Research Papers:

SNPs in the interleukin-12 signaling pathway are associated with breast cancer risk in Puerto Rican women

Angel Núñez-Marrero, Nelly Arroyo, Lenin Godoy, Mohammad Zillur Rahman, Jaime L. Matta and Julie Dutil _

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Oncotarget. 2020; 11:3420-3431. https://doi.org/10.18632/oncotarget.27707

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Angel Núñez-Marrero1, Nelly Arroyo1, Lenin Godoy1, Mohammad Zillur Rahman1, Jaime L. Matta1 and Julie Dutil1

1 Cancer Biology Division, Ponce Research Institute, Ponce Health Sciences University, Ponce, Puerto Rico

Correspondence to:

Julie Dutil,email: [email protected]

Keywords: breast cancer; interleukin-12 (IL-12); IL-12 signaling; genetic association; single nucleotide polymorphisms

Received: October 27, 2019     Accepted: July 14, 2020     Published: September 15, 2020


Interleukin-12 (IL-12) is a proinflammatory cytokine that links innate and adaptive immune responses against tumor cells. Single Nucleotide Polymorphisms (SNPs) in IL-12 genes have been associated with cancer risk. However, limited studies have assessed the role of IL-12 in breast cancer (BC) risk comprehensively, and these were done in European and Asian populations. Here, we evaluated the association of the IL-12 signaling pathway and BC risk in Puerto Rican women. A genetic association study was completed with 461 BC cases and 463 non-BC controls. By logistic regression, IL-12 signaling SNPs were associated with an increased BC risk, including rs2243123 (IL12A), rs3761041, rs401502 and rs404733 (IL12RB1), rs7849191 (JAK2), rs280500 (TYK2) and rs4274624 (STAT4). Conversely, other SNPs were associated with reduced BC risk including rs438421 (IL12RB1), rs6693065 (IL12RB2), rs10974947, and rs2274471 (JAK2), rs10168266 and rs925847 (STAT4), and rs2069718 (IFNG). Analyses based in hormone receptors such as estrogen (ER) and progesterone (PR) receptors also revealed protective (for SNPs rs3212227-IL12B; rs3024896 and rs3821236-STAT4) and predisposing (for rs2069705-IFNG SNP) BC associations. Haplotype analysis showed a decreased BC risk for IL12B and STAT4 SNPs, whereas increased risk for IL12RB1 SNPs. This study suggests a role of the IL-12 signaling axis and BC risk. SNPs in this pathway may alter IL-12 induced anti-tumor responses and modulate BC predisposition in a population-specific context. Functional studies will be necessary to confirm these findings, which potentially may benefit IL-12 related immunotherapeutic approaches towards BC.

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