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Breast Cancer Research
Published in: Breast Cancer Research 1/2015

Open Access 01-12-2015 | Research article

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

Authors: 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 García-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 Alnæs, Anne-Lise Borresen-Dale, Silje Nord, Janet E Olson, Emily Hallberg, Celine Vachon, Diana Torres, Hans-Ulrich Ulmer, Thomas Rüdiger, Agnes Jager, Carolien HM van Deurzen, Madeleine MA Tilanus-Linthorst, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Sara Margolin, Veli-Matti Kosma, Jaana M Hartikainen, Vesa Kataja, Sigrid Hatse, Hans Wildiers, Ann Smeets, Jonine Figueroa, Stephen J Chanock, Jolanta Lissowska, Jingmei Li, Keith Humphreys, Kelly-Anne Phillips, Sabine Linn, Sten Cornelissen, Sandra Alexandra J van den Broek, Daehee Kang, Ji-Yeob Choi, Sue K Park, Keun-Young Yoo, Chia-Ni Hsiung, Pei-Ei Wu, Ming-Feng Hou, Chen-Yang Shen, Soo Hwang Teo, Nur Aishah Mohd Taib, Cheng Har Yip, Gwo Fuang Ho, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Kazuo Tajima, Alison M Dunning, Javier Benitez, Kamila Czene, Lara E Sucheston, Tom Maishman, William J Tapper, Diana Eccles, Douglas F Easton, Marjanka K Schmidt, Jenny Chang-Claude, kConFab Investigators

Published in: Breast Cancer Research | Issue 1/2015

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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 × 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 (r2 = 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 × 10−4), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 × 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 × 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.
Appendix
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Metadata
Title
Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy
Authors
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 García-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 Alnæs
Anne-Lise Borresen-Dale
Silje Nord
Janet E Olson
Emily Hallberg
Celine Vachon
Diana Torres
Hans-Ulrich Ulmer
Thomas Rüdiger
Agnes Jager
Carolien HM van Deurzen
Madeleine MA Tilanus-Linthorst
Taru A Muranen
Kristiina Aittomäki
Carl Blomqvist
Sara Margolin
Veli-Matti Kosma
Jaana M Hartikainen
Vesa Kataja
Sigrid Hatse
Hans Wildiers
Ann Smeets
Jonine Figueroa
Stephen J Chanock
Jolanta Lissowska
Jingmei Li
Keith Humphreys
Kelly-Anne Phillips
Sabine Linn
Sten Cornelissen
Sandra Alexandra J van den Broek
Daehee Kang
Ji-Yeob Choi
Sue K Park
Keun-Young Yoo
Chia-Ni Hsiung
Pei-Ei Wu
Ming-Feng Hou
Chen-Yang Shen
Soo Hwang Teo
Nur Aishah Mohd Taib
Cheng Har Yip
Gwo Fuang Ho
Keitaro Matsuo
Hidemi Ito
Hiroji Iwata
Kazuo Tajima
Alison M Dunning
Javier Benitez
Kamila Czene
Lara E Sucheston
Tom Maishman
William J Tapper
Diana Eccles
Douglas F Easton
Marjanka K Schmidt
Jenny Chang-Claude
kConFab Investigators
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2015
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-015-0522-2

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