Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics

Montserrat Garcia-Closas, Per Hall, Heli Nevanlinna, Karen Pooley, Jonathan Morrison, Douglas A. Richesson, Stig E. Bojesen, Børge G. Nordestgaard, Christen K. Axelsson, Jose I. Arias, Roger L. Milne, Gloria Ribas, Anna González-Neira, Javier Benítez, Pilar Zamora, Hiltrud Brauch, Christina Justenhoven, Ute Hamann, Yon Dschun Ko, Thomas Bruening & 91 others Susanne Haas, Thilo Dörk, Peter Schürmann, Peter Hillemanns, Natalia Bogdanova, Michael Bremer, Johann Hinrich Karstens, Rainer Fagerholm, Kirsimari Aaltonen, Kristiina Aittomäki, Karl Von Smitten, Carl Blomqvist, Arto Mannermaa, Matti Uusitupa, Matti Eskelinen, Maria Tengström, Veli Matti Kosma, Vesa Kataja, Georgia Chenevix-Trench, Amanda B. Spurdle, Jonathan Beesley, Xiaoqing Chen, Peter Devilee, Christi J. Van Asperen, Catharina E. Jacobi, Rob A E M Tollenaar, Petra E A Huijts, Jan G M Klijn, Jenny Chang-Claude, Silke Kropp, Tracy Slanger, Dieter Flesch-Janys, Elke Mutschelknauss, Ramona Salazar, Shan Wang-Gohrke, Fergus J Couch, Ellen L Goode, Janet E Olson, Celine M Vachon, Zachary S. Fredericksen, Graham G. Giles, Laura Baglietto, Gianluca Severi, John L. Hopper, Dallas R. English, Melissa C. Southey, Christopher A. Haiman, Brian E. Henderson, Laurence N. Kolonel, Loic Le Marchand, Daniel O. Stram, David J. Hunter, Susan E. Hankinson, David G. Cox, Rulla Tamimi, Peter Kraft, Mark E. Sherman, Stephen J. Chanock, Jolanta Lissowska, Louise A. Brinton, Beata Peplonska, Maartje J. Hooning, Han Meijers-Heijboer, J. Margriet Collee, Ans Van Den Ouweland, Andre G. Uitterlinden, Jianjun Liu, Yen Lin Low, Li Yuqing, Keith Humphreys, Kamila Czene, Angela Cox, Sabapathy P. Balasubramanian, Simon S. Cross, Malcolm W R Reed, Fiona Blows, Kristy Driver, Alison Dunning, Jonathan Tyrer, Bruce A J Ponder, Suleeporn Sangrajrang, Paul Brennan, James McKay, Fabrice Odefrey, Valerie Gabrieau, Alice Sigurdson, Michele Doody, Jeffrey P. Struewing, Bruce Alexander, Douglas F. Easton, Paul D. Pharoah

Research output: Contribution to journalArticle

269 Citations (Scopus)

Abstract

A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10-13). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10-5, 10 -8, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10-4, respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.

Original languageEnglish (US)
Article numbere1000054
JournalPLoS Genetics
Volume4
Issue number4
DOIs
StatePublished - Apr 2008

Fingerprint

breast neoplasms
single nucleotide polymorphism
Single Nucleotide Polymorphism
cancer
polymorphism
tumor
Breast Neoplasms
loci
Trinucleotide Repeats
neoplasms
Neoplasms
allele
Alleles
microsatellite repeats
alleles
protein
Mitogen-Activated Protein Kinase 3
Genome-Wide Association Study
mitogen-activated protein kinase
fibroblasts

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Garcia-Closas, M., Hall, P., Nevanlinna, H., Pooley, K., Morrison, J., Richesson, D. A., ... Pharoah, P. D. (2008). Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genetics, 4(4), [e1000054]. https://doi.org/10.1371/journal.pgen.1000054

Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. / Garcia-Closas, Montserrat; Hall, Per; Nevanlinna, Heli; Pooley, Karen; Morrison, Jonathan; Richesson, Douglas A.; Bojesen, Stig E.; Nordestgaard, Børge G.; Axelsson, Christen K.; Arias, Jose I.; Milne, Roger L.; Ribas, Gloria; González-Neira, Anna; Benítez, Javier; Zamora, Pilar; Brauch, Hiltrud; Justenhoven, Christina; Hamann, Ute; Ko, Yon Dschun; Bruening, Thomas; Haas, Susanne; Dörk, Thilo; Schürmann, Peter; Hillemanns, Peter; Bogdanova, Natalia; Bremer, Michael; Karstens, Johann Hinrich; Fagerholm, Rainer; Aaltonen, Kirsimari; Aittomäki, Kristiina; Von Smitten, Karl; Blomqvist, Carl; Mannermaa, Arto; Uusitupa, Matti; Eskelinen, Matti; Tengström, Maria; Kosma, Veli Matti; Kataja, Vesa; Chenevix-Trench, Georgia; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Devilee, Peter; Van Asperen, Christi J.; Jacobi, Catharina E.; Tollenaar, Rob A E M; Huijts, Petra E A; Klijn, Jan G M; Chang-Claude, Jenny; Kropp, Silke; Slanger, Tracy; Flesch-Janys, Dieter; Mutschelknauss, Elke; Salazar, Ramona; Wang-Gohrke, Shan; Couch, Fergus J; Goode, Ellen L; Olson, Janet E; Vachon, Celine M; Fredericksen, Zachary S.; Giles, Graham G.; Baglietto, Laura; Severi, Gianluca; Hopper, John L.; English, Dallas R.; Southey, Melissa C.; Haiman, Christopher A.; Henderson, Brian E.; Kolonel, Laurence N.; Le Marchand, Loic; Stram, Daniel O.; Hunter, David J.; Hankinson, Susan E.; Cox, David G.; Tamimi, Rulla; Kraft, Peter; Sherman, Mark E.; Chanock, Stephen J.; Lissowska, Jolanta; Brinton, Louise A.; Peplonska, Beata; Hooning, Maartje J.; Meijers-Heijboer, Han; Collee, J. Margriet; Van Den Ouweland, Ans; Uitterlinden, Andre G.; Liu, Jianjun; Low, Yen Lin; Yuqing, Li; Humphreys, Keith; Czene, Kamila; Cox, Angela; Balasubramanian, Sabapathy P.; Cross, Simon S.; Reed, Malcolm W R; Blows, Fiona; Driver, Kristy; Dunning, Alison; Tyrer, Jonathan; Ponder, Bruce A J; Sangrajrang, Suleeporn; Brennan, Paul; McKay, James; Odefrey, Fabrice; Gabrieau, Valerie; Sigurdson, Alice; Doody, Michele; Struewing, Jeffrey P.; Alexander, Bruce; Easton, Douglas F.; Pharoah, Paul D.

In: PLoS Genetics, Vol. 4, No. 4, e1000054, 04.2008.

