Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy
Authors: Lei Jieping , Rudolph Anja , Moysich Kirsten B , Rafiq Sajjad , Behrens Sabine , Goode Ellen L , Pharoah Paul PD , Seibold Petra , Fasching Peter A , Andrulis Irene L , Kristensen Vessela N , Couch Fergus J , Hamann Ute , Hooning Maartje J , Nevanlinna Heli , Eilber Ursula , Bolla Manjeet K , Dennis Joe , Wang Qin , Lindblom Annika , Mannermaa Arto , Lambrechts Diether , García-Closas Montserrat , Hall Per , Chenevix-Trench Georgia , Shah Mitul , Luben Robert , Haeberle Lothar , Ekici Arif B , Beckmann Matthias W , Knight Julia A , Glendon Gord , Tchatchou Sandrine , Alnæs Grethe I Grenaker , Borresen-Dale Anne-Lise , Nord Silje , Olson Janet E , Hallberg Emily , Vachon Celine , Torres Diana , Ulmer Hans-Ulrich , Rüdiger Thomas , Jager Agnes , van Deurzen Carolien HM , Tilanus-Linthorst Madeleine MA , Muranen Taru A , Aittomäki Kristiina , Blomqvist Carl , Margolin Sara , Kosma Veli-Matti , Hartikainen Jaana M , Kataja Vesa , Hatse Sigrid , Wildiers Hans , Smeets Ann , Figueroa Jonine , Chanock Stephen J , Lissowska Jolanta , Li Jingmei , Humphreys Keith , Phillips Kelly-Anne ,   kConFab Investigators, Linn Sabine , Cornelissen Sten , van den Broek Sandra Alexandra J , Kang Daehee , Choi Ji-Yeob , Park Sue K , Yoo Keun-Young , Hsiung Chia-Ni , Wu Pei-Ei , Hou Ming-Feng , Shen Chen-Yang , Teo Soo Hwang , Taib Nur Aishah Mohd , Yip Cheng Har , Ho Gwo Fuang , Matsuo Keitaro , Ito Hidemi , Iwata Hiroji , Tajima Kazuo , Dunning Alison M , Benitez Javier , Czene Kamila , Sucheston Lara E , Maishman Tom , Tapper William J , Eccles Diana , Easton Douglas F , Schmidt Marjanka K , Chang-Claude Jenny 
Published: February 2015

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.