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

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

doi:10.1371/journal.pgen.1009254

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 (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<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.

Lesseur, C., Ferreiro-Iglesias, A., Mckay, J. D., Bosse, Y., Johansson, M., Gaborieau, V., Landi, M. T., Christiani, D. C., Caporaso, N. C., Bojesen, S. E., Amos, C. I., Shete, S., Liu, G., Rennert, G., Albanes, D., Aldrich, M. C., Tardon, A., Chen, C., Triantafillos, L., Field, J. K., Teare, M. D., Kiemeney, L. A., Diergaarde, B., Ferris, R. L., Zienolddiny, S., Lam, S., Olshan, A. F., Weissler, M. C., Lacko, M., Risch, A., Bickeboller, H., Ness, A. R., Thomas, S., Le Marchand, L., Schabath, M. B., Wunsch-Filho, V., Tajara, E. H., Andrew, A. S., Clifford, G. M., Lazarus, P., Grankvist, K., Johansson, M., Arnold, S., Melander, O., Brunnstrom, H., Boccia, S., Cadoni, G., Timens, W., Obeidat, M., Xiao, X., Houlston, R. S., Hung, R. J., Brennan, P., Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers, <<PLOS GENETICS>>, 2021; 17 (3): e1009254-e1009254. [doi:10.1371/journal.pgen.1009254] [http://hdl.handle.net/10807/175363]