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

Siddhartha P Kar; Jonathan Beesley; Ali Amin Al Olama; Kyriaki Michailidou; Jonathan Tyrer; ZSofia Kote-Jarai; Kate Lawrenson; Sara Lindstrom; Susan J Ramus; Deborah J Thompson; Adam S Kibel; Agnieszka Dansonka-Mieszkowska; Agnieszka Michael; Aida K Dieffenbach; Aleksandra Gentry-Maharaj; Alice S Whittemore; Alicja Wolk; Alvaro Monteiro; Ana Peixoto; Andrzej Kierzek; Angela Cox; Anja Rudolph; Anna Gonzalez-Neira; Anna H Wu; Annika Lindblom; Anthony Swerdlow; Argyrios Ziogas; Arif B Ekici; Barbara Burwinkel; Beth Y Karlan; Børge G Nordestgaard; Carl Blomqvist; Catherine Phelan; Catriona McLean; Celeste Leigh Pearce; Celine Vachon; Cezary Cybulski; Chavdar Slavov; Christa Stegmaier; Christiane Maier; Christine B Ambrosone; Claus K Høgdall; Craig C Teerlink; Daehee Kang; Daniel C Tessier; Daniel J Schaid; Daniel O Stram; Estrid Høgdall; Stig E Bojesen; Susanne Krüger Kjær; ABCTB Investigators

doi:10.1158/2159-8290.cd-15-1227

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

Siddhartha P Kar, Jonathan Beesley, Ali Amin Al Olama, Kyriaki Michailidou, Jonathan Tyrer, ZSofia Kote-Jarai, Kate Lawrenson, Sara Lindstrom, Susan J Ramus, Deborah J Thompson, Adam S Kibel, Agnieszka Dansonka-Mieszkowska, Agnieszka Michael, Aida K Dieffenbach, Aleksandra Gentry-Maharaj, Alice S Whittemore, Alicja Wolk, Alvaro Monteiro, Ana Peixoto, Andrzej KierzekAngela Cox, Anja Rudolph, Anna Gonzalez-Neira, Anna H Wu, Annika Lindblom, Anthony Swerdlow, Argyrios Ziogas, Arif B Ekici, Barbara Burwinkel, Beth Y Karlan, Børge G Nordestgaard, Carl Blomqvist, Catherine Phelan, Catriona McLean, Celeste Leigh Pearce, Celine Vachon, Cezary Cybulski, Chavdar Slavov, Christa Stegmaier, Christiane Maier, Christine B Ambrosone, Claus K Høgdall, Craig C Teerlink, Daehee Kang, Daniel C Tessier, Daniel J Schaid, Daniel O Stram, Estrid Høgdall, Stig E Bojesen, Susanne Krüger Kjær, ABCTB Investigators

Department of Clinical Medicine

78 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Cancer Discovery
Volume	6
Issue number	9
Pages (from-to)	1052-67
Number of pages	16
ISSN	2159-8274
DOIs	https://doi.org/10.1158/2159-8290.cd-15-1227
Publication status	Published - 1 Sept 2016

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/2159-8290.cd-15-1227

1052.full.pdfFinal published version, 2.23 MB

Cite this

Kar, S. P., Beesley, J., Amin Al Olama, A., Michailidou, K., Tyrer, J., Kote-Jarai, ZS., Lawrenson, K., Lindstrom, S., Ramus, S. J., Thompson, D. J., Kibel, A. S., Dansonka-Mieszkowska, A., Michael, A., Dieffenbach, A. K., Gentry-Maharaj, A., Whittemore, A. S., Wolk, A., Monteiro, A., Peixoto, A., ... ABCTB Investigators (2016). Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types. Cancer Discovery, 6(9), 1052-67. https://doi.org/10.1158/2159-8290.cd-15-1227

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 et al.
In: Cancer Discovery, Vol. 6, No. 9, 01.09.2016, p. 1052-67.

