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Replication study for reported SNP associations with breast cancer survival

Abstract

Purpose

Nine previously reported associations between single nucleotide polymorphisms (SNPs) and breast cancer outcomes from the Shanghai Breast Cancer Study (Stage 1) were further evaluated in relation to disease-free survival (DFS) and overall survival (OS) among 5,192 additional breast cancer patients (Stage 2).

Methods

Hazard ratios (HR) and 95% confidence intervals (CI) were calculated by proportional hazards regression in models adjusted for age, disease stage, estrogen and progesterone receptor status, and treatment regimens.

Results

Two SNPs had generally consistent results and significant associations with OS in combined analyses. Compared to women with MMP7 rs11225297 AA genotypes, OS was moderately better for women with AT genotypes (HR: 0.8, 95% CI: 0.7–1.0) and much better for women with TT genotypes (HR: 0.4, 95% CI: 0.2–0.8). Compared to women with MMP8 rs11225395 CC genotypes, OS was slightly better for women with CT genotypes (HR: 0.9, 95% CI: 0.7–1.1) and moderately better for women with TT genotypes (HR: 0.6, 95% CI: 0.4–0.9). Joint analysis showed significant dose–response relationships with increasing numbers of rare alleles for both OS (p < 0.001) and DFS (p = 0.001).

Conclusions

A functional variant in MMP8 and a SNP in high linkage disequilibrium with a functional variant in MMP7 were significantly associated with breast cancer survival in a large two-stage survival study among Chinese women. This supports the hypothesis that SNPs in matrix metalloproteinase genes may influence breast cancer prognosis; additional research on these and other SNPs in genes important in metastasis, angiogenesis, and the regulation of the tumor microenvironment is warranted.

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Fig. 1

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Acknowledgments

The authors wish to thank Dr. Fan Jin for her contributions to data collection and study implementation, Dr. Wanqing Wen for assistance with Kaplan–Meier analyses, and Ms. Bethanie Rammer and Ms. Jacqueline Stern for manuscript editing and submission. We also gratefully acknowledge the participants and research staff of the Shanghai Breast Cancer Study and Shanghai Breast Cancer Survival Study. This research was supported by grants from the National Institute of Health, National Cancer Institute (R01 CA064277 and R01 CA124558, PI: W. Zheng and R01 CA118229, PI: XO Shu), and the Department of Defense Breast Cancer Research Program (DAMD 17-02-1-0607, PI: XO Shu). Dr. Beeghly-Fadiel is supported in part by a grant from the National Institutes of Health, National Institute of Child Health and Human Development (5K12 HD043483-09; PI: N. Brown).

Conflict of Interest

We declare that we have no conflict of interest.

Author information

Correspondence to Xiao Ou Shu.

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Beeghly-Fadiel, A., Zheng, W., Lu, W. et al. Replication study for reported SNP associations with breast cancer survival. J Cancer Res Clin Oncol 138, 1019–1026 (2012). https://doi.org/10.1007/s00432-012-1174-6

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Keywords

  • Breast cancer
  • Survival
  • Genetic variants
  • Replication
  • Matrix metalloproteinases