Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes

Findings from the Breast Cancer Association Consortium

Annegien Broeks, Marjanka K. Schmidt, Mark E. Sherman, Fergus J. Couch, John L. Hopper, Gillian S. Dite, Carmel Apicella, Letitia D. Smith, Fleur Hammet, Melissa C. Southey, Laura J. Van't Veer, Renate De Groot, Vincent T H B M Smit, Peter A. Fasching, Matthias W. Beckmann, Sebastian Jud, Arif B. Ekici, Arndt Hartmann, Alexander Hein, Ruediger Schulz-Wendtland & 133 others Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Hans Peter Sinn, Christof Sohn, Sandrine Tchatchou, Stig E. Bojesen, Børge G. Nordestgaard, Henrik Flyger, David D. Ørsted, Diljit Kaur-Knudsen, Roger L. Milne, Jose I Arias Pérez, Pilar Zamora, Primitiva Menéndez Rodríguez, Javier Benítez, Hiltrud Brauch, Christina Justenhoven, Yon Dschun Ko, The Genica Network, Ute Hamann, Hans Peter Fischer, Thomas Brüning, Beate Pesch, Jenny Chang-Claude, Shan Wang-Gohrke, Michael Bremer, Johann H. Karstens, Peter Hillemanns, Thilo Dörk, Heli A. Nevanlinna, Tuomas Heikkinen, Päivi Heikkilä, Carl Blomqvist, Kristiina Aittomäki, Kirsimari Aaltonen, Annika Lindblom, Sara Margolin, Arto Mannermaa, Veli Matti Kosma, Jaana M. Kauppinen, Vesa Kataja, Päivi Auvinen, Matti Eskelinen, Ylermi Soini, Georgia Chenevix-Trench, Amanda B. Spurdle, Jonathan Beesley, Xiaoqing Chen, Helene Holland, Diether Lambrechts, Bart Claes, Thijs Vandorpe, Patrick Neven, Hans Wildiers, Dieter Flesch-Janys, Rebecca Hein, Thomas Löning, Matthew Kosel, Zachary S. Fredericksen, Xianshu Wang, Graham G. Giles, Laura Baglietto, Gianluca Severi, Catriona McLean, Christopher A. Haiman, Brian E. Henderson, Loic Le Marchand, Laurence N. Kolonel, Grethe Grenaker Alnæs, Vessela Kristensen, Anne Lise Børresen-Dale, David J. Hunter, Susan E. Hankinson, Irene L. Andrulis, Anna Marie Mulligan, Frances P. O'Malley, Peter Devilee, Petra E A Huijts, Rob A E M Tollenaar, Christi J. Van Asperen, Caroline S. Seynaeve, Stephen J. Chanock, Jolanta Lissowska, Louise Brinton, Beata Peplonska, Jonine Figueroa, Xiaohong R. Yang, Maartje J. Hooning, Antoinette Hollestelle, Rogier A. Oldenburg, Agnes Jager, Mieke Kriege, Bahar Ozturk, Geert J L H Van Leenders, Per Hall, Kamila Czene, Keith Humphreys, Jianjun Liu, Angela Cox, Daniel Connley, Helen E. Cramp, Simon S. Cross, Sabapathy P. Balasubramanian, Malcolm W R Reed, Alison M. Dunning, Douglas F. Easton, Manjeet K. Humphreys, Carlos Caldas, Fiona Blows, Kristy Driver, Elena Provenzano, Jan Lubinski, Anna Jakubowska, Tomasz Huzarski, Tomasz Byrski, Cezary Cybulski, Bohdan Gorski, Jacek Gronwald, Paul Brennan, Suleeporn Sangrajrang, Valerie Gaborieau, Chen Yang Shen, Chia Ni Hsiung, Jyh Cherng Yu, Shou Tung Chen, Giu Cheng Hsu, Ming Feng Hou, Chiun Sheng Huang, Hoda Anton-Culver, Argyrios Ziogas, Paul D P Pharoah, Montserrat Garcia-Closas

Research output: Contribution to journalArticle

Abstract

Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER1 than ER2 tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10-18), rs3803662 (16q12) (P = 3.7 × 10-5), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10-6 and P = 4.1 × 10-4, respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ≤ 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.

