Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy

Jieping Lei; Anja Rudolph; Kirsten B. Moysich; Sajjad Rafiq; Sabine Behrens; Ellen L. Goode; Paul Pd Pharoah; Petra Seibold; Peter A. Fasching; Irene L. Andrulis; Vessela N. Kristensen; Fergus J. Couch; Ute Hamann; Maartje J. Hooning; Heli Nevanlinna; Ursula Eilber; Manjeet K. Bolla; Joe Dennis; Qin Wang; Annika Lindblom; Arto Mannermaa; Diether Lambrechts; Montserrat Garcia-Closas; Per Hall; Georgia Chenevix-Trench; Mitul Shah; Robert Luben; Lothar Haeberle; Arif B. Ekici; Matthias W. Beckmann; Julia A. Knight; Gord Glendon; Sandrine Tchatchou; Grethe I. Grenaker Alnaes; Anne-Lise Borresen-Dale; Silje Nord; Janet E. Olson; Emily Hallberg; Celine Vachon; Diana Torres; Hans-Ulrich Ulmer; Thomas Ruediger; Agnes Jager; Carolien Hm van Deurzen; Madeleine Ma Tilanus-Linthorst; Taru A. Muranen; Kristiina Aittomaki; Carl Blomqvist; Sara Margolin; Sabine Linn

doi:10.1186/s13058-015-0522-2

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy

Jieping Lei, Anja Rudolph, Kirsten B. Moysich, Sajjad Rafiq, Sabine Behrens, Ellen L. Goode, Paul Pd Pharoah, Petra Seibold, Peter A. Fasching, Irene L. Andrulis, Vessela N. Kristensen, Fergus J. Couch, Ute Hamann, Maartje J. Hooning, Heli Nevanlinna, Ursula Eilber, Manjeet K. Bolla, Joe Dennis, Qin Wang, Annika LindblomArto Mannermaa, Diether Lambrechts, Montserrat Garcia-Closas, Per Hall, Georgia Chenevix-Trench, Mitul Shah, Robert Luben, Lothar Haeberle, Arif B. Ekici, Matthias W. Beckmann, Julia A. Knight, Gord Glendon, Sandrine Tchatchou, Grethe I. Grenaker Alnaes, Anne-Lise Borresen-Dale, Silje Nord, Janet E. Olson, Emily Hallberg, Celine Vachon, Diana Torres, Hans-Ulrich Ulmer, Thomas Ruediger, Agnes Jager, Carolien Hm van Deurzen, Madeleine Ma Tilanus-Linthorst, Taru A. Muranen, Kristiina Aittomaki, Carl Blomqvist, Sara Margolin, Sabine Linn,

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

Abstract

Introduction: Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy).

Methods: We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test.

Results: Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10(-3)) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 x 10(-4)) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10-3). Two SNPs in IL12B (r(2) = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 x 10(-4)), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 x 10(-4)). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 x 10(-5)) without study heterogeneity.

Conclusions: TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.

Original language	English
Article number	18
Number of pages	13
Journal	Breast Cancer Research
Volume	17
DOIs	https://doi.org/10.1186/s13058-015-0522-2
Publication status	Published - 10 Feb 2015
Externally published	Yes

Keywords

REGULATORY T-CELLS
GENOME-WIDE ASSOCIATION
TUMOR-INFILTRATING LYMPHOCYTES
ANTITUMOR IMMUNITY
SUPPRESSOR-CELLS
PREDICT RESPONSE
PROGRESSION
ADJUVANT
OUTCOMES
SYSTEM

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10.1186/s13058-015-0522-2

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Lei, J., Rudolph, A., Moysich, K. B., Rafiq, S., Behrens, S., Goode, E. L., Pharoah, P. P., Seibold, P., Fasching, P. A., Andrulis, I. L., Kristensen, V. N., Couch, F. J., Hamann, U., Hooning, M. J., Nevanlinna, H., Eilber, U., Bolla, M. K., Dennis, J., Wang, Q. (2015). Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy. Breast Cancer Research, 17, Article 18. https://doi.org/10.1186/s13058-015-0522-2

@article{e72036e7f11f43859abe31ee871e4af6,

title = "Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy",

abstract = "Introduction: Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy).Methods: We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test.Results: Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10(-3)) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 x 10(-4)) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10-3). Two SNPs in IL12B (r(2) = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 x 10(-4)), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 x 10(-4)). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 x 10(-5)) without study heterogeneity.Conclusions: TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.",

keywords = "REGULATORY T-CELLS, GENOME-WIDE ASSOCIATION, TUMOR-INFILTRATING LYMPHOCYTES, ANTITUMOR IMMUNITY, SUPPRESSOR-CELLS, PREDICT RESPONSE, PROGRESSION, ADJUVANT, OUTCOMES, SYSTEM",

