The role of genetic breast cancer susceptibility variants as prognostic factors

Peter A. Fasching; Paul D P Pharoah; Angela Cox; Heli Nevanlinna; Stig E Bojesen; Thomas Karn; Annegien Broeks; Flora E van Leeuwen; Laura J. Van't Veer; Renate Udo; Alison M Dunning; Dario Greco; Kristiina Aittomäki; Carl Blomqvist; Mitul Shah; Børge G. Nordestgaard; Henrik Flyger; John L. Hopper; Melissa C. Southey; Carmel Apicella; Montserrat Garcia-Closas; Mark E Sherman; Jolanta Lissowska; Caroline Seynaeve; Petra E.A. Huijts; Rob A.E.M. Tollenaar; Argyrios Ziogas; Arif B Ekici; Claudia Rauh; Arto Mannermaa; Vesa Kataja; Veli-Matti Kosma; Jaana M. Hartikainen; Irene L Andrulis; Hilmi Ozcelik; Anna Marie Mulligan; Gord Glendon; Per Hall; Kamila Czene; Jianjun Liu; Jenny Chang-Claude; Shan Wang-Gohrke; Ursula Eilber; Stefan Nickels; Thilo Dörk; Maria Schiekel; Michael Bremer; Tjoung-Won Park-Simon; Graham G. Giles; Gianluca Severi; Laura Baglietto; Maartje J Hooning; John W M Martens; Agnes Jager; Mieke Kriege; Annika Lindblom; Sara Margolin; Fergus J Couch; Kristen N. Stevens; Janet E Olson; Matthew Kosel; Simon S Cross; Sabapathy P Balasubramanian; Malcolm W R Reed; Alexander Miron; Esther M. John; Robert Winqvist; Katri Pylkäs; Arja Jukkola-Vuorinen; Saila Kauppila; Barbara Burwinkel; Frederik Marme; Andreas Schneeweiss; Christof Sohn; Georgia Chenevix-Trench; Diether Lambrechts; Anne Sophie Dieudonne; Sigrid Hatse; Erik Van Limbergen; Javier Benitez; Roger L Milne; Pilar M. Zamora; José Ignacio Arias Pérez; Bernardo Bonanni; Bernard Peissel; Bernard Loris; Paolo Peterlongo; Preetha Rajaraman; Sara J. Schonfeld; Hoda Anton-Culver; Peter Devilee; Matthias W. Beckmann; Dennis J Slamon; Kelly Anne Phillips; Jonine D Figueroa; Manjeet K. Humphreys; Douglas F Easton; Marjanka K. Schmidt

doi:10.1093/hmg/dds159

The role of genetic breast cancer susceptibility variants as prognostic factors

Peter A. Fasching, Paul D P Pharoah, Angela Cox, Heli Nevanlinna, Stig E Bojesen, Thomas Karn, Annegien Broeks, Flora E van Leeuwen, Laura J. Van't Veer, Renate Udo, Alison M Dunning, Dario Greco, Kristiina Aittomäki, Carl Blomqvist, Mitul Shah, Børge G. Nordestgaard, Henrik Flyger, John L. Hopper, Melissa C. Southey, Carmel ApicellaMontserrat Garcia-Closas, Mark E Sherman, Jolanta Lissowska, Caroline Seynaeve, Petra E.A. Huijts, Rob A.E.M. Tollenaar, Argyrios Ziogas, Arif B Ekici, Claudia Rauh, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Irene L Andrulis, Hilmi Ozcelik, Anna Marie Mulligan, Gord Glendon, Per Hall, Kamila Czene, Jianjun Liu, Jenny Chang-Claude, Shan Wang-Gohrke, Ursula Eilber, Stefan Nickels, Thilo Dörk, Maria Schiekel, Michael Bremer, Tjoung-Won Park-Simon, Graham G. Giles, Gianluca Severi, Laura Baglietto, Maartje J Hooning, John W M Martens, Agnes Jager, Mieke Kriege, Annika Lindblom, Sara Margolin, Fergus J Couch, Kristen N. Stevens, Janet E Olson, Matthew Kosel, Simon S Cross, Sabapathy P Balasubramanian, Malcolm W R Reed, Alexander Miron, Esther M. John, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Georgia Chenevix-Trench, Diether Lambrechts, Anne Sophie Dieudonne, Sigrid Hatse, Erik Van Limbergen, Javier Benitez, Roger L Milne, Pilar M. Zamora, José Ignacio Arias Pérez, Bernardo Bonanni, Bernard Peissel, Bernard Loris, Paolo Peterlongo, Preetha Rajaraman, Sara J. Schonfeld, Hoda Anton-Culver, Peter Devilee, Matthias W. Beckmann, Dennis J Slamon, Kelly Anne Phillips, Jonine D Figueroa, Manjeet K. Humphreys, Douglas F Easton, Marjanka K. Schmidt

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

67 Citations (Scopus)

Abstract

Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.

Original language	English
Article number	dds159
Pages (from-to)	3926-3939
Number of pages	14
Journal	Human Molecular Genetics
Volume	21
Issue number	17
DOIs	https://doi.org/10.1093/hmg/dds159
Publication status	Published - Sep 2012
Externally published	Yes

Access to Document

10.1093/hmg/dds159

Link to publication in Scopus

Cite this

Fasching, P. A., Pharoah, P. D. P., Cox, A., Nevanlinna, H., Bojesen, S. E., Karn, T., Broeks, A., van Leeuwen, F. E., Van't Veer, L. J., Udo, R., Dunning, A. M., Greco, D., Aittomäki, K., Blomqvist, C., Shah, M., Nordestgaard, B. G., Flyger, H., Hopper, J. L., Southey, M. C., ... Schmidt, M. K. (2012). The role of genetic breast cancer susceptibility variants as prognostic factors. Human Molecular Genetics, 21(17), 3926-3939. [dds159]. https://doi.org/10.1093/hmg/dds159

Fasching, Peter A. ; Pharoah, Paul D P ; Cox, Angela ; Nevanlinna, Heli ; Bojesen, Stig E ; Karn, Thomas ; Broeks, Annegien ; van Leeuwen, Flora E ; Van't Veer, Laura J. ; Udo, Renate ; Dunning, Alison M ; Greco, Dario ; Aittomäki, Kristiina ; Blomqvist, Carl ; Shah, Mitul ; Nordestgaard, Børge G. ; Flyger, Henrik ; Hopper, John L. ; Southey, Melissa C. ; Apicella, Carmel ; Garcia-Closas, Montserrat ; Sherman, Mark E ; Lissowska, Jolanta ; Seynaeve, Caroline ; Huijts, Petra E.A. ; Tollenaar, Rob A.E.M. ; Ziogas, Argyrios ; Ekici, Arif B ; Rauh, Claudia ; Mannermaa, Arto ; Kataja, Vesa ; Kosma, Veli-Matti ; Hartikainen, Jaana M. ; Andrulis, Irene L ; Ozcelik, Hilmi ; Mulligan, Anna Marie ; Glendon, Gord ; Hall, Per ; Czene, Kamila ; Liu, Jianjun ; Chang-Claude, Jenny ; Wang-Gohrke, Shan ; Eilber, Ursula ; Nickels, Stefan ; Dörk, Thilo ; Schiekel, Maria ; Bremer, Michael ; Park-Simon, Tjoung-Won ; Giles, Graham G. ; Severi, Gianluca ; Baglietto, Laura ; Hooning, Maartje J ; Martens, John W M ; Jager, Agnes ; Kriege, Mieke ; Lindblom, Annika ; Margolin, Sara ; Couch, Fergus J ; Stevens, Kristen N. ; Olson, Janet E ; Kosel, Matthew ; Cross, Simon S ; Balasubramanian, Sabapathy P ; Reed, Malcolm W R ; Miron, Alexander ; John, Esther M. ; Winqvist, Robert ; Pylkäs, Katri ; Jukkola-Vuorinen, Arja ; Kauppila, Saila ; Burwinkel, Barbara ; Marme, Frederik ; Schneeweiss, Andreas ; Sohn, Christof ; Chenevix-Trench, Georgia ; Lambrechts, Diether ; Dieudonne, Anne Sophie ; Hatse, Sigrid ; Van Limbergen, Erik ; Benitez, Javier ; Milne, Roger L ; Zamora, Pilar M. ; Pérez, José Ignacio Arias ; Bonanni, Bernardo ; Peissel, Bernard ; Loris, Bernard ; Peterlongo, Paolo ; Rajaraman, Preetha ; Schonfeld, Sara J. ; Anton-Culver, Hoda ; Devilee, Peter ; Beckmann, Matthias W. ; Slamon, Dennis J ; Phillips, Kelly Anne ; Figueroa, Jonine D ; Humphreys, Manjeet K. ; Easton, Douglas F ; Schmidt, Marjanka K. / The role of genetic breast cancer susceptibility variants as prognostic factors. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 17. pp. 3926-3939.