Original languageEnglish (US)
Pages (from-to)3289-3303
Number of pages15
JournalHuman Molecular Genetics
Volume20
Issue number16
DOIs
StatePublished - 2011
Externally publishedYes

Fingerprint

Penetrance
Breast Neoplasms
Genome-Wide Association Study
Neoplasms
Phenotype
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes : Findings from the Breast Cancer Association Consortium. / Broeks, Annegien; Schmidt, Marjanka K.; Sherman, Mark E.; Couch, Fergus J.; Hopper, John L.; Dite, Gillian S.; Apicella, Carmel; Smith, Letitia D.; Hammet, Fleur; Southey, Melissa C.; Van't Veer, Laura J.; De Groot, Renate; Smit, Vincent T H B M; Fasching, Peter A.; Beckmann, Matthias W.; Jud, Sebastian; Ekici, Arif B.; Hartmann, Arndt; Hein, Alexander; Schulz-Wendtland, Ruediger; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sinn, Hans Peter; Sohn, Christof; Tchatchou, Sandrine; Bojesen, Stig E.; Nordestgaard, Børge G.; Flyger, Henrik; Ørsted, David D.; Kaur-Knudsen, Diljit; Milne, Roger L.; Pérez, Jose I Arias; Zamora, Pilar; Rodríguez, Primitiva Menéndez; Benítez, Javier; Brauch, Hiltrud; Justenhoven, Christina; Ko, Yon Dschun; Network, The Genica; Hamann, Ute; Fischer, Hans Peter; Brüning, Thomas; Pesch, Beate; Chang-Claude, Jenny; Wang-Gohrke, Shan; Bremer, Michael; Karstens, Johann H.; Hillemanns, Peter; Dörk, Thilo; Nevanlinna, Heli A.; Heikkinen, Tuomas; Heikkilä, Päivi; Blomqvist, Carl; Aittomäki, Kristiina; Aaltonen, Kirsimari; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli Matti; Kauppinen, Jaana M.; Kataja, Vesa; Auvinen, Päivi; Eskelinen, Matti; Soini, Ylermi; Chenevix-Trench, Georgia; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Holland, Helene; Lambrechts, Diether; Claes, Bart; Vandorpe, Thijs; Neven, Patrick; Wildiers, Hans; Flesch-Janys, Dieter; Hein, Rebecca; Löning, Thomas; Kosel, Matthew; Fredericksen, Zachary S.; Wang, Xianshu; Giles, Graham G.; Baglietto, Laura; Severi, Gianluca; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Le Marchand, Loic; Kolonel, Laurence N.; Alnæs, Grethe Grenaker; Kristensen, Vessela; Børresen-Dale, Anne Lise; Hunter, David J.; Hankinson, Susan E.; Andrulis, Irene L.; Mulligan, Anna Marie; O'Malley, Frances P.; Devilee, Peter; Huijts, Petra E A; Tollenaar, Rob A E M; Van Asperen, Christi J.; Seynaeve, Caroline S.; Chanock, Stephen J.; Lissowska, Jolanta; Brinton, Louise; Peplonska, Beata; Figueroa, Jonine; Yang, Xiaohong R.; Hooning, Maartje J.; Hollestelle, Antoinette; Oldenburg, Rogier A.; Jager, Agnes; Kriege, Mieke; Ozturk, Bahar; Van Leenders, Geert J L H; Hall, Per; Czene, Kamila; Humphreys, Keith; Liu, Jianjun; Cox, Angela; Connley, Daniel; Cramp, Helen E.; Cross, Simon S.; Balasubramanian, Sabapathy P.; Reed, Malcolm W R; Dunning, Alison M.; Easton, Douglas F.; Humphreys, Manjeet K.; Caldas, Carlos; Blows, Fiona; Driver, Kristy; Provenzano, Elena; Lubinski, Jan; Jakubowska, Anna; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Gorski, Bohdan; Gronwald, Jacek; Brennan, Paul; Sangrajrang, Suleeporn; Gaborieau, Valerie; Shen, Chen Yang; Hsiung, Chia Ni; Yu, Jyh Cherng; Chen, Shou Tung; Hsu, Giu Cheng; Hou, Ming Feng; Huang, Chiun Sheng; Anton-Culver, Hoda; Ziogas, Argyrios; Pharoah, Paul D P; Garcia-Closas, Montserrat.

