Germline determinants of humoral immune response to HPV-16 protect against oropharyngeal cancer
Aida Ferreiro-Iglesias, James McKay, Nicole Brenner, Shama Virani, Corina Lesseur, Valérie Gaborieau, Andy Ness, Rayjean J. Hung, Geoffrey Liu, Brenda Diergaarde, Andrew F. Olshan, D. Neil Hayes, Mark C. Weissler, Lea Schroeder, Noemi Bender, Michael Pawlita, Steve Thomas, Miranda Pring, Tom Dudding, Beatriz Kanterewicz, Robert L. Ferris, Sera Thomas, Yonathan Brhane, Virginia Díez‐Obrero, Maja Milojevic, Karl Smith-Byrne, Daniela Mariosa, Mattias Johansson, Rolando Herrero, Stefania Boccia, Gabriella Cadoni, Martin Lacko, Ivana Holcátová, Wolfgang Ahrens, Παγώνα Λάγιου, Areti Lagiou, Jerry Polesel, Lorenzo Simonato, Franco Merletti, Claire M. Healy, Bo T. Hansen, Mari Nygård, David I. Conway, Sylvia Wright, Tatiana V. Macfarlane, Max Robinson, Laia Alemany, Antonio Agudo, Ariana Znaor, Christopher I. Amos, Tim Waterboer, Paul Brennan
Abstract
Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC.