Cytokine and cytokine receptor genes of the adaptive immune response are differentially associated with breast cancer risk in American women of African and European ancestry

Lei Quan, Zhihong Gong, Song Yao, Elisa V. Bandera, Gary Zirpoli, Helena Hwang, Michelle Roberts, Gregory Ciupak, Warren Davis, Lara Sucheston, Karen Pawlish, Dana H. Bovbjerg, Lina Jandorf, Citadel Cabasag, Jean Gabriel Coignet, Christine B. Ambrosone, Chi Chen Hong

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Abstract

Disparities in breast cancer biology are evident between American women of African ancestry (AA) and European ancestry (EA) and may be due, in part, to differences in immune function. To assess the potential role of constitutional host immunity on breast carcinogenesis, we tested associations between breast cancer risk and 47 single nucleotide polymorphisms (SNPs) in 26 cytokine-related genes of the adaptive immune system using 650 EA (n = 335 cases) and 864 AA (n = 458 cases) women from the Women's Circle of Health Study (WCHS). With additional participant accrual to the WCHS, promising SNPs from the initial analysis were evaluated in a larger sample size (1,307 EAs and 1,365 AAs). Multivariate logistic regression found SNPs in genes important for T helper type 1 (Th1) immunity (IFNGR2 rs1059293, IL15RA rs2296135, LTA rs1041981), Th2 immunity (IL4R rs1801275), and T regulatory cell-mediated immunosuppression (TGFB1 rs1800469) associated with breast cancer risk, mainly among AAs. The combined effect of these five SNPs was highly significant among AAs (P-trend = 0.0005). When stratified by estrogen receptor (ER) status, LTA rs1041981 was associated with ER-positive breast cancers among EAs and marginally among AAs. Only among AA women, IL15 rs10833 and IL15RA rs2296135 were associated with ER-positive tumors, and IL12RB1 rs375947, IL15 rs10833 and TGFB1 rs1800469 were associated with ER-negative tumors. Our study systematically identified genetic variants in the adaptive immune response pathway associated with breast cancer risk, which appears to differ by ancestry groups, menopausal status and ER status. What's new? African American women are affected by aggressive and early-onset breast cancers more often than American women of European descent, though the reasons for this are not fully understood. Here, single nucleotide polymorphisms (SNPs) in genes involved in Th1 and Th2 immunity and in T regulatory cell-mediated immunosuppression were linked to breast cancer risk in African American women. Stratification according to estrogen-receptor status (ER positive or ER negative) revealed sets of risk-associated SNPs exclusive to African Americans. The findings suggest that host adaptive immunity plays a more prominent role in breast carcinogenesis among African Americans compared with European Americans.

Original languageEnglish (US)
Pages (from-to)1408-1421
Number of pages14
JournalInternational Journal of Cancer
Volume134
Issue number6
DOIs
StatePublished - Mar 15 2014

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Cytokine Receptors
Adaptive Immunity
Estrogen Receptors
African Americans
Breast Neoplasms
Cytokines
Single Nucleotide Polymorphism
Genes
Immunity
Interleukin-15
Women's Health
Regulatory T-Lymphocytes
Immunosuppression
Carcinogenesis
Breast
Sample Size
Immune System
Neoplasms
Logistic Models

Keywords

  • adaptive immune response
  • African-American
  • breast cancer
  • cytokine
  • disparity
  • estrogen receptor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cytokine and cytokine receptor genes of the adaptive immune response are differentially associated with breast cancer risk in American women of African and European ancestry. / Quan, Lei; Gong, Zhihong; Yao, Song; Bandera, Elisa V.; Zirpoli, Gary; Hwang, Helena; Roberts, Michelle; Ciupak, Gregory; Davis, Warren; Sucheston, Lara; Pawlish, Karen; Bovbjerg, Dana H.; Jandorf, Lina; Cabasag, Citadel; Coignet, Jean Gabriel; Ambrosone, Christine B.; Hong, Chi Chen.

