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A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium

2011; Public Library of Science; Volume: 7; Issue: 3 Linguagem: Inglês

10.1371/journal.pgen.1001333

1553-7404

James McKay, Thérèse Truong, Valérie Gaborieau, Amélie Chabrier, Shu-Chun Chuang, Graham Byrnes, Давид Заридзе, Oxana Shangina, Neonila Szeszenia‐Dąbrowska, Jolanta Lissowska, Péter Rudnai, Eleonóra Fabiánová, Alexandru Bucur, Vladimír Bencko, Ivana Holcátová, Vladimí­r Janout, Lenka Foretová, Παγώνα Λάγιου, Dimitrios Trichopoulos, Simone Benhamou, Christine Bouchardy, Wolfgang Ahrens, Franco Merletti, Lorenzo Richiardi, Renato Talamini, Luigi Barzan, Kristina Kjærheim, Gary J. Macfarlane, Tatiana V. Macfarlane, Lorenzo Simonato, Cristina Canova, Antonio Agudo, Xavier Castellsagué, Ray Lowry, David I. Conway, Patricia A. McKinney, Claire M. Healy, Mary Toner, Ariana Znaor, María Paula Curado, Sérgio Koifman, Ana Menezes, Victor Wünsch‐Filho, José Eluf‐Neto, Letícia Fernández Garrote, Stefania Boccia, Gabriella Cadoni, Dario Arzani, Andrew F. Olshan, Mark C. Weissler, William K. Funkhouser, Jingchun Luo, Jan Lubiński, Joanna Trubicka, Marcin Lener, Dorota Oszutowska–Mazurek, Stephen M. Schwartz, Chu Chen, Sherianne Fish, David R. Doody, Joshua Muscat, Philip Lazarus, Carla J. Gallagher, Shen-Chih Chang, Zuo‐Feng Zhang, Qingyi Wei, Erich M. Sturgis, Li‐E Wang, Silvia Franceschi, Rolando Herrero, Karl T. Kelsey, Michael D. McClean, Carmen J. Marsit, Heather H. Nelson, Marjorie Romkes, Shama Buch, Tomoko Nukui, Shilong Zhong, Martin Lacko, Johannes J. Manni, Wilbert H.M. Peters, Rayjean J. Hung, Esther M. John, Lars J. Vatten, Inger Njølstad, Gary E. Goodman, John K. Field, Triantafillos Liloglou, Paolo Vineis, Françoise Clavel‐Chapelon, Domenico Palli, ­Rosario ­Tumino, Vittorio Krogh, Salvatore Panico, Carlos A. González, J. Ramón Quirós, Carmen Martı́nez, Carmen Navarro, Eva Ardanáz, Nerea Larrañaga, Kay‐Tee Khaw, Timothy J. Key, H. Bas Bueno-de-Mesquita, Petra H. Peeters, Antonia Trichopoulou, Jakob Linseisen, Heiner Boeing, Göran Hallmans, Kim Overvad, Anne Tjønneland, Merethe Kumle, Elio Ríboli, Kristjan Välk, Tõnu Voodern, Andres Metspalu, Diana Zélénika, Anne Boland, Marc Delépine, Mario Foglio, Doris Lechner, Hélène Blanché, Marta Gut, Pilar Galán, Simon Heath, Mia Hashibe, Richard B. Hayes, Paolo Boffetta, Mark Lathrop, Paul Brennan,

RNA modifications and cancer

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.