Exploration of Immunology

Table 3. Evidence summary for repeatedly investigated variants by outcome category, genetic model, and population.

Gene	Genetic variant	Reference	Population	Outcome	Genetic model	Effect size (OR, 95% CI)	Direction
TGFB1	rs1800470	[27]	North Indian	Susceptibility	Dominant TT + TC vs. CC	1.7 (1.1–2.6)	↑ Risk
		[15]¹	Brazilian	Susceptibility	Haplotype	Not extractable	—
		[16]	Brazilian	Susceptibility	Recessive TT vs. CT + CC	0.39 (0.1–0.8)	↓ Risk
		[34]²	Indian	Susceptibility	Dominant TC + CC vs. TT	0.50 (0.2–0.9)	↓ Risk
	rs1800469	[15]¹	Brazilian	Susceptibility	Haplotype	Not extractable	—
	rs1800469	[16]	Brazilian	Susceptibility	Dominant CT + TT vs. CC	2.1 (1.1–3.8)	↑ Risk
	rs1800471	[15]¹	Brazilian	Susceptibility	Haplotype	Not extractable	—
	rs1800471	[16]	Brazilian	Susceptibility	Recessive CC vs. GG + GC	11.3 (1.6–78.2)	↑ Risk
IL6	rs1800795	[20]	South Indian	Susceptibility	Dominant GC + CC vs. GG	2.1 (1.5–2.9)	↑ Risk
		[5]	Multiethnic*	Susceptibility	Dominant GC + CC vs. GG	0.8 (0.8–0.9)	↓ Risk
		[19]	Caucasian Americans	Susceptibility	Log-additive per C allele	1.0 (0.9–1.2)	No effect
	rs1800797	[20]	South Indian	Susceptibility	Dominant GC + CC vs. GG	2.11 (1.5–2.9)	↑ Risk
	rs1800797	[5]	Multiethnic*	Susceptibility	Dominant GT + TT vs. GG	0.8 (0.7–0.9)	↓ Risk
IL1B	rs1143627	[5]	Multiethnic*	Susceptibility	Dominant TC + CC vs. TT	0.9 (0.8–0.9)	↓ Risk
IL1B	rs1143627	[24]	Turkish	Susceptibility	Codominant/homozygote comparison TT vs. CC	2.06 (1.1–3.6)	↑ Risk
IL10	rs1800871	[32]	Egyptian	Susceptibility	Dominant TC + CC vs. TT	4.02 (1.4–10.9)	↑ Risk
IL10	rs1800871	[5]	Multiethnic*	Susceptibility	Recessive TT vs. CC + CT	0.79 (0.6–0.9)	↓ Risk
CXCL12	rs1801157	[9]	Chinese	Susceptibility	Dominant GA + AA vs. GG	1.35 (1.0–1.7)	↑ Risk
CXCL12	rs1801157	[13]	Brazilian	Gene expression	Dominant GA vs. GG	Not applicable	↓ CXCL12 expression
B7H4	rs10754339	[33]	Turkish	Susceptibility	Codominant AG + GG vs. AA	Not reported	No effect
B7H4	rs10754339	[12]	Chinese	Susceptibility	1-locus model³	1.67 (1.2–2.2)	↑ Risk

Return to article view

¹: Ref. [15] focused on TGFBR2 and TGFB1 haplotypes and did not report extractable OR (95% CI) for the individual variants listed in this table; ²: this study reports multiple genetic models; the value shown here corresponds to the dominant model in Maharashtrian women aged < 40 years and is age-adjusted; ³: high-risk genotype combination vs. low-risk genotype combination; *: non-Hispanic White and Hispanic/Native American; ↑: increased; ↓: decreased. OR: odds ratio; CI: confidence interval.

Supplementary materials

The supplementary material for this article is available at: https://www.explorationpub.com/uploads/Article/file/1003245_sup_1.pdf. The supplementary table for this article is available at: https://www.explorationpub.com/uploads/Article/file/1003245_sup_2.xlsx.

Declarations

Author contributions

JFV: Conceptualization, Formal analysis, Methodology, Resources, Writing—original draft, Writing—review & editing. MPA: Formal analysis, Methodology, Resources, Writing—original draft, Writing—review & editing. JHV: Formal analysis, Methodology, Resources, Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that there are no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

The datasets that support the findings of this study are available from the corresponding author upon reasonable request.

