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Lung adenocarcinoma driven by somatic  EGFR  mutations is more prevalent in East Asians (30–50%) than in European/Americans (10–20%). Here we investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with  EGFR  mutation-positive lung adenocarcinoma and 15,158 controls. Four loci, 5p15.33 ( TERT ), 6p21.3 ( BTNL2 ), 3q28 ( TP63 ) and 17q24.2 ( BPTF ), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to  EGFR  mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA class II at 6p21.32 (rs2179920;  P  =5.1 × 10 −17 , per-allele OR=1.36) and 6p21.1 ( FOXP4 ) (rs2495239;  P =3.9 × 10 −9 , per-allele OR=1.19) were newly identified as loci associated with  EGFR  mutation-positive lung adenocarcinoma. This study indicates that multiple genetic factors underlie the risk of lung adenocarcinomas with  EGFR  mutations.

Association of variations in HLA class II and other loci with susceptibility to EGFR-mutated lung adenocarcinoma