In: Human Molecular Genetics, Vol. 20, No. 16, 2011, p. 3289-3303.

Research output: Contribution to journalArticle

Broeks, A, Schmidt, MK, Sherman, ME, Couch, FJ, Hopper, JL, Dite, GS, Apicella, C, Smith, LD, Hammet, F, Southey, MC, Van't Veer, LJ, De Groot, R, Smit, VTHBM, Fasching, PA, Beckmann, MW, Jud, S, Ekici, AB, Hartmann, A, Hein, A, Schulz-Wendtland, R, Burwinkel, B, Marme, F, Schneeweiss, A, Sinn, HP, Sohn, C, Tchatchou, S, Bojesen, SE, Nordestgaard, BG, Flyger, H, Ørsted, DD, Kaur-Knudsen, D, Milne, RL, Pérez, JIA, Zamora, P, Rodríguez, PM, Benítez, J, Brauch, H, Justenhoven, C, Ko, YD, Network, TG, Hamann, U, Fischer, HP, Brüning, T, Pesch, B, Chang-Claude, J, Wang-Gohrke, S, Bremer, M, Karstens, JH, Hillemanns, P, Dörk, T, Nevanlinna, HA, Heikkinen, T, Heikkilä, P, Blomqvist, C, Aittomäki, K, Aaltonen, K, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, VM, Kauppinen, JM, Kataja, V, Auvinen, P, Eskelinen, M, Soini, Y, Chenevix-Trench, G, Spurdle, AB, Beesley, J, Chen, X, Holland, H, Lambrechts, D, Claes, B, Vandorpe, T, Neven, P, Wildiers, H, Flesch-Janys, D, Hein, R, Löning, T, Kosel, M, Fredericksen, ZS, Wang, X, Giles, GG, Baglietto, L, Severi, G, McLean, C, Haiman, CA, Henderson, BE, Le Marchand, L, Kolonel, LN, Alnæs, GG, Kristensen, V, Børresen-Dale, AL, Hunter, DJ, Hankinson, SE, Andrulis, IL, Mulligan, AM, O'Malley, FP, Devilee, P, Huijts, PEA, Tollenaar, RAEM, Van Asperen, CJ, Seynaeve, CS, Chanock, SJ, Lissowska, J, Brinton, L, Peplonska, B, Figueroa, J, Yang, XR, Hooning, MJ, Hollestelle, A, Oldenburg, RA, Jager, A, Kriege, M, Ozturk, B, Van Leenders, GJLH, Hall, P, Czene, K, Humphreys, K, Liu, J, Cox, A, Connley, D, Cramp, HE, Cross, SS, Balasubramanian, SP, Reed, MWR, Dunning, AM, Easton, DF, Humphreys, MK, Caldas, C, Blows, F, Driver, K, Provenzano, E, Lubinski, J, Jakubowska, A, Huzarski, T, Byrski, T, Cybulski, C, Gorski, B, Gronwald, J, Brennan, P, Sangrajrang, S, Gaborieau, V, Shen, CY, Hsiung, CN, Yu, JC, Chen, ST, Hsu, GC, Hou, MF, Huang, CS, Anton-Culver, H, Ziogas, A, Pharoah, PDP & Garcia-Closas, M 2011, 'Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: Findings from the Breast Cancer Association Consortium', Human Molecular Genetics, vol. 20, no. 16, pp. 3289-3303. https://doi.org/10.1093/hmg/ddr228
Broeks, Annegien ; Schmidt, Marjanka K. ; Sherman, Mark E. ; Couch, Fergus J. ; Hopper, John L. ; Dite, Gillian S. ; Apicella, Carmel ; Smith, Letitia D. ; Hammet, Fleur ; Southey, Melissa C. ; Van't Veer, Laura J. ; De Groot, Renate ; Smit, Vincent T H B M ; Fasching, Peter A. ; Beckmann, Matthias W. ; Jud, Sebastian ; Ekici, Arif B. ; Hartmann, Arndt ; Hein, Alexander ; Schulz-Wendtland, Ruediger ; Burwinkel, Barbara ; Marme, Frederik ; Schneeweiss, Andreas ; Sinn, Hans Peter ; Sohn, Christof ; Tchatchou, Sandrine ; Bojesen, Stig E. ; Nordestgaard, Børge G. ; Flyger, Henrik ; Ørsted, David D. ; Kaur-Knudsen, Diljit ; Milne, Roger L. ; Pérez, Jose I Arias ; Zamora, Pilar ; Rodríguez, Primitiva Menéndez ; Benítez, Javier ; Brauch, Hiltrud ; Justenhoven, Christina ; Ko, Yon Dschun ; Network, The Genica ; Hamann, Ute ; Fischer, Hans Peter ; Brüning, Thomas ; Pesch, Beate ; Chang-Claude, Jenny ; Wang-Gohrke, Shan ; Bremer, Michael ; Karstens, Johann H. ; Hillemanns, Peter ; Dörk, Thilo ; Nevanlinna, Heli A. ; Heikkinen, Tuomas ; Heikkilä, Päivi ; Blomqvist, Carl ; Aittomäki, Kristiina ; Aaltonen, Kirsimari ; Lindblom, Annika ; Margolin, Sara ; Mannermaa, Arto ; Kosma, Veli Matti ; Kauppinen, Jaana M. ; Kataja, Vesa ; Auvinen, Päivi ; Eskelinen, Matti ; Soini, Ylermi ; Chenevix-Trench, Georgia ; Spurdle, Amanda B. ; Beesley, Jonathan ; Chen, Xiaoqing ; Holland, Helene ; Lambrechts, Diether ; Claes, Bart ; Vandorpe, Thijs ; Neven, Patrick ; Wildiers, Hans ; Flesch-Janys, Dieter ; Hein, Rebecca ; Löning, Thomas ; Kosel, Matthew ; Fredericksen, Zachary S. ; Wang, Xianshu ; Giles, Graham G. ; Baglietto, Laura ; Severi, Gianluca ; McLean, Catriona ; Haiman, Christopher A. ; Henderson, Brian E. ; Le Marchand, Loic ; Kolonel, Laurence N. ; Alnæs, Grethe Grenaker ; Kristensen, Vessela ; Børresen-Dale, Anne Lise ; Hunter, David J. ; Hankinson, Susan E. ; Andrulis, Irene L. ; Mulligan, Anna Marie ; O'Malley, Frances P. ; Devilee, Peter ; Huijts, Petra E A ; Tollenaar, Rob A E M ; Van Asperen, Christi J. ; Seynaeve, Caroline S. ; Chanock, Stephen J. ; Lissowska, Jolanta ; Brinton, Louise ; Peplonska, Beata ; Figueroa, Jonine ; Yang, Xiaohong R. ; Hooning, Maartje J. ; Hollestelle, Antoinette ; Oldenburg, Rogier A. ; Jager, Agnes ; Kriege, Mieke ; Ozturk, Bahar ; Van Leenders, Geert J L H ; Hall, Per ; Czene, Kamila ; Humphreys, Keith ; Liu, Jianjun ; Cox, Angela ; Connley, Daniel ; Cramp, Helen E. ; Cross, Simon S. ; Balasubramanian, Sabapathy P. ; Reed, Malcolm W R ; Dunning, Alison M. ; Easton, Douglas F. ; Humphreys, Manjeet K. ; Caldas, Carlos ; Blows, Fiona ; Driver, Kristy ; Provenzano, Elena ; Lubinski, Jan ; Jakubowska, Anna ; Huzarski, Tomasz ; Byrski, Tomasz ; Cybulski, Cezary ; Gorski, Bohdan ; Gronwald, Jacek ; Brennan, Paul ; Sangrajrang, Suleeporn ; Gaborieau, Valerie ; Shen, Chen Yang ; Hsiung, Chia Ni ; Yu, Jyh Cherng ; Chen, Shou Tung ; Hsu, Giu Cheng ; Hou, Ming Feng ; Huang, Chiun Sheng ; Anton-Culver, Hoda ; Ziogas, Argyrios ; Pharoah, Paul D P ; Garcia-Closas, Montserrat. / Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes : Findings from the Breast Cancer Association Consortium. In: Human Molecular Genetics. 2011 ; Vol. 20, No. 16. pp. 3289-3303.
@article{0f4136dc43174ca5a91d0a83ecf26b84,
title = "Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: Findings from the Breast Cancer Association Consortium",
abstract = "Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER1 than ER2 tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10-18), rs3803662 (16q12) (P = 3.7 × 10-5), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10-6 and P = 4.1 × 10-4, respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ≤ 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.",
