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Cancer-associated cachexia (CAC) is a major determinant of morbidity and mortality in patients with non-small cell lung cancer (NSCLC). Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate possible biological processes and mediators that contribute to the development of CAC. Computed tomography-based (CT) body composition analysis of 651 patients in TRACERx suggested that patients with low skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, represented by the bottom 20 th percentile, had significantly shorter lung cancer-specific survival (LCSS) and overall survival (OS). This finding was validated in 420 patients in the independent Boston Lung Cancer Study. In a longitudinal subset of 272 patients in TRACERx who experienced disease relapse, loss of adipose tissue, skeletal muscle, or body weight in the interval between diagnosis and relapse, was significantly associated with shorter LCSS and OS. Patients with one or more features encompassing loss of adipose or muscle tissue, or BMI-adjusted weight loss according to specific thresholds were classified as having developed CAC and were found to have distinct tumour genomic and transcriptomic profiles compared with patients who did not develop such features at relapse. Primary NSCLCs from patients in the CAC group were characterised by enrichment of inflammatory signalling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumours included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3 . In an exploratory analysis of putative circulating cachexia mediators performed in a subset of 256 baseline and relapse plasma samples from TRACERx, proteomic analysis revealed a significant association between circulating GDF15 and loss of body weight, skeletal muscle, and adipose tissue at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC.

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.