Interplay between mosaic chromosomal alterations and polygenic risk score increases risk of non-small cell lung cancer

We investigated autosomal mosaic chromosomal alterations (mCAs) in 10,248 non-small cell lung cancer (NSCLC) cases and 9,298 cancer-free controls of Chinese ancestry. Mosaic loss and copy-neutral loss of heterozygosity were associated with an increased risk of NSCLC, while mosaic gain was associated with a decreased risk of NSCLC, especially those spanning telomeres. The increased cell fraction of mCAs was also correlated with an increasing NSCLC risk in the affected individuals. Both multiplicative and additive interactions were observed between polygenic risk score (PRS) and the presence of mosaic loss, where carriers of mosaic loss events with cell fractions ≥5% among the high genetic risk group had the greatest risk for developing NSCLC. These findings suggest that mCA events may act as a new endogenous indicator for risk of NSCLC and have the potential to be jointly used with PRS to optimize risk stratification of NSCLC.