author = "Annegien Broeks and Schmidt, {Marjanka K.} and Sherman, {Mark E.} and Couch, {Fergus J.} and Hopper, {John L.} and Dite, {Gillian S.} and Carmel Apicella and Smith, {Letitia D.} and Fleur Hammet and Southey, {Melissa C.} and {Van't Veer}, {Laura J.} and {De Groot}, Renate and Smit, {Vincent T H B M} and Fasching, {Peter A.} and Beckmann, {Matthias W.} and Sebastian Jud and Ekici, {Arif B.} and Arndt Hartmann and Alexander Hein and Ruediger Schulz-Wendtland and Barbara Burwinkel and Frederik Marme and Andreas Schneeweiss and Sinn, {Hans Peter} and Christof Sohn and Sandrine Tchatchou and Bojesen, {Stig E.} and Nordestgaard, {B{\o}rge G.} and Henrik Flyger and {\O}rsted, {David D.} and Diljit Kaur-Knudsen and Milne, {Roger L.} and P{\'e}rez, {Jose I Arias} and Pilar Zamora and Rodr{\'i}guez, {Primitiva Men{\'e}ndez} and Javier Ben{\'i}tez and Hiltrud Brauch and Christina Justenhoven and Ko, {Yon Dschun} and Network, {The Genica} and Ute Hamann and Fischer, {Hans Peter} and Thomas Br{\"u}ning and Beate Pesch and Jenny Chang-Claude and Shan Wang-Gohrke and Michael Bremer and Karstens, {Johann H.} and Peter Hillemanns and Thilo D{\"o}rk and Nevanlinna, {Heli A.} and Tuomas Heikkinen and P{\"a}ivi Heikkil{\"a} and Carl Blomqvist and Kristiina Aittom{\"a}ki and Kirsimari Aaltonen and Annika Lindblom and Sara Margolin and Arto Mannermaa and Kosma, {Veli Matti} and Kauppinen, {Jaana M.} and Vesa Kataja and P{\"a}ivi Auvinen and Matti Eskelinen and Ylermi Soini and Georgia Chenevix-Trench and Spurdle, {Amanda B.} and Jonathan Beesley and Xiaoqing Chen and Helene Holland and Diether Lambrechts and Bart Claes and Thijs Vandorpe and Patrick Neven and Hans Wildiers and Dieter Flesch-Janys and Rebecca Hein and Thomas L{\"o}ning and Matthew Kosel and Fredericksen, {Zachary S.} and Xianshu Wang and Giles, {Graham G.} and Laura Baglietto and Gianluca Severi and Catriona McLean and Haiman, {Christopher A.} and Henderson, {Brian E.} and {Le Marchand}, Loic and Kolonel, {Laurence N.} and Aln{\ae}s, {Grethe Grenaker} and Vessela Kristensen and B{\o}rresen-Dale, {Anne Lise} and Hunter, {David J.} and Hankinson, {Susan E.} and Andrulis, {Irene L.} and Mulligan, {Anna Marie} and O'Malley, {Frances P.} and Peter Devilee and Huijts, {Petra E A} and Tollenaar, {Rob A E M} and {Van Asperen}, {Christi J.} and Seynaeve, {Caroline S.} and Chanock, {Stephen J.} and Jolanta Lissowska and Louise Brinton and Beata Peplonska and Jonine Figueroa and Yang, {Xiaohong R.} and Hooning, {Maartje J.} and Antoinette Hollestelle and Oldenburg, {Rogier A.} and Agnes Jager and Mieke Kriege and Bahar Ozturk and {Van Leenders}, {Geert J L H} and Per Hall and Kamila Czene and Keith Humphreys and Jianjun Liu and Angela Cox and Daniel Connley and Cramp, {Helen E.} and Cross, {Simon S.} and Balasubramanian, {Sabapathy P.} and Reed, {Malcolm W R} and Dunning, {Alison M.} and Easton, {Douglas F.} and Humphreys, {Manjeet K.} and Carlos Caldas and Fiona Blows and Kristy Driver and Elena Provenzano and Jan Lubinski and Anna Jakubowska and Tomasz Huzarski and Tomasz Byrski and Cezary Cybulski and Bohdan Gorski and Jacek Gronwald and Paul Brennan and Suleeporn Sangrajrang and Valerie Gaborieau and Shen, {Chen Yang} and Hsiung, {Chia Ni} and Yu, {Jyh Cherng} and Chen, {Shou Tung} and Hsu, {Giu Cheng} and Hou, {Ming Feng} and Huang, {Chiun Sheng} and Hoda Anton-Culver and Argyrios Ziogas and Pharoah, {Paul D P} and Montserrat Garcia-Closas",
year = "2011",
doi = "10.1093/hmg/ddr228",
language = "English (US)",
volume = "20",
pages = "3289--3303",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "16",