@article{c63ac3709d514cd2b75d51af992fce17,

title = "The role of genetic breast cancer susceptibility variants as prognostic factors",

abstract = "Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.",

author = "Fasching, {Peter A.} and Pharoah, {Paul D P} and Angela Cox and Heli Nevanlinna and Bojesen, {Stig E} and Thomas Karn and Annegien Broeks and {van Leeuwen}, {Flora E} and {Van't Veer}, {Laura J.} and Renate Udo and Dunning, {Alison M} and Dario Greco and Kristiina Aittom{\"a}ki and Carl Blomqvist and Mitul Shah and Nordestgaard, {B{\o}rge G.} and Henrik Flyger and Hopper, {John L.} and Southey, {Melissa C.} and Carmel Apicella and Montserrat Garcia-Closas and Sherman, {Mark E} and Jolanta Lissowska and Caroline Seynaeve and Huijts, {Petra E.A.} and Tollenaar, {Rob A.E.M.} and Argyrios Ziogas and Ekici, {Arif B} and Claudia Rauh and Arto Mannermaa and Vesa Kataja and Veli-Matti Kosma and Hartikainen, {Jaana M.} and Andrulis, {Irene L} and Hilmi Ozcelik and Mulligan, {Anna Marie} and Gord Glendon and Per Hall and Kamila Czene and Jianjun Liu and Jenny Chang-Claude and Shan Wang-Gohrke and Ursula Eilber and Stefan Nickels and Thilo D{\"o}rk and Maria Schiekel and Michael Bremer and Tjoung-Won Park-Simon and Giles, {Graham G.} and Gianluca Severi and Laura Baglietto and Hooning, {Maartje J} and Martens, {John W M} and Agnes Jager and Mieke Kriege and Annika Lindblom and Sara Margolin and Couch, {Fergus J} and Stevens, {Kristen N.} and Olson, {Janet E} and Matthew Kosel and Cross, {Simon S} and Balasubramanian, {Sabapathy P} and Reed, {Malcolm W R} and Alexander Miron and John, {Esther M.} and Robert Winqvist and Katri Pylk{\"a}s and Arja Jukkola-Vuorinen and Saila Kauppila and Barbara Burwinkel and Frederik Marme and Andreas Schneeweiss and Christof Sohn and Georgia Chenevix-Trench and Diether Lambrechts and Dieudonne, {Anne Sophie} and Sigrid Hatse and {Van Limbergen}, Erik and Javier Benitez and Milne, {Roger L} and Zamora, {Pilar M.} and P{\'e}rez, {Jos{\'e} Ignacio Arias} and Bernardo Bonanni and Bernard Peissel and Bernard Loris and Paolo Peterlongo and Preetha Rajaraman and Schonfeld, {Sara J.} and Hoda Anton-Culver and Peter Devilee and Beckmann, {Matthias W.} and Slamon, {Dennis J} and Phillips, {Kelly Anne} and Figueroa, {Jonine D} and Humphreys, {Manjeet K.} and Easton, {Douglas F} and Schmidt, {Marjanka K.}",

