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Chinese lung cancer patients have distinct epidemiologic and genomic features, highlighting the presence of specific etiologic mechanisms other than smoking. Here, we present a comprehensive genomic landscape of 149 non-small cell lung cancer (NSCLC) cases and identify 15 potential driver genes. We reveal that Chinese patients are specially characterized by not only highly clustered  EGFR  mutations but a mutational signature (MS3, 33.7%), that is associated with inflammatory tumor-infiltrating B lymphocytes ( P  = 0.001). The  EGFR  mutation rate is significantly increased with the proportion of the MS3 signature ( P  = 9.37 × 10 −5 ). TCGA data confirm that the infiltrating B lymphocyte abundance is significantly higher in the  EGFR -mutated patients ( P  = 0.007). Additionally, MS3-high patients carry a higher contribution of distant chromosomal rearrangements >1 Mb ( P  = 1.35 × 10 −7 ), some of which result in fusions involving genes with important functions (i.e.,  ALK  and  RET ). Thus, inflammatory infiltration may contribute to the accumulation of  EGFR  mutations, especially in never-smokers.

Whole-genome sequencing reveals genomic signatures associated with the inflammatory microenvironments in Chinese NSCLC patients