Abstract
Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03–1.08; p value = 1.4 × 10−6). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10−3 and 7.0 × 10−3, respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10−3, 4.5 × 10−4 and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3,IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 137-154 |
| Number of pages | 18 |
| Journal | Human genetics |
| Volume | 135 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2016 |
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
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Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility : a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium. / Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B. et al.
In: Human genetics, Vol. 135, No. 1, 01.01.2016, p. 137-154.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility
T2 - a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium
AU - Lei, Jieping
AU - Rudolph, Anja
AU - Moysich, Kirsten B.
AU - Behrens, Sabine
AU - Goode, Ellen L.
AU - Bolla, Manjeet K.
AU - Dennis, Joe
AU - Dunning, Alison M.
AU - Easton, Douglas F.
AU - Wang, Qin
AU - Benitez, Javier
AU - Hopper, John L.
AU - Southey, Melissa C.
AU - Schmidt, Marjanka K.
AU - Broeks, Annegien
AU - Fasching, Peter A.
AU - Haeberle, Lothar
AU - Peto, Julian
AU - dos-Santos-Silva, Isabel
AU - Sawyer, Elinor J.
AU - Tomlinson, Ian
AU - Burwinkel, Barbara
AU - Marmé, Frederik
AU - Guénel, Pascal
AU - Truong, Thérèse
AU - Bojesen, Stig E.
AU - Flyger, Henrik
AU - Nielsen, Sune F.
AU - Nordestgaard, Børge G.
AU - González-Neira, Anna
AU - Menéndez, Primitiva
AU - Anton-Culver, Hoda
AU - Neuhausen, Susan L.
AU - Brenner, Hermann
AU - Arndt, Volker
AU - Meindl, Alfons
AU - Schmutzler, Rita K.
AU - Brauch, Hiltrud
AU - Hamann, Ute
AU - Nevanlinna, Heli
AU - Fagerholm, Rainer
AU - Dörk, Thilo
AU - Bogdanova, Natalia V.
AU - Mannermaa, Arto
AU - Hartikainen, Jaana M.
AU - Australian Ovarian Study Group, Ovarian Study Group
AU - kConFab Investigators, Investigators
AU - Van Dijck, Laurien
AU - Smeets, Ann
AU - Flesch-Janys, Dieter
AU - Eilber, Ursula
AU - Radice, Paolo
AU - Peterlongo, Paolo
AU - Couch, Fergus J.
AU - Hallberg, Emily
AU - Giles, Graham G.
AU - Milne, Roger L.
AU - Haiman, Christopher A.
AU - Schumacher, Fredrick
AU - Simard, Jacques
AU - Goldberg, Mark S.
AU - Kristensen, Vessela
AU - Borresen-Dale, Anne Lise
AU - Zheng, Wei
AU - Beeghly-Fadiel, Alicia
AU - Winqvist, Robert
AU - Grip, Mervi
AU - Andrulis, Irene L.
AU - Glendon, Gord
AU - García-Closas, Montserrat
AU - Figueroa, Jonine
AU - Czene, Kamila
AU - Brand, Judith S.
AU - Darabi, Hatef
AU - Eriksson, Mikael
AU - Hall, Per
AU - Li, Jingmei
AU - Cox, Angela
AU - Cross, Simon S.
AU - Pharoah, Paul D.P.
AU - Shah, Mitul
AU - Kabisch, Maria
AU - Torres, Diana
AU - Jakubowska, Anna
AU - Lubinski, Jan
AU - Ademuyiwa, Foluso
AU - Ambrosone, Christine B.
AU - Swerdlow, Anthony
AU - Jones, Michael
AU - Chang-Claude, Jenny
N1 - Funding Information: We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians, and administrative staff who have enabled this work to be carried out. This analysis would not have been possible without the contributions of the following: Per Hall (COGS) ; Douglas F. Easton, Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC) , Andrew Berchuck (OCAC) , Rosalind A. Eeles, Douglas F. Easton, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL) , Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch and Ken Offit (CIMBA) , Joe Dennis, Alison M. Dunning, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière and Frederic Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. ABCFS would like to thank Maggie Angelakos, Judi Maskiell, and Gillian Dite. ABCS would like to thank Sanquin Amsterdam, the Netherlands. BBCS thanks Eileen Williams, Elaine Ryder-Mills, and Kara Sargus. BIGGS thanks Niall McInerney, Gabrielle Colleran, Andrew Rowan, and Angela Jones. BSUCH would like to thank Peter Bugert and Medical Faculty Mannheim. CGPS thanks Staff and participants of the Copenhagen General Population Study, as well as excellent technical assistance from Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, and Dorthe Kjeldgård Hansen. CNIO-BCS would like to thank Guillermo Pita, Charo Alonso, Daniel Herrero, Nuria Álvarez, Pilar Zamora, Primitiva Menendez, and the Human Genotyping-CEGEN Unit. CTS would like to thank the CTS Steering Committee including Leslie Bernstein, Susan Neuhausen, James Lacey, Sophia Wang, Huiyan Ma, Yani Lu, and Jessica Clague DeHart at the Beckman Research Institute of City of Hope, Dennis Deapen, Rich Pinder, Eunjung Lee, and Fred Schumacher at the University of Southern California, Pam Horn-Ross, Peggy Reynolds, Christina Clarke Dur and David Nelson at the Cancer Prevention Institute of California, and Hoda Anton-Culver, Argyrios Ziogas, and Hannah Park at the University of California Irvine. ESTHER thanks Hartwig Ziegler, Christa Stegmaier, Sonja Wolf, and Volker Hermann. GC-HBOC thanks Stefanie Engert, Heide Hellebrand, and Sandra Kröber. GENICA would like to thank the GENICA Network, including Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany (HB, Wing-Yee Lo, Christina Justenhoven), German Cancer Consortium (DKTK) and Deutsches Krebsforschungszentrum (DKFZ) (HB), Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany (Yon-Dschun Ko, Christian Baisch), Institute of Pathology, University of Bonn, Germany (Hans-Peter Fischer), Molecular Genetics of Breast Cancer, DKFZ, Heidelberg, Germany (UH), Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany (Thomas Brüning, Beate Pesch, Sylvia Rabstein, Anne Lotz), and Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany (Volker Harth). HEBCS would like