-wide association study (GWAS) of lung cancer among East Asian and European populations and identified 25 single nucleotide variants (SNVs) associated with LUAD among East Asian individuals, which highlights the importance of genetic susceptibility to the etiology of LUAD. 9 The US Preventive Services Task Force recommends screening with low-dose computed tomography scan in current and former heavy smokers. 10 Comparable lung cancer screening guidelines for heavy smokers have been adopted in mainland China, South Korea, Japan, and Taiwan.…”

Lung cancer statistics, 2023

“…77 Genomewide association studies have identified rare-variant associations, some of which vary in prevalence by race. 78,79 A history of lung disease is associated with an increased risk of lung cancer. 80,81 Diseases that increase risk include asthma and pneumonia among those who have never smoked; emphysema among those with a history of smoking; and pulmonary fibrosis, including asbestosis, chronic bronchitis, chronic obstructive pulmonary disease, and tuberculosis, regardless of smoking status.…”

Identification of pathogenic germline variants in a large Chinese lung cancer cohort by clinical sequencing

“…The first is genome‐wide association study (GWAS), which is applied to explore the genetic predisposition of common genetic variants for cancer. Up to now, over 50 susceptibility single nucleotide polymorphisms (SNPs) have been identified to be associated with lung cancer risk in Chinese and European populations [ 5 , 6 , 7 , 8 , 9 ]. The second is to identify pathogenic/likely pathogenic (P/LP) germline variants in cancer susceptibility genes, making it possible to explore the functional impact of rare and very rare germline variants in the cancer development [ 10 , 11 ].…”