}

TY - JOUR

T1 - Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes

T2 - Findings from the Breast Cancer Association Consortium

AU - Broeks, Annegien

AU - Schmidt, Marjanka K.

AU - Sherman, Mark E.

AU - Couch, Fergus J.

AU - Hopper, John L.

AU - Dite, Gillian S.

AU - Apicella, Carmel

AU - Smith, Letitia D.

AU - Hammet, Fleur

AU - Southey, Melissa C.

AU - Van't Veer, Laura J.

AU - De Groot, Renate

AU - Smit, Vincent T H B M

AU - Fasching, Peter A.

AU - Beckmann, Matthias W.

AU - Jud, Sebastian

AU - Ekici, Arif B.

AU - Hartmann, Arndt

AU - Hein, Alexander

AU - Schulz-Wendtland, Ruediger

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Schneeweiss, Andreas

AU - Sinn, Hans Peter

AU - Sohn, Christof

AU - Tchatchou, Sandrine

AU - Bojesen, Stig E.

AU - Nordestgaard, Børge G.

AU - Flyger, Henrik

AU - Ørsted, David D.

AU - Kaur-Knudsen, Diljit

AU - Milne, Roger L.

AU - Pérez, Jose I Arias

AU - Zamora, Pilar

AU - Rodríguez, Primitiva Menéndez

AU - Benítez, Javier

AU - Brauch, Hiltrud

AU - Justenhoven, Christina

AU - Ko, Yon Dschun

AU - Network, The Genica

AU - Hamann, Ute

AU - Fischer, Hans Peter

AU - Brüning, Thomas

AU - Pesch, Beate

AU - Chang-Claude, Jenny

AU - Wang-Gohrke, Shan

AU - Bremer, Michael

AU - Karstens, Johann H.

AU - Hillemanns, Peter

AU - Dörk, Thilo

AU - Nevanlinna, Heli A.

