Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers

C. Lesseur, A. Ferreiro-Iglesias, J.D. McKay, Y. Bosse, M. Johansson, V. Gaborieau, M.T. Landi, D.C. Christiani, N.C. Caporaso, S.E. Bojesen, C.I. Amos, S. Shete, G. Liu, G. Rennert, D. Albanes, M.C. Aldrich, A. Tardon, C. Chen, L. Triantafillos, J.K. FieldM.D. Teare, L.A. Kiemeney, B. Diergaarde, R.L. Ferris, S. Zienolddiny, S. Lam, A.F. Olshan, M.C. Weissler, M. Lacko, A. Risch, H. Bickeboller, A.R. Ness, S. Thomas, L. Le Marchand, M.B. Schabath, V. Wunsch, E.H. Tajara, A.S. Andrew, G.M. Clifford, P. Lazarus, K. Grankvist, S. Arnold, O. Melander, H. Brunnstrom, S. Boccia, G. Cadoni, W. Timens, M. Obeidat, X.J. Xiao, P. Brennan*

*Corresponding author for this work

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Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (P-meta<5x10(-8)) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (P-meta<5x10(-7)): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.Author summarySquamous cell carcinomas are specific type of cancer that can arise in multiple organs of the aerodigestive tract including the lung, oral cavity, oropharynx, larynx and esophagus. Previous studies have shown that aerodigestive squamous cell carcinomas share common environmental risk factors (tobacco smoking and alcohol intake). Here, we investigate genetic factors involved in the risk of aerodigestive squamous cell carcinomas as a group in a large genetic association study involving 13,887 cancer cases and 61,961 controls. We identified one genome-wide significant region within 2q33.1 and 3 other suggestive regions at 1q32.1, 5q31.2 and 19p13.11. Gene-based analyses also identify a list of SqCC-related genes that are involved in DNA damage response and epigenetic regulation. Our results suggest some overlap in the genetic factors influencing the risk of aerodigestive squamous cell carcinomas in European populations and highlights the importance of cross-cancer studies.
Original languageEnglish
Article numbere1009254
Number of pages19
JournalPlos Genetics
Issue number3
Publication statusPublished - 1 Mar 2021


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