Research output: Contribution to journalArticle

Garcia-Closas, M, Hall, P, Nevanlinna, H, Pooley, K, Morrison, J, Richesson, DA, Bojesen, SE, Nordestgaard, BG, Axelsson, CK, Arias, JI, Milne, RL, Ribas, G, González-Neira, A, Benítez, J, Zamora, P, Brauch, H, Justenhoven, C, Hamann, U, Ko, YD, Bruening, T, Haas, S, Dörk, T, Schürmann, P, Hillemanns, P, Bogdanova, N, Bremer, M, Karstens, JH, Fagerholm, R, Aaltonen, K, Aittomäki, K, Von Smitten, K, Blomqvist, C, Mannermaa, A, Uusitupa, M, Eskelinen, M, Tengström, M, Kosma, VM, Kataja, V, Chenevix-Trench, G, Spurdle, AB, Beesley, J, Chen, X, Devilee, P, Van Asperen, CJ, Jacobi, CE, Tollenaar, RAEM, Huijts, PEA, Klijn, JGM, Chang-Claude, J, Kropp, S, Slanger, T, Flesch-Janys, D, Mutschelknauss, E, Salazar, R, Wang-Gohrke, S, Couch, FJ, Goode, EL, Olson, JE, Vachon, CM, Fredericksen, ZS, Giles, GG, Baglietto, L, Severi, G, Hopper, JL, English, DR, Southey, MC, Haiman, CA, Henderson, BE, Kolonel, LN, Le Marchand, L, Stram, DO, Hunter, DJ, Hankinson, SE, Cox, DG, Tamimi, R, Kraft, P, Sherman, ME, Chanock, SJ, Lissowska, J, Brinton, LA, Peplonska, B, Hooning, MJ, Meijers-Heijboer, H, Collee, JM, Van Den Ouweland, A, Uitterlinden, AG, Liu, J, Low, YL, Yuqing, L, Humphreys, K, Czene, K, Cox, A, Balasubramanian, SP, Cross, SS, Reed, MWR, Blows, F, Driver, K, Dunning, A, Tyrer, J, Ponder, BAJ, Sangrajrang, S, Brennan, P, McKay, J, Odefrey, F, Gabrieau, V, Sigurdson, A, Doody, M, Struewing, JP, Alexander, B, Easton, DF & Pharoah, PD 2008, 'Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics', PLoS Genetics, vol. 4, no. 4, e1000054. https://doi.org/10.1371/journal.pgen.1000054
Garcia-Closas, Montserrat ; Hall, Per ; Nevanlinna, Heli ; Pooley, Karen ; Morrison, Jonathan ; Richesson, Douglas A. ; Bojesen, Stig E. ; Nordestgaard, Børge G. ; Axelsson, Christen K. ; Arias, Jose I. ; Milne, Roger L. ; Ribas, Gloria ; González-Neira, Anna ; Benítez, Javier ; Zamora, Pilar ; Brauch, Hiltrud ; Justenhoven, Christina ; Hamann, Ute ; Ko, Yon Dschun ; Bruening, Thomas ; Haas, Susanne ; Dörk, Thilo ; Schürmann, Peter ; Hillemanns, Peter ; Bogdanova, Natalia ; Bremer, Michael ; Karstens, Johann Hinrich ; Fagerholm, Rainer ; Aaltonen, Kirsimari ; Aittomäki, Kristiina ; Von Smitten, Karl ; Blomqvist, Carl ; Mannermaa, Arto ; Uusitupa, Matti ; Eskelinen, Matti ; Tengström, Maria ; Kosma, Veli Matti ; Kataja, Vesa ; Chenevix-Trench, Georgia ; Spurdle, Amanda B. ; Beesley, Jonathan ; Chen, Xiaoqing ; Devilee, Peter ; Van Asperen, Christi J. ; Jacobi, Catharina E. ; Tollenaar, Rob A E M ; Huijts, Petra E A ; Klijn, Jan G M ; Chang-Claude, Jenny ; Kropp, Silke ; Slanger, Tracy ; Flesch-Janys, Dieter ; Mutschelknauss, Elke ; Salazar, Ramona ; Wang-Gohrke, Shan ; Couch, Fergus J ; Goode, Ellen L ; Olson, Janet E ; Vachon, Celine M ; Fredericksen, Zachary S. ; Giles, Graham G. ; Baglietto, Laura ; Severi, Gianluca ; Hopper, John L. ; English, Dallas R. ; Southey, Melissa C. ; Haiman, Christopher A. ; Henderson, Brian E. ; Kolonel, Laurence N. ; Le Marchand, Loic ; Stram, Daniel O. ; Hunter, David J. ; Hankinson, Susan E. ; Cox, David G. ; Tamimi, Rulla ; Kraft, Peter ; Sherman, Mark E. ; Chanock, Stephen J. ; Lissowska, Jolanta ; Brinton, Louise A. ; Peplonska, Beata ; Hooning, Maartje J. ; Meijers-Heijboer, Han ; Collee, J. Margriet ; Van Den Ouweland, Ans ; Uitterlinden, Andre G. ; Liu, Jianjun ; Low, Yen Lin ; Yuqing, Li ; Humphreys, Keith ; Czene, Kamila ; Cox, Angela ; Balasubramanian, Sabapathy P. ; Cross, Simon S. ; Reed, Malcolm W R ; Blows, Fiona ; Driver, Kristy ; Dunning, Alison ; Tyrer, Jonathan ; Ponder, Bruce A J ; Sangrajrang, Suleeporn ; Brennan, Paul ; McKay, James ; Odefrey, Fabrice ; Gabrieau, Valerie ; Sigurdson, Alice ; Doody, Michele ; Struewing, Jeffrey P. ; Alexander, Bruce ; Easton, Douglas F. ; Pharoah, Paul D. / Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. In: PLoS Genetics. 2008 ; Vol. 4, No. 4.