In: International Journal of Cancer, Vol. 134, No. 6, 15.03.2014, p. 1408-1421.

Research output: Contribution to journalArticle

Quan, L, Gong, Z, Yao, S, Bandera, EV, Zirpoli, G, Hwang, H, Roberts, M, Ciupak, G, Davis, W, Sucheston, L, Pawlish, K, Bovbjerg, DH, Jandorf, L, Cabasag, C, Coignet, JG, Ambrosone, CB & Hong, CC 2014, 'Cytokine and cytokine receptor genes of the adaptive immune response are differentially associated with breast cancer risk in American women of African and European ancestry', International Journal of Cancer, vol. 134, no. 6, pp. 1408-1421. https://doi.org/10.1002/ijc.28458
Quan, Lei ; Gong, Zhihong ; Yao, Song ; Bandera, Elisa V. ; Zirpoli, Gary ; Hwang, Helena ; Roberts, Michelle ; Ciupak, Gregory ; Davis, Warren ; Sucheston, Lara ; Pawlish, Karen ; Bovbjerg, Dana H. ; Jandorf, Lina ; Cabasag, Citadel ; Coignet, Jean Gabriel ; Ambrosone, Christine B. ; Hong, Chi Chen. / Cytokine and cytokine receptor genes of the adaptive immune response are differentially associated with breast cancer risk in American women of African and European ancestry. In: International Journal of Cancer. 2014 ; Vol. 134, No. 6. pp. 1408-1421.
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AU - Quan, Lei

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AU - Zirpoli, Gary

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AU - Roberts, Michelle

AU - Ciupak, Gregory

AU - Davis, Warren

AU - Sucheston, Lara

AU - Pawlish, Karen

AU - Bovbjerg, Dana H.

AU - Jandorf, Lina

AU - Cabasag, Citadel

AU - Coignet, Jean Gabriel

AU - Ambrosone, Christine B.

AU - Hong, Chi Chen

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N2 - Disparities in breast cancer biology are evident between American women of African ancestry (AA) and European ancestry (EA) and may be due, in part, to differences in immune function. To assess the potential role of constitutional host immunity on breast carcinogenesis, we tested associations between breast cancer risk and 47 single nucleotide polymorphisms (SNPs) in 26 cytokine-related genes of the adaptive immune system using 650 EA (n = 335 cases) and 864 AA (n = 458 cases) women from the Women's Circle of Health Study (WCHS). With additional participant accrual to the WCHS, promising SNPs from the initial analysis were evaluated in a larger sample size (1,307 EAs and 1,365 AAs). Multivariate logistic regression found SNPs in genes important for T helper type 1 (Th1) immunity (IFNGR2 rs1059293, IL15RA rs2296135, LTA rs1041981), Th2 immunity (IL4R rs1801275), and T regulatory cell-mediated immunosuppression (TGFB1 rs1800469) associated with breast cancer risk, mainly among AAs. The combined effect of these five SNPs was highly significant among AAs (P-trend = 0.0005). When stratified by estrogen receptor (ER) status, LTA rs1041981 was associated with ER-positive breast cancers among EAs and marginally among AAs. Only among AA women, IL15 rs10833 and IL15RA rs2296135 were associated with ER-positive tumors, and IL12RB1 rs375947, IL15 rs10833 and TGFB1 rs1800469 were associated with ER-negative tumors. Our study systematically identified genetic variants in the adaptive immune response pathway associated with breast cancer risk, which appears to differ by ancestry groups, menopausal status and ER status. What's new? African American women are affected by aggressive and early-onset breast cancers more often than American women of European descent, though the reasons for this are not fully understood. Here, single nucleotide polymorphisms (SNPs) in genes involved in Th1 and Th2 immunity and in T regulatory cell-mediated immunosuppression were linked to breast cancer risk in African American women. Stratification according to estrogen-receptor status (ER positive or ER negative) revealed sets of risk-associated SNPs exclusive to African Americans. The findings suggest that host adaptive immunity plays a more prominent role in breast carcinogenesis among African Americans compared with European Americans.

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