Association of the interaction between mosaic chromosomal alterations and polygenic risk score with the risk of lung cancer: an array-based case-control association and prospective cohort study

Background Mosaic chromosomal alterations (mCAs) detected from blood-derived DNA are large structural alterations of clonal haematopoietic origin and are associated with various diseases, such as haematological malignancies, infections, and solid cancers. We aimed to investigate whether mCAs contribute to the risk of lung cancer and modify the effect of polygenic risk score (PRS) on lung cancer risk prediction. Methods The blood-derived DNA of patients with lung cancer and cancer-free controls with Chinese ancestry from the Nanjing Lung Cancer Cohort (NJLCC) study were genotyped with a Global Screening Array, and mCAs were detected with the Mosaic Chromosomal Alterations (MoChA) pipeline. mCA call sets of individuals with European ancestry were obtained from the prospective cohort UK Biobank (UKB) study, including documented incident lung cancer. All patients with lung cancer from the NJLCC study (aged 15 years or older at diagnosis) were histopathologically confirmed as new lung cancer cases by at least two pathologists and were free of chemotherapy or radiotherapy before diagnosis. Participants with incident lung cancer (aged 37–73 years at assessment) diagnosed after recruitment to the UKB were identified through linkage to national cancer registries. Logistic regression and Cox proportional hazard models were applied to evaluate associations between mCAs and risk of lung cancer in the NJLCC (logistic regression) and UKB (Cox proportional hazard model) studies. Findings The NJLCC study included 10 248 individuals (6445 [62·89%] men and 3803 [37·11%] women; median age 60·0 years [IQR 53·0–66·0]) with lung cancer and 9298 individuals (5871 [63·14%] men and 3427 [36·86%] women; median age 60·0 years [52·0–65·0]) without lung cancer recruited from three sub-regions (north, central, and south) across China between April 15, 2003, and Aug 18, 2017. The UKB included 450 821 individuals recruited from 22 centres across the UK between March 13, 2006, and Nov 1, 2010, including 2088 individuals with lung cancer (1075 [51·48%] men and 1013 [48·52%] women; median age 63·0 years [IQR 59·0–66·0]), and 448 733 participants were free of lung cancer (204 713 [45·62%] men and 244 020 [54·38%] women; median age 58·0 years [IQR 50·0–63·0]). Compared with non-carriers of mosaic losses, carriers had a significantly increased risk of lung cancer in the NJLCC (odds ratio [OR] 1·81, 95% CI 1·43–2·28; p=6·69 × 10−7) and UKB (hazard ratio [HR] 1·40, 95% CI 1·00–1·95; p=0·048) studies. This increased risk was even higher in patients with expanded cell fractions of mCAs (ie, cell fractions ≥10% vs cell fractions <10%) in the NJLCC (OR 1·61 [95% CI 1·26–2·08] vs 1·03 [0·83–1·26]; p for heterogeneity test=6·41 × 10−3). A significant multiplicative interaction was observed between PRS and mosaic losses on the risk of lung cancer in both the NJLCC (interaction p value=0·030) and UKB (p=0·043). Compared with non-carriers of mosaic loss abnormalities with low genetic risk, participants with expanded mosaic losses (cell fractions ≥10%) and high genetic risk had around a six-times increased risk of lung cancer in the NJLCC study (OR 6·40 [95% CI 3·22–12·69]), and an almost four-times increased risk of lung cancer (HR 3·75 [95% CI 1·86–7·55]) in the UKB study. The additive interaction also contributed a 3·67 (95% CI 0·49–6·85) relative excess risk of developing lung cancer in the NJLCC study, and a 2·15 (0·12–4·19) relative excess risk in the UKB study. Interpretation mCAs act as a new endogenous indicator for the risk of lung cancer and might be jointly used with PRS to optimise personalised risk stratification for lung cancer. Funding National Natural Science Foundation of China, Outstanding Youth Foundation of Jiangsu Province, Natural Science Foundation of Jiangsu Province, and Postdoctoral Science Foundation of China. Translation For the Chinese translation of the abstract see Supplementary Materials section.