A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium.
McKay JD., Truong T., Gaborieau V., Chabrier A., Chuang S-C., Byrnes G., Zaridze D., Shangina O., Szeszenia-Dabrowska N., Lissowska J., Rudnai P., Fabianova E., Bucur A., Bencko V., Holcatova I., Janout V., Foretova L., Lagiou P., Trichopoulos D., Benhamou S., Bouchardy C., Ahrens W., Merletti F., Richiardi L., Talamini R., Barzan L., Kjaerheim K., Macfarlane GJ., Macfarlane TV., Simonato L., Canova C., Agudo A., Castellsagué X., Lowry R., Conway DI., McKinney PA., Healy CM., Toner ME., Znaor A., Curado MP., Koifman S., Menezes A., Wünsch-Filho V., Neto JE., Garrote LF., Boccia S., Cadoni G., Arzani D., Olshan AF., Weissler MC., Funkhouser WK., Luo J., Lubiński J., Trubicka J., Lener M., Oszutowska D., Schwartz SM., Chen C., Fish S., Doody DR., Muscat JE., Lazarus P., Gallagher CJ., Chang S-C., Zhang Z-F., Wei Q., Sturgis EM., Wang L-E., Franceschi S., Herrero R., Kelsey KT., McClean MD., Marsit CJ., Nelson HH., Romkes M., Buch S., Nukui T., Zhong S., Lacko M., Manni JJ., Peters WHM., Hung RJ., McLaughlin J., Vatten L., Njølstad I., Goodman GE., Field JK., Liloglou T., Vineis P., Clavel-Chapelon F., Palli D., Tumino R., Krogh V., Panico S., González CA., Quirós JR., Martínez C., Navarro C., Ardanaz E., Larrañaga N., Khaw K-T., Key T., Bueno-de-Mesquita HB., Peeters PHM., Trichopoulou A., Linseisen J., Boeing H., Hallmans G., Overvad K., Tjønneland A., Kumle M., Riboli E., Välk K., Vooder T., Metspalu A., Zelenika D., Boland A., Delepine M., Foglio M., Lechner D., Blanché H., Gut IG., Galan P., Heath S., Hashibe M., Hayes RB., Boffetta P., Lathrop M., Brennan P.
Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻⁷). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 × 10⁻⁸) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻⁸); rs1229984-ADH1B, p = 7 × 10⁻⁹; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.