year = "2012",

month = sep,

doi = "10.1093/hmg/dds159",

language = "English",

volume = "21",

pages = "3926--3939",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "17",

}

Fasching, PA, Pharoah, PDP, Cox, A, Nevanlinna, H, Bojesen, SE, Karn, T, Broeks, A, van Leeuwen, FE, Van't Veer, LJ, Udo, R, Dunning, AM, Greco, D, Aittomäki, K, Blomqvist, C, Shah, M, Nordestgaard, BG, Flyger, H, Hopper, JL, Southey, MC, Apicella, C, Garcia-Closas, M, Sherman, ME, Lissowska, J, Seynaeve, C, Huijts, PEA, Tollenaar, RAEM, Ziogas, A, Ekici, AB, Rauh, C, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Andrulis, IL, Ozcelik, H, Mulligan, AM, Glendon, G, Hall, P, Czene, K, Liu, J, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Nickels, S, Dörk, T, Schiekel, M, Bremer, M, Park-Simon, T-W, Giles, GG, Severi, G, Baglietto, L, Hooning, MJ, Martens, JWM, Jager, A, Kriege, M, Lindblom, A, Margolin, S, Couch, FJ, Stevens, KN, Olson, JE, Kosel, M, Cross, SS, Balasubramanian, SP, Reed, MWR, Miron, A, John, EM, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Kauppila, S, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Chenevix-Trench, G, Lambrechts, D, Dieudonne, AS, Hatse, S, Van Limbergen, E, Benitez, J, Milne, RL, Zamora, PM, Pérez, JIA, Bonanni, B, Peissel, B, Loris, B, Peterlongo, P, Rajaraman, P, Schonfeld, SJ, Anton-Culver, H, Devilee, P, Beckmann, MW, Slamon, DJ, Phillips, KA, Figueroa, JD, Humphreys, MK, Easton, DF & Schmidt, MK 2012, 'The role of genetic breast cancer susceptibility variants as prognostic factors', Human Molecular Genetics, vol. 21, no. 17, dds159, pp. 3926-3939. https://doi.org/10.1093/hmg/dds159

The role of genetic breast cancer susceptibility variants as prognostic factors. / Fasching, Peter A.; Pharoah, Paul D P; Cox, Angela; Nevanlinna, Heli; Bojesen, Stig E; Karn, Thomas; Broeks, Annegien; van Leeuwen, Flora E; Van't Veer, Laura J.; Udo, Renate; Dunning, Alison M; Greco, Dario; Aittomäki, Kristiina; Blomqvist, Carl; Shah, Mitul; Nordestgaard, Børge G.; Flyger, Henrik; Hopper, John L.; Southey, Melissa C.; Apicella, Carmel; Garcia-Closas, Montserrat; Sherman, Mark E; Lissowska, Jolanta; Seynaeve, Caroline; Huijts, Petra E.A.; Tollenaar, Rob A.E.M.; Ziogas, Argyrios; Ekici, Arif B; Rauh, Claudia; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Andrulis, Irene L; Ozcelik, Hilmi; Mulligan, Anna Marie; Glendon, Gord; Hall, Per; Czene, Kamila; Liu, Jianjun; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Nickels, Stefan; Dörk, Thilo; Schiekel, Maria; Bremer, Michael; Park-Simon, Tjoung-Won; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; Hooning, Maartje J; Martens, John W M; Jager, Agnes; Kriege, Mieke; Lindblom, Annika; Margolin, Sara; Couch, Fergus J; Stevens, Kristen N.; Olson, Janet E; Kosel, Matthew; Cross, Simon S; Balasubramanian, Sabapathy P; Reed, Malcolm W R; Miron, Alexander; John, Esther M.; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Chenevix-Trench, Georgia; Lambrechts, Diether; Dieudonne, Anne Sophie; Hatse, Sigrid; Van Limbergen, Erik; Benitez, Javier; Milne, Roger L; Zamora, Pilar M.; Pérez, José Ignacio Arias; Bonanni, Bernardo; Peissel, Bernard; Loris, Bernard; Peterlongo, Paolo; Rajaraman, Preetha; Schonfeld, Sara J.; Anton-Culver, Hoda; Devilee, Peter; Beckmann, Matthias W.; Slamon, Dennis J; Phillips, Kelly Anne; Figueroa, Jonine D; Humphreys, Manjeet K.; Easton, Douglas F; Schmidt, Marjanka K.