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title = "Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics",
abstract = "A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95{\%}CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10-13). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10-5, 10 -8, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10-4, respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.",
author = "Montserrat Garcia-Closas and Per Hall and Heli Nevanlinna and Karen Pooley and Jonathan Morrison and Richesson, {Douglas A.} and Bojesen, {Stig E.} and Nordestgaard, {B{\o}rge G.} and Axelsson, {Christen K.} and Arias, {Jose I.} and Milne, {Roger L.} and Gloria Ribas and Anna Gonz{\'a}lez-Neira and Javier Ben{\'i}tez and Pilar Zamora and Hiltrud Brauch and Christina Justenhoven and Ute Hamann and Ko, {Yon Dschun} and Thomas Bruening and Susanne Haas and Thilo D{\"o}rk and Peter Sch{\"u}rmann and Peter Hillemanns and Natalia Bogdanova and Michael Bremer and Karstens, {Johann Hinrich} and Rainer Fagerholm and Kirsimari Aaltonen and Kristiina Aittom{\"a}ki and {Von Smitten}, Karl and Carl Blomqvist and Arto Mannermaa and Matti Uusitupa and Matti Eskelinen and Maria Tengstr{\"o}m and Kosma, {Veli Matti} and Vesa Kataja and Georgia Chenevix-Trench and Spurdle, {Amanda B.} and Jonathan Beesley and Xiaoqing Chen and Peter Devilee and {Van Asperen}, {Christi J.} and Jacobi, {Catharina E.} and Tollenaar, {Rob A E M} and Huijts, {Petra E A} and Klijn, {Jan G M} and Jenny Chang-Claude and Silke Kropp and Tracy Slanger and Dieter Flesch-Janys and Elke Mutschelknauss and Ramona Salazar and Shan Wang-Gohrke and Couch, {Fergus J} and Goode, {Ellen L} and Olson, {Janet E} and Vachon, {Celine M} and Fredericksen, {Zachary S.} and Giles, {Graham G.} and Laura Baglietto and Gianluca Severi and Hopper, {John L.} and English, {Dallas R.} and Southey, {Melissa C.} and Haiman, {Christopher A.} and Henderson, {Brian E.} and Kolonel, {Laurence N.} and {Le Marchand}, Loic and Stram, {Daniel O.} and Hunter, {David J.} and Hankinson, {Susan E.} and Cox, {David G.} and Rulla Tamimi and Peter Kraft and Sherman, {Mark E.} and Chanock, {Stephen J.} and Jolanta Lissowska and Brinton, {Louise A.} and Beata Peplonska and Hooning, {Maartje J.} and Han Meijers-Heijboer and Collee, {J. Margriet} and {Van Den Ouweland}, Ans and Uitterlinden, {Andre G.} and Jianjun Liu and Low, {Yen Lin} and Li Yuqing and Keith Humphreys and Kamila Czene and Angela Cox and Balasubramanian, {Sabapathy P.} and Cross, {Simon S.} and Reed, {Malcolm W R} and Fiona Blows and Kristy Driver and Alison Dunning and Jonathan Tyrer and Ponder, {Bruce A J} and Suleeporn Sangrajrang and Paul Brennan and James McKay and Fabrice Odefrey and Valerie Gabrieau and Alice Sigurdson and Michele Doody and Struewing, {Jeffrey P.} and Bruce Alexander and Easton, {Douglas F.} and Pharoah, {Paul D.}",
year = "2008",
month = "4",
doi = "10.1371/journal.pgen.1000054",
language = "English (US)",
volume = "4",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
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}

