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Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Kar, Siddhartha P; Beesley, Jonathan; Amin Al Olama, Ali; Michailidou, Kyriaki; Tyrer, Jonathan; Kote-Jarai, ZSofia; Lawrenson, Kate; Lindstrom, Sara; Ramus, Susan J and Thompson, Deborah J, et al. (2016) In Cancer Discovery 6(9). p.67-1052
Abstract

UNLABELLED: 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).... (More)

UNLABELLED: 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. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

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Cancer Discovery
volume
6
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9
pages
16 pages
publisher
American Association for Cancer Research
external identifiers
  • wos:000383356400028
  • scopus:85012028638
ISSN
2159-8274
DOI
10.1158/2159-8290.CD-15-1227
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English
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yes
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487832de-4e6e-4ab8-8bcd-851cea227454
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2016-09-18 11:28:34
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2018-09-23 04:40:25
@article{487832de-4e6e-4ab8-8bcd-851cea227454,
  abstract     = {<p>UNLABELLED: 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 &lt; 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 &lt; 10(-5) in the three-cancer meta-analysis.</p><p>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. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.</p>},
  author       = {Kar, Siddhartha P and Beesley, Jonathan and Amin Al Olama, Ali and Michailidou, Kyriaki and Tyrer, Jonathan and Kote-Jarai, ZSofia and Lawrenson, Kate and Lindstrom, Sara and Ramus, Susan J and Thompson, Deborah J and Kibel, Adam S and Dansonka-Mieszkowska, Agnieszka and Michael, Agnieszka and Dieffenbach, Aida K and Gentry-Maharaj, Aleksandra and Whittemore, Alice S and Wolk, Alicja and Monteiro, Alvaro and Peixoto, Ana and Kierzek, Andrzej and Cox, Angela and Rudolph, Anja and Gonzalez-Neira, Anna and Wu, Anna H and Lindblom, Annika and Swerdlow, Anthony and Ziogas, Argyrios and Ekici, Arif B and Burwinkel, Barbara and Karlan, Beth Y and Nordestgaard, Børge G and Blomqvist, Carl and Phelan, Catherine and McLean, Catriona and Pearce, Celeste Leigh and Vachon, Celine and Cybulski, Cezary and Slavov, Chavdar and Stegmaier, Christa and Maier, Christiane and Ambrosone, Christine B and Høgdall, Claus K and Teerlink, Craig C and Kang, Daehee and Tessier, Daniel C and Schaid, Daniel J and Wiklund, Fredrik and Olsson, Håkan and Darabi, Hatef and Broberg, Per and , },
  issn         = {2159-8274},
  language     = {eng},
  number       = {9},
  pages        = {67--1052},
  publisher    = {American Association for Cancer Research},
  series       = {Cancer Discovery},
  title        = {Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types},
  url          = {http://dx.doi.org/10.1158/2159-8290.CD-15-1227},
  volume       = {6},
  year         = {2016},
}