Host genotype and tumor phenotype of chemokine decoy receptors integrally affect breast cancer relapse
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Ke-Da Yu1,*, Xin Wang2,*, Chen Yang3,*, Xiao-Hua Zeng4,*, Zhi-Ming Shao1
1Department of Breast Surgery, Shanghai Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, P.R. China
2Department of Anesthesiology, Shanghai Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, P.R. China
3Department of Medical Oncology, Ruijin Hospital, Shanghai JiaoTong University, Shanghai, P.R. China
4Department of Breast Surgery, Chongqing Cancer Institute/Hospital, Chongqing, P.R. China
*These authors have contributed equally to this work
Ke-Da Yu, e-mail: [email protected]
Keywords: chemokine decoy receptor, breast cancer, metastasis, phenotype, genotype
Received: March 22, 2015 Accepted: June 25, 2015 Published: July 06, 2015
Purpose: Chemokines may play vital roles in breast cancer progression and metastasis. The primary members of chemokine decoy receptors (CDR), DARC and D6, are expressed in breast tumors and lymphatic/hematogenous vessels. CDRs sequestrate the pro-malignant chemokines. We hypothesized that breast cancer patients carrying different levels of CDR expression in tumor and/or in host might have differing clinical outcomes.
Methods: This prospective observational study measured both expression and germline genotype of DARC and D6 in 463 primary breast cancer patients enrolled between 2004 and 2006. The endpoint was breast cancer relapse-free survival (RFS).
Results: There was a significant association between the co-expression of CDR (immunohistochemical expression of both DARC and D6) with RFS (hazard ratio [HR] of 0.32, 95% confidence interval [CI] 0.19 to 0.54). Furthermore, the co-genotype of two non-synonymous polymorphisms (with two major alleles of DARC-rs12075 and D6-rs2228468 versus the others) significantly related to relapse. Mechanistically, the variant-alleles of these two polymorphisms significantly decreased by 20–30% of CCL2/CCL5 (CDR ligands) levels relative to their major counterparts. Multivariate analysis highlighted that the co-expression and co-genotype of CDR were independent predictors of RFS, with HR of 0.46 (95% CI 0.27 to 0.80) and 0.56 (95% CI 0.37 to 0.85), respectively. The addition of host CDR genetic information to tumor-based factors (including co-expression of CDR) improved the relapse prediction ability (P = 0.02 of AUC comparison).
Conclusion: The host genotype and tumor phenotype of CDR integrally affect breast cancer relapse. Host-related factors should be considered for individualized prediction of prognosis.
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