Research output: Contribution to journal › Journal article › Research › peer-review

Kar, SP, Beesley, J, Amin Al Olama, A, Michailidou, K, Tyrer, J, Kote-Jarai, ZS, Lawrenson, K, Lindstrom, S, Ramus, SJ, Thompson, DJ, Kibel, AS, Dansonka-Mieszkowska, A, Michael, A, Dieffenbach, AK, Gentry-Maharaj, A, Whittemore, AS, Wolk, A, Monteiro, A, Peixoto, A, Kierzek, A, Cox, A, Rudolph, A, Gonzalez-Neira, A, Wu, AH, Lindblom, A, Swerdlow, A, Ziogas, A, Ekici, AB, Burwinkel, B, Karlan, BY, Nordestgaard, BG, Blomqvist, C, Phelan, C, McLean, C, Pearce, CL, Vachon, C, Cybulski, C, Slavov, C, Stegmaier, C, Maier, C, Ambrosone, CB, Høgdall, CK, Teerlink, CC, Kang, D, Tessier, DC, Schaid, DJ, Stram, DO, Høgdall, E , Bojesen, SE , Kjær, SK & ABCTB Investigators 2016, 'Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types', Cancer Discovery, vol. 6, no. 9, pp. 1052-67. https://doi.org/10.1158/2159-8290.cd-15-1227

@article{16b2fbd4663d45cb93d016a358e8a181,

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",

abstract = "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.",

keywords = "Journal Article",

author = "Kar, {Siddhartha P} and Jonathan Beesley and {Amin Al Olama}, Ali and Kyriaki Michailidou and Jonathan Tyrer and ZSofia Kote-Jarai and Kate Lawrenson and Sara Lindstrom and Ramus, {Susan J} and Thompson, {Deborah J} and Kibel, {Adam S} and Agnieszka Dansonka-Mieszkowska and Agnieszka Michael and Dieffenbach, {Aida K} and Aleksandra Gentry-Maharaj and Whittemore, {Alice S} and Alicja Wolk and Alvaro Monteiro and Ana Peixoto and Andrzej Kierzek and Angela Cox and Anja Rudolph and Anna Gonzalez-Neira and Wu, {Anna H} and Annika Lindblom and Anthony Swerdlow and Argyrios Ziogas and Ekici, {Arif B} and Barbara Burwinkel and Karlan, {Beth Y} and Nordestgaard, {B{\o}rge G} and Carl Blomqvist and Catherine Phelan and Catriona McLean and Pearce, {Celeste Leigh} and Celine Vachon and Cezary Cybulski and Chavdar Slavov and Christa Stegmaier and Christiane Maier and Ambrosone, {Christine B} and H{\o}gdall, {Claus K} and Teerlink, {Craig C} and Daehee Kang and Tessier, {Daniel C} and Schaid, {Daniel J} and Stram, {Daniel O} and Estrid H{\o}gdall and Bojesen, {Stig E} and Kj{\ae}r, {Susanne Kr{\"u}ger} and {ABCTB Investigators}",

note = "{\textcopyright}2016 American Association for Cancer Research.",

year = "2016",

month = sep,

day = "1",

doi = "10.1158/2159-8290.cd-15-1227",

language = "English",

volume = "6",

pages = "1052--67",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research",

number = "9",

}

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 - Amin Al Olama, Ali

AU - Michailidou, Kyriaki

AU - Tyrer, Jonathan

AU - Kote-Jarai, ZSofia

AU - Lawrenson, Kate

AU - Lindstrom, Sara

AU - Ramus, Susan J

AU - Thompson, Deborah J

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, Børge 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 - Høgdall, Claus K

AU - Teerlink, Craig C

AU - Kang, Daehee

AU - Tessier, Daniel C

AU - Schaid, Daniel J

AU - Stram, Daniel O

AU - Høgdall, Estrid

AU - Bojesen, Stig E

AU - Kjær, Susanne Krüger

AU - ABCTB Investigators

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.

KW - Journal Article

U2 - 10.1158/2159-8290.cd-15-1227

DO - 10.1158/2159-8290.cd-15-1227

M3 - Journal article

C2 - 27432226

SN - 2159-8274

VL - 6

SP - 1052

EP - 1067

JO - Cancer Discovery

JF - Cancer Discovery

IS - 9

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this