In: Human Molecular Genetics, Vol. 21, No. 17, dds159, 09.2012, p. 3926-3939.

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

TY - JOUR

T1 - The role of genetic breast cancer susceptibility variants as prognostic factors

AU - Fasching, Peter A.

AU - Pharoah, Paul D P

AU - Cox, Angela

AU - Nevanlinna, Heli

AU - Bojesen, Stig E

AU - Karn, Thomas

AU - Broeks, Annegien

AU - van Leeuwen, Flora E

AU - Van't Veer, Laura J.

AU - Udo, Renate

AU - Dunning, Alison M

AU - Greco, Dario

AU - Aittomäki, Kristiina

AU - Blomqvist, Carl

AU - Shah, Mitul

AU - Nordestgaard, Børge G.

AU - Flyger, Henrik

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Apicella, Carmel

AU - Garcia-Closas, Montserrat

AU - Sherman, Mark E

AU - Lissowska, Jolanta

AU - Seynaeve, Caroline

AU - Huijts, Petra E.A.

AU - Tollenaar, Rob A.E.M.

AU - Ziogas, Argyrios

AU - Ekici, Arif B

AU - Rauh, Claudia

AU - Mannermaa, Arto

AU - Kataja, Vesa

AU - Kosma, Veli-Matti

AU - Hartikainen, Jaana M.

AU - Andrulis, Irene L

AU - Ozcelik, Hilmi

AU - Mulligan, Anna Marie

AU - Glendon, Gord

AU - Hall, Per

AU - Czene, Kamila

AU - Liu, Jianjun

AU - Chang-Claude, Jenny

AU - Wang-Gohrke, Shan

AU - Eilber, Ursula

AU - Nickels, Stefan

AU - Dörk, Thilo

AU - Schiekel, Maria

AU - Bremer, Michael

AU - Park-Simon, Tjoung-Won

AU - Giles, Graham G.

AU - Severi, Gianluca

AU - Baglietto, Laura

AU - Hooning, Maartje J

AU - Martens, John W M

AU - Jager, Agnes

AU - Kriege, Mieke

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Couch, Fergus J

AU - Stevens, Kristen N.

AU - Olson, Janet E

AU - Kosel, Matthew

AU - Cross, Simon S

AU - Balasubramanian, Sabapathy P

AU - Reed, Malcolm W R

AU - Miron, Alexander

AU - John, Esther M.

AU - Winqvist, Robert

AU - Pylkäs, Katri

AU - Jukkola-Vuorinen, Arja

AU - Kauppila, Saila

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Schneeweiss, Andreas

AU - Sohn, Christof

AU - Chenevix-Trench, Georgia

AU - Lambrechts, Diether

AU - Dieudonne, Anne Sophie

AU - Hatse, Sigrid

AU - Van Limbergen, Erik

AU - Benitez, Javier

AU - Milne, Roger L

AU - Zamora, Pilar M.

AU - Pérez, José Ignacio Arias

AU - Bonanni, Bernardo

AU - Peissel, Bernard

AU - Loris, Bernard

AU - Peterlongo, Paolo

AU - Rajaraman, Preetha

AU - Schonfeld, Sara J.

AU - Anton-Culver, Hoda

AU - Devilee, Peter

AU - Beckmann, Matthias W.

AU - Slamon, Dennis J

AU - Phillips, Kelly Anne

AU - Figueroa, Jonine D

AU - Humphreys, Manjeet K.

AU - Easton, Douglas F

AU - Schmidt, Marjanka K.

PY - 2012/9

Y1 - 2012/9

N2 - Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.

AB - Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.

UR - http://www.scopus.com/inward/record.url?scp=84865065666&partnerID=8YFLogxK

U2 - 10.1093/hmg/dds159

DO - 10.1093/hmg/dds159

M3 - Article

C2 - 22532573

AN - SCOPUS:84865065666

VL - 21

SP - 3926

EP - 3939

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 17

M1 - dds159

ER -