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

Institut for Klinisk Medicin

78 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Cancer Discovery
Vol/bind	6
Udgave nummer	9
Sider (fra-til)	1052-67
Antal sider	16
ISSN	2159-8274
DOI	https://doi.org/10.1158/2159-8290.cd-15-1227
Status	Udgivet - 1 sep. 2016

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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.

I: Cancer Discovery, Bind 6, Nr. 9, 01.09.2016, s. 1052-67.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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, bind 6, nr. 9, s. 1052-67. https://doi.org/10.1158/2159-8290.cd-15-1227

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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.",

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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",

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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

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