TY - JOUR

T1 - Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics

AU - Garcia-Closas, Montserrat

AU - Hall, Per

AU - Nevanlinna, Heli

AU - Pooley, Karen

AU - Morrison, Jonathan

AU - Richesson, Douglas A.

AU - Bojesen, Stig E.

AU - Nordestgaard, Børge G.

AU - Axelsson, Christen K.

AU - Arias, Jose I.

AU - Milne, Roger L.

AU - Ribas, Gloria

AU - González-Neira, Anna

AU - Benítez, Javier

AU - Zamora, Pilar

AU - Brauch, Hiltrud

AU - Justenhoven, Christina

AU - Hamann, Ute

AU - Ko, Yon Dschun

AU - Bruening, Thomas

AU - Haas, Susanne

AU - Dörk, Thilo

AU - Schürmann, Peter

AU - Hillemanns, Peter

AU - Bogdanova, Natalia

AU - Bremer, Michael

AU - Karstens, Johann Hinrich

AU - Fagerholm, Rainer

AU - Aaltonen, Kirsimari

AU - Aittomäki, Kristiina

AU - Von Smitten, Karl

AU - Blomqvist, Carl

AU - Mannermaa, Arto

AU - Uusitupa, Matti

AU - Eskelinen, Matti

AU - Tengström, Maria

AU - Kosma, Veli Matti

AU - Kataja, Vesa

AU - Chenevix-Trench, Georgia

AU - Spurdle, Amanda B.

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - Devilee, Peter

AU - Van Asperen, Christi J.

AU - Jacobi, Catharina E.

AU - Tollenaar, Rob A E M

AU - Huijts, Petra E A

AU - Klijn, Jan G M

AU - Chang-Claude, Jenny

AU - Kropp, Silke

AU - Slanger, Tracy

AU - Flesch-Janys, Dieter

AU - Mutschelknauss, Elke

AU - Salazar, Ramona

AU - Wang-Gohrke, Shan

AU - Couch, Fergus J

AU - Goode, Ellen L

AU - Olson, Janet E

AU - Vachon, Celine M

AU - Fredericksen, Zachary S.

AU - Giles, Graham G.

AU - Baglietto, Laura

AU - Severi, Gianluca

AU - Hopper, John L.

AU - English, Dallas R.

AU - Southey, Melissa C.

AU - Haiman, Christopher A.

AU - Henderson, Brian E.

AU - Kolonel, Laurence N.

AU - Le Marchand, Loic

AU - Stram, Daniel O.

AU - Hunter, David J.

AU - Hankinson, Susan E.

AU - Cox, David G.

AU - Tamimi, Rulla

AU - Kraft, Peter

AU - Sherman, Mark E.

AU - Chanock, Stephen J.

AU - Lissowska, Jolanta

AU - Brinton, Louise A.

AU - Peplonska, Beata

AU - Hooning, Maartje J.

AU - Meijers-Heijboer, Han

AU - Collee, J. Margriet

AU - Van Den Ouweland, Ans

AU - Uitterlinden, Andre G.

AU - Liu, Jianjun

AU - Low, Yen Lin

AU - Yuqing, Li

AU - Humphreys, Keith

AU - Czene, Kamila

AU - Cox, Angela

AU - Balasubramanian, Sabapathy P.

AU - Cross, Simon S.

AU - Reed, Malcolm W R

AU - Blows, Fiona

AU - Driver, Kristy

AU - Dunning, Alison

AU - Tyrer, Jonathan

AU - Ponder, Bruce A J

AU - Sangrajrang, Suleeporn

AU - Brennan, Paul

AU - McKay, James

AU - Odefrey, Fabrice

AU - Gabrieau, Valerie

AU - Sigurdson, Alice

AU - Doody, Michele

AU - Struewing, Jeffrey P.

AU - Alexander, Bruce

AU - Easton, Douglas F.

AU - Pharoah, Paul D.

PY - 2008/4

Y1 - 2008/4

N2 - A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10-13). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10-5, 10 -8, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10-4, respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.

AB - A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10-13). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10-5, 10 -8, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10-4, respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.

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