author = "Jieping Lei and Anja Rudolph and Moysich, {Kirsten B.} and Sajjad Rafiq and Sabine Behrens and Goode, {Ellen L.} and Pharoah, {Paul Pd} and Petra Seibold and Fasching, {Peter A.} and Andrulis, {Irene L.} and Kristensen, {Vessela N.} and Couch, {Fergus J.} and Ute Hamann and Hooning, {Maartje J.} and Heli Nevanlinna and Ursula Eilber and Bolla, {Manjeet K.} and Joe Dennis and Qin Wang and Annika Lindblom and Arto Mannermaa and Diether Lambrechts and Montserrat Garcia-Closas and Per Hall and Georgia Chenevix-Trench and Mitul Shah and Robert Luben and Lothar Haeberle and Ekici, {Arif B.} and Beckmann, {Matthias W.} and Knight, {Julia A.} and Gord Glendon and Sandrine Tchatchou and Alnaes, {Grethe I. Grenaker} and Anne-Lise Borresen-Dale and Silje Nord and Olson, {Janet E.} and Emily Hallberg and Celine Vachon and Diana Torres and Hans-Ulrich Ulmer and Thomas Ruediger and Agnes Jager and {van Deurzen}, {Carolien Hm} and Tilanus-Linthorst, {Madeleine Ma} and Muranen, {Taru A.} and Kristiina Aittomaki and Carl Blomqvist and Sara Margolin and Sabine Linn",

year = "2015",

month = feb,

day = "10",

doi = "10.1186/s13058-015-0522-2",

language = "English",

volume = "17",

journal = "Breast Cancer Research",

issn = "1465-542X",

publisher = "BioMed Central Ltd.",

}

Lei, J, Rudolph, A, Moysich, KB, Rafiq, S, Behrens, S, Goode, EL, Pharoah, PP, Seibold, P, Fasching, PA, Andrulis, IL, Kristensen, VN, Couch, FJ, Hamann, U, Hooning, MJ, Nevanlinna, H, Eilber, U, Bolla, MK, Dennis, J, Wang, Q, Lindblom, A, Mannermaa, A, Lambrechts, D, Garcia-Closas, M, Hall, P, Chenevix-Trench, G, Shah, M, Luben, R, Haeberle, L, Ekici, AB, Beckmann, MW, Knight, JA, Glendon, G, Tchatchou, S, Alnaes, GIG, Borresen-Dale, A-L, Nord, S, Olson, JE, Hallberg, E, Vachon, C, Torres, D, Ulmer, H-U, Ruediger, T, Jager, A, van Deurzen, CH, Tilanus-Linthorst, MM, Muranen, TA, Aittomaki, K, Blomqvist, C, Margolin, S, Linn, S 2015, 'Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy', Breast Cancer Research, vol. 17, 18. https://doi.org/10.1186/s13058-015-0522-2

TY - JOUR

T1 - Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy

AU - Lei, Jieping

AU - Rudolph, Anja

AU - Moysich, Kirsten B.

AU - Rafiq, Sajjad

AU - Behrens, Sabine

AU - Goode, Ellen L.

AU - Pharoah, Paul Pd

AU - Seibold, Petra

AU - Fasching, Peter A.

AU - Andrulis, Irene L.

AU - Kristensen, Vessela N.

AU - Couch, Fergus J.

AU - Hamann, Ute

AU - Hooning, Maartje J.

AU - Nevanlinna, Heli

AU - Eilber, Ursula

AU - Bolla, Manjeet K.

AU - Dennis, Joe

AU - Wang, Qin

AU - Lindblom, Annika

AU - Mannermaa, Arto

AU - Lambrechts, Diether

AU - Garcia-Closas, Montserrat

AU - Hall, Per

AU - Chenevix-Trench, Georgia

AU - Shah, Mitul

AU - Luben, Robert

AU - Haeberle, Lothar

AU - Ekici, Arif B.

AU - Beckmann, Matthias W.

AU - Knight, Julia A.

AU - Glendon, Gord

AU - Tchatchou, Sandrine

AU - Alnaes, Grethe I. Grenaker

AU - Borresen-Dale, Anne-Lise

AU - Nord, Silje

AU - Olson, Janet E.

AU - Hallberg, Emily

AU - Vachon, Celine

AU - Torres, Diana

AU - Ulmer, Hans-Ulrich

AU - Ruediger, Thomas

AU - Jager, Agnes

AU - van Deurzen, Carolien Hm

AU - Tilanus-Linthorst, Madeleine Ma

AU - Muranen, Taru A.

AU - Aittomaki, Kristiina

AU - Blomqvist, Carl

AU - Margolin, Sara

AU - Linn, Sabine

PY - 2015/2/10

Y1 - 2015/2/10

N2 - Introduction: Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy).Methods: We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test.Results: Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10(-3)) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 x 10(-4)) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10-3). Two SNPs in IL12B (r(2) = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 x 10(-4)), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 x 10(-4)). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 x 10(-5)) without study heterogeneity.Conclusions: TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.

AB - Introduction: Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy).Methods: We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test.Results: Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10(-3)) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 x 10(-4)) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10-3). Two SNPs in IL12B (r(2) = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 x 10(-4)), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 x 10(-4)). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 x 10(-5)) without study heterogeneity.Conclusions: TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.

KW - REGULATORY T-CELLS

KW - GENOME-WIDE ASSOCIATION

KW - TUMOR-INFILTRATING LYMPHOCYTES

KW - ANTITUMOR IMMUNITY

KW - SUPPRESSOR-CELLS

KW - PREDICT RESPONSE

KW - PROGRESSION

KW - ADJUVANT

KW - OUTCOMES

KW - SYSTEM

U2 - 10.1186/s13058-015-0522-2

DO - 10.1186/s13058-015-0522-2

M3 - Article

SN - 1465-542X

VL - 17

JO - Breast Cancer Research

JF - Breast Cancer Research

M1 - 18

ER -

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy

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Keywords

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