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.
Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.Carcinogenesis. 2015 Feb;36(2):256-71. doi: 10.1093/carcin/bgu326. Epub 2015 Jan 13. Carcinogenesis. 2015. PMID: 25586992 Free PMC article.
Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium.Hum Mol Genet. 2011 Dec 1;20(23):4693-706. doi: 10.1093/hmg/ddr368. Epub 2011 Aug 18. Hum Mol Genet. 2011. PMID: 21852249 Free PMC article.
Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy.Breast Cancer Res. 2015 Feb 10;17(1):18. doi: 10.1186/s13058-015-0522-2. Breast Cancer Res. 2015. PMID: 25849327 Free PMC article.
Genetic variation in the Hippo pathway and breast cancer risk in women of African ancestry.Mol Carcinog. 2018 Oct;57(10):1311-1318. doi: 10.1002/mc.22845. Epub 2018 Jun 14. Mol Carcinog. 2018. PMID: 29873413 Free PMC article. Clinical Trial.
Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.PLoS One. 2016 Aug 24;11(8):e0160316. doi: 10.1371/journal.pone.0160316. eCollection 2016. PLoS One. 2016. PMID: 27556229 Free PMC article.
Cited by 4 articles
Genetic Variants Associated with Clinicopathological Profiles in Sporadic Breast Cancer in Sri Lankan Women.J Breast Cancer. 2018 Jun;21(2):165-172. doi: 10.4048/jbc.2018.21.2.165. Epub 2018 Jun 20. J Breast Cancer. 2018. PMID: 29963112 Free PMC article.
Evaluation of three polygenic risk score models for the prediction of breast cancer risk in Singapore Chinese.Oncotarget. 2018 Jan 31;9(16):12796-12804. doi: 10.18632/oncotarget.24374. eCollection 2018 Feb 27. Oncotarget. 2018. PMID: 29560110 Free PMC article.
Genetic Variants in Immune-Related Pathways and Breast Cancer Risk in African American Women in the AMBER Consortium.Cancer Epidemiol Biomarkers Prev. 2018 Mar;27(3):321-330. doi: 10.1158/1055-9965.EPI-17-0434. Epub 2018 Jan 16. Cancer Epidemiol Biomarkers Prev. 2018. PMID: 29339359 Free PMC article.
Association between NF-κB Pathway Gene Variants and sICAM1 Levels in Taiwanese.PLoS One. 2017 Jan 17;12(1):e0169516. doi: 10.1371/journal.pone.0169516. eCollection 2017. PLoS One. 2017. PMID: 28095483 Free PMC article.
- Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens D, Mni M, Rutgeerts P, Van Gossum A, Zelenika D, Franchimont D, Hugot JP, de Vos M, Vermeire S, Louis E, Cardon LR, Anderson CA, Drummond H, Nimmo E, Ahmad T, Prescott NJ, Onnie CM, Fisher SA, Marchini J, Ghori J, Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes M, Georges M, Daly MJ. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40:955–962. doi: 10.1038/ng.175. - DOI - PMC - PubMed
- CA54281/CA/NCI NIH HHS/United States
- CA128978/CA/NCI NIH HHS/United States
- R01 CA176785/CA/NCI NIH HHS/United States
- P30 CA68485/CA/NCI NIH HHS/United States
- C490/A10124/CRUK_/Cancer Research UK/United Kingdom
- CRN-87521/CAPMC/ CIHR/Canada
- 1U19 CA148065/CA/NCI NIH HHS/United States
- R01 CA122443/CA/NCI NIH HHS/United States
- C1287/A10118/CRUK_/Cancer Research UK/United Kingdom
- CA098758/CA/NCI NIH HHS/United States
- CA122443/CA/NCI NIH HHS/United States
- R37 CA054281/CA/NCI NIH HHS/United States
- MC_PC_14105/MRC_/Medical Research Council/United Kingdom
- CA116201/CA/NCI NIH HHS/United States
- C5047/A10692/CRUK_/Cancer Research UK/United Kingdom
- UM1 CA164920/CA/NCI NIH HHS/United States
- 1U19 CA148537/CA/NCI NIH HHS/United States
- R01 CA100374/CA/NCI NIH HHS/United States
- CA63464/CA/NCI NIH HHS/United States
- U01 CA116167/CA/NCI NIH HHS/United States
- C5047/A8384/CRUK_/Cancer Research UK/United Kingdom
- C12292/A11174/CRUK_/Cancer Research UK/United Kingdom
- R01 CA128978/CA/NCI NIH HHS/United States
- R01CA100374/CA/NCI NIH HHS/United States
- CA116167/CA/NCI NIH HHS/United States
- CA176785/CA/NCI NIH HHS/United States
- U19 CA148537/CA/NCI NIH HHS/United States
- P50 CA116201/CA/NCI NIH HHS/United States
- C8197/A16565/CRUK_/Cancer Research UK/United Kingdom
- R01 CA077398/CA/NCI NIH HHS/United States
- U01 CA063464/CA/NCI NIH HHS/United States
- R01 CA132839/CA/NCI NIH HHS/United States
- P30 CA068485/CA/NCI NIH HHS/United States
- R01 CA77398/CA/NCI NIH HHS/United States
- 1U19 CA148112/CA/NCI NIH HHS/United States
- C1281/A12014/CRUK_/Cancer Research UK/United Kingdom
- U01 CA098758/CA/NCI NIH HHS/United States
- C1287/A10710/CRUK_/Cancer Research UK/United Kingdom
- CA132839/CA/NCI NIH HHS/United States
- U19 CA148065/CA/NCI NIH HHS/United States
- 10119/CRUK_/Cancer Research UK/United Kingdom
- C5047/A15007/CRUK_/Cancer Research UK/United Kingdom
- 10124/CRUK_/Cancer Research UK/United Kingdom