to thank Kirsimari Aaltonen, Karl von Smitten, Sofia Khan, Tuomas Heikkinen, and Irja Erkkilä. HMBCS would like to thank Peter Hillemanns, Hans Christiansen, and Johann H. Karstens. KBCP thanks Eija Myöhänen and Helena Kemiläinen. LMBC thanks Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel, and Kathleen Corthouts. MARIE would like to thank Petra Seibold, Judith Heinz, Nadia Obi, Alina Vrieling, Muhabbet Celik, Til Olchers, and Stefan Nickels. MBCSG thanks Siranoush Manoukian, Bernard Peissel and Daniela Zaffaroni at the Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Monica Barile and Irene Feroce at the Istituto Europeo di Oncologia (IEO), and the personnel of the Cogentech Cancer Genetic Test Laboratory. MTLGEBCS would like to thank Martine Tranchant at the CHU de Québec Research Center, Marie-France Valois, Annie Turgeon and Lea Heguy at the McGill University Health Center, Royal Victoria Hospital, McGill University for DNA extraction, sample management and skillful technical assistance, and J.S. who is the Chairholder of the Canada Research Chair in Oncogenetics. NBCS would like to thank Dr. Kristine Kleivi, PhD (K.G. Jebsen Centre for Breast Cancer Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway and Department of Research, Vestre Viken, Drammen, Norway), Dr. Lars Ottestad, MD (Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Prof. Em. Rolf Kåresen, MD (Department of Oncology, Oslo University Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway), Dr. Anita Langerød, PhD (Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr. Ellen Schlichting, MD (Department for Breast and Endocrine Surgery, Oslo University Hospital Ullevaal, Oslo, Norway), Dr. Marit Muri Holmen, MD (Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway), Prof. Toril Sauer, MD (Department of Pathology at Akershus University hospital, Lørenskog, Norway), Dr. Vilde Haakensen, MD (Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr. Olav Engebråten, MD (Institute for Clinical Medicine, Faculty of Medicine, University of Oslo and Department of Oncology, Oslo University Hospital, Oslo, Norway), Prof. Bjørn Naume, MD (Division of Cancer Medicine and Radiotherapy, Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr. Cecile E. Kiserud, MD (National Advisory Unit on Late Effects after Cancer Treatment, Department of Oncology, Oslo University Hospital, Oslo, Norway and Department of Oncology, Oslo University Hospital, Oslo, Norway), Dr. Kristin V. Reinertsen, MD (National Advisory Unit on Late Effects after Cancer Treatment, Department of Oncology, Oslo University Hospital, Oslo, Norway and Department of Oncology, Oslo University Hospital, Oslo, Norway), Assoc. Prof. Åslaug Helland, MD (Department of Genetics, Institute for Cancer Research and Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway), Dr. Margit Riis, MD (Dept of Breast- and Endocrine Surgery, Oslo University Hospital, Ullevål, Oslo, Norway), Dr. Ida Bukholm, MD (Department of Breast-Endocrine Surgery, Akershus University Hospital, Oslo, Norway and Department of Oncology, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway), Prof. Per Eystein Lønning, MD (Section of Oncology, Institute of Medicine, University of Bergen and Department of Oncology, Haukeland University Hospital, Bergen, Norway), Dr Silje Nord, PhD (Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway) and Grethe I. Grenaker Alnæs, M.Sc. (Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway). NBHS would like to thank study participants and research staff for their contributions and commitment to this study. OBCS thanks Meeri Otsukka and Kari Mononen. OFBCR thanks Teresa Selander and Nayana Weerasooriya. PBCS thanks Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, and Michael Stagner. SASBAC would like to thank the Swedish Medical Research Counsel. SBCS would like to thank Sue Higham, Helen Cramp, Ian Brock, Sabapathy Balasubramanian, and Dan Connley. SEARCH thanks the SEARCH and EPIC teams. SKKDKFZS thanks all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study. TNBCC thanks Robert Pilarski and Charles Shapiro who were instrumental in the formation of the OSU Breast Cancer Tissue Bank, and also thanks the Human Genetics Sample Bank for processing of samples and providing OSU Columbus area control samples. UKBGS would like to thank Breast Cancer Now and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study, and acknowledge the NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. kConFab/AOCS wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and many families who contribute to kConFab. pKARMA would like to thank the Swedish Medical Research Counsel. Publisher Copyright: © 2015, The Author(s).
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03–1.08; p value = 1.4 × 10−6). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10−3 and 7.0 × 10−3, respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10−3, 4.5 × 10−4 and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3,IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.
AB - Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03–1.08; p value = 1.4 × 10−6). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10−3 and 7.0 × 10−3, respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10−3, 4.5 × 10−4 and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3,IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.
UR - http://www.scopus.com/inward/record.url?scp=84952716859&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84952716859&partnerID=8YFLogxK
U2 - 10.1007/s00439-015-1616-8
DO - 10.1007/s00439-015-1616-8
M3 - Article
C2 - 26621531
AN - SCOPUS:84952716859
SN - 0340-6717
VL - 135
SP - 137
EP - 154
JO - Human Genetics
JF - Human Genetics
IS - 1
ER -