Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA–tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.
Digital Object Identifier (DOI)
Transdisciplinary Research for Cancer in Lung (TRICL) research team of the International Lung Cancer Consortium (ILCCO) was supported by (U19-CA148127 and CA148127S1). The ILCCO data harmonization is supported by Cancer Care Ontario Research Chair of Population Studies to R. H. and Lunenfeld-Tanenbaum Research Institute, Sinai Health System. TRICL-ILCCO Oncoarray was supported by in-kind genotyping Centre for Inherited Disease Research (26820120008i-0-26800068-1).
Due to the large number of funding sources, only the first few are listed in this section. For the complete list of funding sources, please download this article.
Genotype data for the lung cancer OncoArray study have been deposited at the database of Genotypes and Phenotypes (dbGaP) under accession phs001273.v1.p1. The Asian replication dataset was downloaded from dbGaP under accession phs000716.v1.p1.
Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467-018-05890-2.
Ferreiro-Iglesias, Aida; Lesseur, Corina; McKay, James; Hung, Rayjean J.; Han, Younghun; Zong, Xuchen; Christiani, David; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Qian, David C.; Ji, Xuemei; Liu, Geoffrey; Caporaso, Neil; Scelo, Ghislaine; Zaridze, David; Mukeriya, Anush; Kontic, Milica; Ognjanovic, Simona; Lissowska, Jolanta; Szołkowska, Małgorzata; Swiatkowska, Beata; Janout, Vladimir; Holcatova, Ivana; Bolca, Ciprian; Savic, Milan; Ognjanovic, Miodrag; Bojesen, Stig Egil; Wu, Xifeng; Albanes, Demetrios; and Arnold, Susanne M., "Fine Mapping of MHC Region in Lung Cancer Highlights Independent Susceptibility Loci by Ethnicity" (2018). Markey Cancer Center Faculty Publications. 129.