Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium

Genica Network; 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; 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; Ute Hamann; Hans-Peter Fischer; Thomas Brüning; Beate Pesch; Jenny Chang-Claude; Shan Wang-Gohrke; Michael Bremer; Johann H Karstens; Peter Hillemanns; Thilo Dörk; Jonine Figueroa

doi:10.1093/hmg/ddr228

Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium

Genica Network, 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 HeinRuediger Schulz-Wendtland, 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, Ute Hamann, Hans-Peter Fischer, Thomas Brüning, Beate Pesch, Jenny Chang-Claude, Shan Wang-Gohrke, Michael Bremer, Johann H Karstens, Peter Hillemanns, Thilo Dörk, Jonine Figueroa

Deanery of Molecular, Genetic and Population Health Sciences

Research output: Contribution to journal › Article › peer-review

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 ER+ than ER- 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 language	English
Pages (from-to)	3289-303
Number of pages	15
Journal	Human Molecular Genetics
Volume	20
Issue number	16
DOIs	https://doi.org/10.1093/hmg/ddr228
Publication status	Published - 15 Aug 2011

Keywords

Asian Continental Ancestry Group
Biomarkers, Tumor
Breast Neoplasms
European Continental Ancestry Group
Female
Genetic Loci
Genetic Predisposition to Disease
Humans
Odds Ratio
Penetrance
Receptor, ErbB-2
Receptors, Estrogen
Receptors, Progesterone
Risk Factors

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10.1093/hmg/ddr228

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Genica Network, Broeks, A., Schmidt, M. K., Sherman, M. E., Couch, F. J., Hopper, J. L., Dite, G. S., Apicella, C., Smith, L. D., Hammet, F., Southey, M. C., Van 't Veer, L. J., de Groot, R., Smit, V. T. H. B. M., Fasching, P. A., Beckmann, M. W., Jud, S., Ekici, A. B., Hartmann, A., ... Figueroa, J. (2011). Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium. Human Molecular Genetics, 20(16), 3289-303. https://doi.org/10.1093/hmg/ddr228

Genica Network ; 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 ; Hamann, Ute ; Fischer, Hans-Peter ; Brüning, Thomas ; Pesch, Beate ; Chang-Claude, Jenny ; Wang-Gohrke, Shan ; Bremer, Michael ; Karstens, Johann H ; Hillemanns, Peter ; Dörk, Thilo ; Figueroa, Jonine. / 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. 3289-303.

@article{47db48612f26471ea8c6ab0039ecb70d,

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 ER+ than ER- 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.",

keywords = "Asian Continental Ancestry Group, Biomarkers, Tumor, Breast Neoplasms, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Humans, Odds Ratio, Penetrance, Receptor, ErbB-2, Receptors, Estrogen, Receptors, Progesterone, Risk Factors",

author = "{Genica Network} and 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 Hans-Peter Sinn 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 Yon-Dschun Ko and Ute Hamann and Hans-Peter Fischer 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 Jonine Figueroa",

year = "2011",

month = aug,

day = "15",

doi = "10.1093/hmg/ddr228",

language = "English",

volume = "20",

pages = "3289--303",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "16",

}

Genica Network, 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, H-P, 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, Y-D, Hamann, U, Fischer, H-P, Brüning, T, Pesch, B, Chang-Claude, J, Wang-Gohrke, S, Bremer, M, Karstens, JH, Hillemanns, P, Dörk, T & Figueroa, J 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. 3289-303. https://doi.org/10.1093/hmg/ddr228

Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes : findings from the Breast Cancer Association Consortium. / Genica Network; 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; Hamann, Ute; Fischer, Hans-Peter; Brüning, Thomas; Pesch, Beate; Chang-Claude, Jenny; Wang-Gohrke, Shan; Bremer, Michael; Karstens, Johann H; Hillemanns, Peter; Dörk, Thilo; Figueroa, Jonine.

In: Human Molecular Genetics, Vol. 20, No. 16, 15.08.2011, p. 3289-303.

Research output: Contribution to journal › Article › peer-review

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 - Genica Network

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 - 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 - Figueroa, Jonine

PY - 2011/8/15

Y1 - 2011/8/15

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 ER+ than ER- 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 ER+ than ER- 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.

KW - Asian Continental Ancestry Group

KW - Biomarkers, Tumor

KW - Breast Neoplasms

KW - European Continental Ancestry Group

KW - Female

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Humans

KW - Odds Ratio

KW - Penetrance

KW - Receptor, ErbB-2

KW - Receptors, Estrogen

KW - Receptors, Progesterone

KW - Risk Factors

U2 - 10.1093/hmg/ddr228

DO - 10.1093/hmg/ddr228

M3 - Article

C2 - 21596841

VL - 20

SP - 3289

EP - 3303

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 16

ER -

Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium

Abstract

Keywords

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