Funding

Not applicable.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Safonov A, Jiang T, Bianchini G, Győrffy B, Karn T, Hatzis C, et al. Immune Gene Expression Is Associated with Genomic Aberrations in Breast Cancer. Cancer Res. 2017;77:3317–24. [DOI] [PubMed]

Pagadala M, Sears TJ, Wu VH, Pérez-Guijarro E, Kim H, Castro A, et al. Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response. Nat Commun. 2023;14:2744. [DOI] [PubMed] [PMC]

Okuyama Kishima M, Brajão de Oliveira K, Ariza CB, de Oliveira CE, Losi Guembarovski R, Banin Hirata BK, et al. Genetic Polymorphism and Expression of CXCR4 in Breast Cancer. Anal Cell Pathol (Amst). 2015;2015:289510. [DOI] [PubMed] [PMC]

Lei J, Rudolph A, Moysich KB, Behrens S, Goode EL, Bolla MK, et al. 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. Hum Genet. 2016;135:137–54. [DOI] [PubMed] [PMC]

Slattery ML, Herrick JS, Torres-Mejia G, John EM, Giuliano AR, Hines LM, et al. Genetic variants in interleukin genes are associated with breast cancer risk and survival in a genetically admixed population: the Breast Cancer Health Disparities Study. Carcinogenesis. 2014;35:1750–9. [DOI] [PubMed] [PMC]

Whittemore R, Knafl K. The integrative review: updated methodology. J Adv Nurs. 2005;52:546–53. [DOI] [PubMed]

Li H, Zhou H, Zhang Q, Zhao S, Zhang Y, Wang Y, et al. Functional polymorphism rs7072793 C > T affect individual susceptibility to breast cancer by modulating CD25 transcription activity. Mol Carcinog. 2013;52:370–6. [DOI] [PubMed]

Chou W, Hsiung C, Chen W, Tseng L, Wang H, Chu H, et al. A functional variant near XCL1 gene improves breast cancer survival via promoting cancer immunity. Int J Cancer. 2020;146:2182–93. [DOI] [PubMed]

Lin S, Zheng Y, Wang M, Zhou L, Zhu Y, Deng Y, et al. Associations of CXCL12 polymorphisms with clinicopathological features in breast cancer: a case-control study. Mol Biol Rep. 2022;49:2255–63. [DOI] [PubMed] [PMC]

10.

Ren H, Li Y, Wang X, Kang H, Jin T, Ma X, et al. PD-1 rs2227982 Polymorphism Is Associated With the Decreased Risk of Breast Cancer in Northwest Chinese Women: A Hospital-Based Observational Study. Medicine (Baltimore). 2016;95:e3760. [DOI] [PubMed] [PMC]

11.

Chen D, Song C, Yu K, Jiang Y, Ye F, Shao Z. A Prospective Evaluation of the Association between a Single Nucleotide Polymorphism rs3775291 in Toll-Like Receptor 3 and Breast Cancer Relapse. PLoS One. 2015;10:e0133184. [DOI] [PubMed] [PMC]

12.

Yu Z, Jiao M, Chen S, Wang F, Fu Z, Chen W, et al. SNP-SNP interactions of immunity related genes involved in the CD28/B7 pathway with susceptibility to invasive ductal carcinoma of the breast. Gene. 2015;566:217–22. [DOI] [PubMed]

13.

de Oliveira KB, Guembarovski RL, Guembarovski AM, da Silva do Amaral Herrera AC, Sobrinho WJ, Ariza CB, et al. CXCL12, CXCR4 and IFNγ genes expression: implications for proinflammatory microenvironment of breast cancer. Clin Exp Med. 2013;13:211–9. [DOI] [PubMed]

14.

Vitiello GAF, Losi Guembarovski R, Amarante MK, Ceribelli JR, Carmelo ECB, Watanabe MAE. Interleukin 7 receptor alpha Thr244Ile genetic polymorphism is associated with susceptibility and prognostic markers in breast cancer subgroups. Cytokine. 2018;103:121–6. [DOI] [PubMed]

15.

Vitiello GAF, Amarante MK, Banin-Hirata BK, Campos CZ, de Oliveira KB, Losi-Guembarovski R, et al. Transforming growth factor beta receptor II (TGFBR2) promoter region polymorphism in Brazilian breast cancer patients: association with susceptibility, clinicopathological features, and interaction with TGFB1 haplotypes. Breast Cancer Res Treat. 2019;178:207–19. [DOI] [PubMed]

16.

Vitiello GAF, Guembarovski RL, Hirata BKB, Amarante MK, de Oliveira CEC, de Oliveira KB, et al. Transforming growth factor beta 1 (TGFβ1) polymorphisms and haplotype structures have dual roles in breast cancer pathogenesis. J Cancer Res Clin Oncol. 2018;144:645–55. [DOI] [PubMed] [PMC]

17.

Hausmann LD, de Almeida BS, de Souza IR, Drehmer MN, Fernandes BL, Wilkens RS, et al. Association of TNFRSF1A and IFNLR1 Gene Polymorphisms with the Risk of Developing Breast Cancer and Clinical Pathologic Features. Biochem Genet. 2021;59:1233–46. [DOI] [PubMed]

18.

Resler AJ, Malone KE, Johnson LG, Malkki M, Petersdorf EW, McKnight B, et al. Genetic variation in TLR or NFkappaB pathways and the risk of breast cancer: a case-control study. BMC Cancer. 2013;13:219. [DOI] [PubMed] [PMC]

19.

Madeleine MM, Johnson LG, Malkki M, Resler AJ, Petersdorf EW, McKnight B, et al. Genetic variation in proinflammatory cytokines IL6, IL6R, TNF-region, and TNFRSF1A and risk of breast cancer. Breast Cancer Res Treat. 2011;129:887–99. [DOI] [PubMed] [PMC]

20.

Padala C, Puranam K, Shyamala N, Kupsal K, Kummari R, Galimudi RK, et al. Genotypic and haplotype analysis of Interleukin-6 and -18 gene polymorphisms in association with clinicopathological factors in breast cancer. Cytokine. 2022;160:156024. [DOI] [PubMed]

21.

Alidoust M, Shamshiri AK, Tajbakhsh A, Gheibihayat SM, Mazloom SM, Alizadeh F, et al. The significant role of a functional polymorphism in the NF-κB1 gene in breast cancer: evidence from an Iranian cohort. Future Oncol. 2021;17:4895–905. [DOI] [PubMed]

22.

Zhang Y, Manjunath M, Yan J, Baur BA, Zhang S, Roy S, et al. The Cancer-Associated Genetic Variant Rs3903072 Modulates Immune Cells in the Tumor Microenvironment. Front Genet. 2019;10:754. [DOI] [PubMed] [PMC]

23.

Deligezer U, Dalay N. Association of the XRCC1 gene polymorphisms with cancer risk in Turkish breast cancer patients. Exp Mol Med. 2004;36:572–5. [DOI] [PubMed]

24.

Eras N, Daloglu FT, Çolak T, Guler M, Akbas E. The Correlation between IL-1β-C31T Gene Polymorphism and Susceptibility to Breast Cancer. J Breast Cancer. 2019;22:210–8. [DOI] [PubMed] [PMC]

25.

Sirisena ND, Adeyemo A, Kuruppu AI, Samaranayake N, Dissanayake VHW. Genetic Variants Associated with Clinicopathological Profiles in Sporadic Breast Cancer in Sri Lankan Women. J Breast Cancer. 2018;21:165–72. [DOI] [PubMed] [PMC]

26.

Lee J, Choi J, Chung S, Park J, Kim J, Sung H, et al. Genetic Predisposition of Polymorphisms in HMGB1-Related Genes to Breast Cancer Prognosis in Korean Women. J Breast Cancer. 2017;20:27–34. [DOI] [PubMed] [PMC]

27.

Pal R, Dutta S. Association Study of Transforming Growth Factor Beta 1 + 29 T/C exon 1 Polymorphism in Breast Cancer Patients from North Indian Population. Appl Biochem Biotechnol. 2023;195:3671–80. [DOI] [PubMed]

28.

Tsai CL, Tsai CW, Chang WS, Su CH, Liu LC, Wang HC, et al. Interleukin-13 Promoter Genotypes and Taiwanese Breast Cancer Susceptibility. Anticancer Res. 2020;40:6743–9. [DOI] [PubMed]

29.

Fawzy MS, Toraih EA. Analysis of the autoimmune regulator (AIRE) gene variant rs2075876 (G/A) association with breast cancer susceptibility. J Clin Lab Anal. 2020;34:e23365. [DOI] [PubMed] [PMC]

30.

Park HM, Park JY, Kim NY, Kim J, Pham TH, Hong JT, et al. Modulatory effects of point-mutated IL-32θ (A94V) on tumor progression in triple-negative breast cancer cells. Biofactors. 2024;50:294–310. [DOI] [PubMed]

31.

Shan J, Chouchane A, Mokrab Y, Saad M, Boujassoum S, Sayaman RW, et al. Genetic Variation in CCL5 Signaling Genes and Triple Negative Breast Cancer: Susceptibility and Prognosis Implications. Front Oncol. 2019;9:1328. [DOI] [PubMed] [PMC]

32.

Sabet S, El-Sayed SK, Mohamed HT, El-Shinawi M, Mohamed MM. Inflammatory breast cancer: High incidence of GCC haplotypes (-1082A/G, -819T/C, and -592A/C) in the interleukin-10 gene promoter correlates with over-expression of interleukin-10 in patients’ carcinoma tissues. Tumour Biol. 2017;39:1010428317713393. [DOI] [PubMed]

33.

