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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.


Type

Article

Change log

Authors

Lei, Jieping 
Rudolph, Anja 
Moysich, Kirsten B 
Behrens, Sabine 
Goode, Ellen L 

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.

Description

Keywords

Breast Neoplasms, Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Immune Tolerance, Polymorphism, Single Nucleotide

Journal Title

Hum Genet

Conference Name

Journal ISSN

0340-6717
1432-1203

Volume Title

135

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)
National Cancer Institute (R01CA128978)
National Cancer Institute (U19CA148537)
National Cancer Institute (U19CA148065)
Cancer Research UK (10710)
Cancer Research UK (12014)
Cancer Research UK (10118)
Cancer Research UK (16563)
Cancer Research UK (16565)
Cancer Research Uk (None)
Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (NIH, CA128978, CA122443) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). The ABCFS study was supported by grant UM1 CA164920 from the National Cancer Institute (USA). This study was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. The ABCS study was supported by the Dutch Cancer Society (grants NKI 2007-3839; 2009 4363), and Biobanking and BioMolecular resources Research Infrastructure—Netherlands (BBMRI-NL), which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007). The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS study was funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges National Health Service (NHS) funding to the National Institute for Health Research (NIHR) Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BIGGS study was supported by NIHR Comprehensive Biomedical Research Centre, Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London, United Kingdom. IT was supported by the Oxford Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the Deutsches Krebsforschungszentrum (DKFZ). The CECILE study was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Sécurité Sanitaire (ANSES), Agence Nationale de la Recherche (ANR). The CGPS study was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The CNIO-BCS study was supported by the Instituto de Salud Carlos III, the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI11/00923 and PI12/00070). The CTS study was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the NIH (R01 CA77398). Collection of cancer incidence data (GLOBOCAN 2012) was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Sect. 103885. HAC received support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GC-HBOC study was supported by the German Cancer Aid (grant no 110837, coordinator: Rita K. Schmutzler). The GENICA study was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, DKFZ, Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The HEBCS study was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, the Nordic Cancer Union and the Sigrid Juselius Foundation. The HMBCS study was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The KBCP study was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. The LMBC study was supported by the ‘Stichting tegen Kanker’ (232-2008 and 196-2010). The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I, 106332, 108253, 108419), the Hamburg Cancer Society, DKFZ and the Federal Ministry of Education and Research (BMBF) Germany (01KH0402). The MBCSG study was supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5 × 1000″). The MCBCS study was supported by the NIH grants CA128978, CA116167, CA176785 and NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. The MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. This study was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index. The MEC study was support by NIH grants CA63464, CA54281, CA098758 and CA132839. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research (CIHR) for the “CIHR Team in Familial Risks of Breast Cancer” program—grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade—grant # PSR-SIIRI-701. The NBCS study has received funding from the K.G. Jebsen Centre for Breast Cancer Research, the Research Council of Norway grant 193387/V50 (to A-L Børresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A-L Børresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A-L Børresen-Dale) and the Norwegian Cancer Society (to A-L Børresen-Dale and V.N. Kristensen). The NBHS study was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The OBCS study was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities. The OFBCR study was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The PBCS study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health and the Susan G. Komen Breast Cancer Foundation. The SBCS study was supported by Yorkshire Cancer Research S295, S299, S305PA and Sheffield Experimental Cancer Medicine Centre. The SEARCH study was funded by a programme grant from Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The SKKDKFZS study was supported by the DKFZ. The SZBCS study was supported by Polish State Committee for Scientific Research Grant PBZ_KBN_122/P05/2004. The TNBCC study was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation, the Stefanie Spielman Breast Cancer fund and the OSU Comprehensive Cancer Center, the Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, the European Union (European Social Fund—ESF), and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF)—ARISTEIA. The UKBGS study was funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledged NHS funding to the NIHR Biomedical Research Centre. The kConFab study was supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command (DAMD17-01-1-0729), Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, the Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). The pKARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer.