TY - JOUR
T1 - Genome-wide meta-analyses of breast, ovarian, and prostate cancer association studies identify multiple new susceptibility loci shared by at least two cancer types
AU - Kar, Siddhartha P.
AU - Beesley, Jonathan
AU - Al Olama, Ali Amin
AU - Michailidou, Kyriaki
AU - Tyrer, Jonathan
AU - Kote-Jarai, Zsofi A.
AU - Lawrenson, Kate
AU - Lindstrom, Sara
AU - Ramus, Susan J.
AU - Thompson, Deborah J.
AU - ABCTB Investigators
AU - OCS Study Group & Australian Cancer Study (Ovarian Cancer)
AU - APCB BioResource
AU - kConFab Investigators66
AU - NBCS Investigators
AU - The GENICA Network
AU - The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium
AU - Kibel, Adam S.
AU - Dansonka-Mieszkowska, Agnieszka
AU - Michael, Agnieszka
AU - Dieffenbach, Aida K.
AU - Gentry-Maharaj, Aleksandra
AU - Whittemore, Alice S.
AU - Wolk, Alicja
AU - Monteiro, Alvaro
AU - Peixoto, Ana
AU - Kierzek, Andrzej
AU - Cox, Angela
AU - Rudolph, Anja
AU - Gonzalez-Neira, Anna
AU - Wu, Anna H.
AU - Lindblom, Annika
AU - Swerdlow, Anthony
AU - Ziogas, Argyrios
AU - Ekici, Arif B.
AU - Burwinkel, Barbara
AU - Karlan, Beth Y.
AU - Nordestgaard, Borge G.
AU - Blomqvist, Carl
AU - Phelan, Catherine
AU - McLean, Catriona
AU - Pearce, Celeste Leigh
AU - Vachon, Celine
AU - Cybulski, Cezary
AU - Slavov, Chavdar
AU - Stegmaier, Christa
AU - Maier, Christiane
AU - Ambrosone, Christine B.
AU - Hogdall, Claus K.
AU - Teerlink, Craig C.
AU - Kang, Daehee
AU - Tessier, Daniel C.
AU - Schaid, Daniel J.
AU - Stram, Daniel O.
AU - Cramer, Daniel W.
AU - Neal, David E.
AU - Eccles, Diana
AU - Flesch-Janys, Dieter
AU - Velez Edwards, Digna R.
AU - Wokozorczyk, Dominika
AU - Levine, Douglas A.
AU - Yannoukakos, Drakoulis
AU - Sawyer, Elinor J.
AU - Bandera, Elisa V.
AU - Poole, Elizabeth M.
AU - Goode, Ellen L.
AU - Khusnutdinova, Elza
AU - Hogdall, Estrid
AU - Song, Fengju
AU - Bruinsma, Fiona
AU - Heitz, Florian
AU - Modugno, Francesmary
AU - Hamdy, Freddie C.
AU - Wiklund, Fredrik
AU - Giles, Graham G.
AU - Olsson, Hakan
AU - Wildiers, Hans
AU - Ulmer, Hans Ulrich
AU - Pandha, Hardev
AU - Risch, Harvey A.
AU - Darabi, Hatef
AU - Salvesen, Helga B.
AU - Nevanlinna, Heli
AU - Gronberg, Henrik
AU - Brenner, Hermann
AU - Brauch, Hiltrud
AU - Anton-Culver, Hoda
AU - Song, Honglin
AU - Lim, Hui Yi
AU - McNeish, Iain
AU - Campbell, Ian
AU - Vergote, Ignace
AU - Gronwald, Jacek
AU - Lubiński, Jan
AU - Stanford, Janet L.
AU - Benitez, Javier
AU - Doherty, Jennifer A.
AU - Permuth, Jennifer B.
AU - Chang-Claude, Jenny
AU - Donovan, Jenny L.
AU - Dennis, Joe
AU - Schildkraut, Joellen M.
AU - Schleutker, Johanna
AU - Hopper, John L.
AU - Kupryjanczyk, Jolanta
AU - Park, Jong Y.
AU - Figueroa, Jonine
PY - 2016/9/1
Y1 - 2016/9/1
N2 - Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/ BCL2L11; rs7937840/11q12/ INCENP; rs1469713/19p13/ GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/ SMC2; rs8037137/15q26/ RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/ NSUN4; rs9375701/6q23/ L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers.
AB - Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/ BCL2L11; rs7937840/11q12/ INCENP; rs1469713/19p13/ GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/ SMC2; rs8037137/15q26/ RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/ NSUN4; rs9375701/6q23/ L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers.
UR - https://www.scopus.com/pages/publications/85012028638
U2 - 10.1158/2159-8290.CD-15-1227
DO - 10.1158/2159-8290.CD-15-1227
M3 - Article
C2 - 27432226
AN - SCOPUS:85012028638
SN - 2159-8274
VL - 6
SP - 1052
EP - 1067
JO - Cancer Discovery
JF - Cancer Discovery
IS - 9
ER -
SDG 3 Good Health and Well-being