AU - Heikkinen, Tuomas

AU - Heikkilä, Päivi

AU - Blomqvist, Carl

AU - Aittomäki, Kristiina

AU - Aaltonen, Kirsimari

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Mannermaa, Arto

AU - Kosma, Veli Matti

AU - Kauppinen, Jaana M.

AU - Kataja, Vesa

AU - Auvinen, Päivi

AU - Eskelinen, Matti

AU - Soini, Ylermi

AU - Chenevix-Trench, Georgia

AU - Spurdle, Amanda B.

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - Holland, Helene

AU - Lambrechts, Diether

AU - Claes, Bart

AU - Vandorpe, Thijs

AU - Neven, Patrick

AU - Wildiers, Hans

AU - Flesch-Janys, Dieter

AU - Hein, Rebecca

AU - Löning, Thomas

AU - Kosel, Matthew

AU - Fredericksen, Zachary S.

AU - Wang, Xianshu

AU - Giles, Graham G.

AU - Baglietto, Laura

AU - Severi, Gianluca

AU - McLean, Catriona

AU - Haiman, Christopher A.

AU - Henderson, Brian E.

AU - Le Marchand, Loic

AU - Kolonel, Laurence N.

AU - Alnæs, Grethe Grenaker

AU - Kristensen, Vessela

AU - Børresen-Dale, Anne Lise

AU - Hunter, David J.

AU - Hankinson, Susan E.

AU - Andrulis, Irene L.

AU - Mulligan, Anna Marie

AU - O'Malley, Frances P.

AU - Devilee, Peter

AU - Huijts, Petra E A

AU - Tollenaar, Rob A E M

AU - Van Asperen, Christi J.

AU - Seynaeve, Caroline S.

AU - Chanock, Stephen J.

AU - Lissowska, Jolanta

AU - Brinton, Louise

AU - Peplonska, Beata

AU - Figueroa, Jonine

AU - Yang, Xiaohong R.

AU - Hooning, Maartje J.

AU - Hollestelle, Antoinette

AU - Oldenburg, Rogier A.

AU - Jager, Agnes

AU - Kriege, Mieke

AU - Ozturk, Bahar

AU - Van Leenders, Geert J L H

AU - Hall, Per

AU - Czene, Kamila

AU - Humphreys, Keith

AU - Liu, Jianjun

AU - Cox, Angela

AU - Connley, Daniel

AU - Cramp, Helen E.

AU - Cross, Simon S.

AU - Balasubramanian, Sabapathy P.

AU - Reed, Malcolm W R

AU - Dunning, Alison M.

AU - Easton, Douglas F.

AU - Humphreys, Manjeet K.

AU - Caldas, Carlos

AU - Blows, Fiona

AU - Driver, Kristy

AU - Provenzano, Elena

AU - Lubinski, Jan

AU - Jakubowska, Anna

AU - Huzarski, Tomasz

AU - Byrski, Tomasz

AU - Cybulski, Cezary

AU - Gorski, Bohdan

AU - Gronwald, Jacek

AU - Brennan, Paul

AU - Sangrajrang, Suleeporn

AU - Gaborieau, Valerie

AU - Shen, Chen Yang

AU - Hsiung, Chia Ni

AU - Yu, Jyh Cherng

AU - Chen, Shou Tung

AU - Hsu, Giu Cheng

AU - Hou, Ming Feng

AU - Huang, Chiun Sheng

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Pharoah, Paul D P

AU - Garcia-Closas, Montserrat

PY - 2011

Y1 - 2011

N2 - Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER1 than ER2 tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10-18), rs3803662 (16q12) (P = 3.7 × 10-5), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10-6 and P = 4.1 × 10-4, respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ≤ 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.

AB - Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER1 than ER2 tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10-18), rs3803662 (16q12) (P = 3.7 × 10-5), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10-6 and P = 4.1 × 10-4, respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ≤ 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.

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U2 - 10.1093/hmg/ddr228

DO - 10.1093/hmg/ddr228

M3 - Article

VL - 20

SP - 3289

EP - 3303

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 16

ER -