Ozgöz A, Samli H, Oztürk KH, Orhan B, Icduygu FM, Aktepe F, et al. An investigation of the effects of FGFR2 and B7-H4 polymorphisms in breast cancer. J Cancer Res Ther. 2013;9:370–5. [DOI] [PubMed]

34.

Joshi NN, Kale MD, Hake SS, Kannan S. Transforming growth factor β signaling pathway associated gene polymorphisms may explain lower breast cancer risk in western Indian women. PLoS One. 2011;6:e21866. [DOI] [PubMed] [PMC]

35.

Adolf IC, Akan G, Mselle TF, Dharsee N, Namkinga LA, Atalar F. Implication of Soluble HLA-G and HLA-G +3142G/C Polymorphism in Breast Cancer Patients Receiving Adjuvant Therapy in Tanzania. Asian Pac J Cancer Prev. 2019;20:3465–72. [DOI] [PubMed] [PMC]

36.

Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44. [DOI] [PubMed]

37.

Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99. [DOI] [PubMed] [PMC]

38.

Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7. [DOI] [PubMed] [PMC]

39.

Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185. [DOI] [PubMed] [PMC]

40.

Nicolini A, Carpi A, Rossi G. Cytokines in breast cancer. Cytokine Growth Factor Rev. 2006;17:325–37. [DOI] [PubMed]

41.

Sanjabi S, Oh SA, Li MO. Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection. Cold Spring Harb Perspect Biol. 2017;9:a022236. [DOI] [PubMed] [PMC]

42.

Wilson CA, Cajulis EE, Green JL, Olsen TM, Chung YA, Damore MA, et al. HER-2 overexpression differentially alters transforming growth factor-beta responses in luminal versus mesenchymal human breast cancer cells. Breast Cancer Res. 2005;7:R1058–79. [DOI] [PubMed] [PMC]

43.

Huang F, Shi Q, Li Y, Xu L, Xu C, Chen F, et al. HER2/EGFR-AKT Signaling Switches TGFβ from Inhibiting Cell Proliferation to Promoting Cell Migration in Breast Cancer. Cancer Res. 2018;78:6073–85. [DOI] [PubMed]

44.

Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16:448–57. [DOI] [PubMed]

45.

Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15:234–48. [DOI] [PubMed] [PMC]

46.

Hirano T. IL-6 in inflammation, autoimmunity and cancer. Int Immunol. 2021;33:127–48. [DOI] [PubMed] [PMC]

47.

Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765. [DOI] [PubMed]

48.

Saraiva M, O’Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol. 2010;10:170–81. [DOI] [PubMed]

49.

Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4:540–50. [DOI] [PubMed]

50.

Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol. 2017;17:559–72. [DOI] [PubMed] [PMC]

51.

Sica GL, Choi IH, Zhu G, Tamada K, Wang SD, Tamura H, et al. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity. 2003;18:849–61. [DOI] [PubMed]

52.

Dawidowicz M, Kot A, Mielcarska S, Psykała K, Kula A, Waniczek D, et al. B7H4 Role in Solid Cancers: A Review of the Literature. Cancers (Basel). 2024;16:2519. [DOI] [PubMed] [PMC]

53.

El Din GS, Youness RA, Assal RA, Gad MZ. miRNA-506-3p Directly Regulates rs10754339 (A/G) in the Immune Checkpoint Protein B7-H4 in Breast Cancer. Microrna. 2020;9:346–53. [DOI] [PubMed]

54.

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64. [DOI] [PubMed] [PMC]

55.

Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2018;18:153–67. [DOI] [PubMed]

56.

Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10. [DOI] [PubMed]

57.

Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24:541–50. [DOI] [PubMed] [PMC]

58.

Norton N, Olson RM, Pegram M, Tenner K, Ballman KV, Clynes R, et al. Association studies of Fcγ receptor polymorphisms with outcome in HER2⁺breast cancer patients treated with trastuzumab in NCCTG (Alliance) Trial N9831. Cancer Immunol Res. 2014;2:962–9. [DOI] [PubMed] [PMC]

59.

Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70. [DOI] [PubMed]

60.

Orrù V, Steri M, Sole G, Sidore C, Virdis F, Dei M, et al. Genetic variants regulating immune cell levels in health and disease. Cell. 2013;155:242–56. [DOI] [PubMed] [PMC]

61.

McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351:1463–9. [DOI] [PubMed] [PMC]

62.

Mellor JD, Brown MP, Irving HR, Zalcberg JR, Dobrovic A. A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer. J Hematol Oncol. 2013;6:1. [DOI] [PubMed] [PMC]