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Case-only analyses of the associations between polymorphisms in the metastasis-modifying genes BRMS1 and SIPA1 and breast tumor characteristics, lymph node metastasis, and survival

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Lymph node metastases and tumor characteristics predict breast cancer prognosis but correlate imperfectly with likelihood of metastatic relapse. Discovery of genetic polymorphisms affecting metastasis may improve identification of patients requiring aggressive adjuvant therapy to prevent recurrence. We investigated associations between several variants in the BRMS1 and SIPA1 metastasis-modifying genes and lymph node metastases, tumor subtype and grade, recurrence, disease-free survival, and overall survival. This cross-sectional and prospective prognostic analysis included 859 patients who received surgery for incident breast cancer at Roswell Park Cancer Institute, participated in the DataBank and BioRepository shared resource, and had DNA, clinical, and pathology data available for analysis. Genotyping for BRMS1 (rs11537993, rs3116068, and rs1052566) and SIPA1 (rs75894763, rs746429, rs3741378, and rs2306364) polymorphisms was performed using Sequenom® iPLEX Gold and Taqman® real-time PCR assays. Logistic and Cox proportional hazards regressions were used to estimate odds ratios (OR) and hazard ratios (HR), respectively. BRMS1 rs1052566 heterozygous individuals were more likely to have node-positive tumors (OR = 1.58, 95 % CI 1.13–2.23), although there was no dose–response relationship, and those with at least one variant allele were less likely to have the luminal B subtype (AG + AA: OR = 0.59, 95 % CI 0.36–0.98). BRMS1 rs3116068 was associated with increased likelihood of having the luminal B and the HER2-enriched tumor subtype (P trend = 0.03). Two SIPA1 SNPs, rs746429 and rs2306364, were associated with decreased risk of triple-negative tumors (P trend = 0.04 and 0.07, respectively). Presence of 8 or more risk alleles was associated with an increased likelihood of having a node-positive tumor (OR = 2.14, 95 % CI 1.18–3.36, P trend = 0.002). There were no significant associations with survival. Polymorphisms in metastasis-associated genes may be related to tumor characteristics and lymph node metastasis, but not survival. Future evaluation of metastasis-modifying gene variants is necessary to better understand the biology of metastasis.

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Abbreviations

BMI:

Body mass index

BRMS1:

Breast cancer metastasis suppressor 1

CI:

Confidence interval

DBBR:

DataBank and BioRepository

DCIS:

Ductal carcinoma in situ

DFS:

Disease-free survival

ER:

Estrogen receptor

HER2:

Human epidermal growth factor receptor 2

HR:

Hazard ratio

HRT:

Hormone replacement therapy

NCCN:

National Comprehensive Cancer Network

OR:

Odds ratio

OS:

Overall survival

PR:

Progesterone receptor

RPCI:

Roswell Park Cancer Institute

SIPA1:

Signal-induced proliferation-associated 1

SNP:

Single nucleotide polymorphism

TTR:

Time to recurrence

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Acknowledgments

This research was supported by a gift from the Jayne and Philip Hubbell Family. MRR is supported by DAMD W81XWH-11-1-0024, a predoctoral fellowship from the Department of Defense Breast Cancer Research Program, and previously supported by R25-CA11395102, an NCI predoctoral award. CBA is a recipient of funding from the Breast Cancer Research Foundation. Biospecimens and data were obtained from the RPCI DataBank and Biorepository, and genotyping was performed in the RPCI Genomics Core Facility, both of which are Cancer Center Support Grant Shared Resources supported by National Institutes of Health P30 CA016056-27. The funding agents played no role in any part of the study, including the design, collection, analysis and interpretation of the data, in the writing of the manuscript, or the decision to submit the manuscript for publication.

Conflict of interests

The authors declare that they have no conflict of interests.

Ethical standard

This work complies with all ethical standards and current laws of the USA.

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Authors and Affiliations

  1. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Michelle R. Roberts, Chi-Chen Hong, Song Yao & Christine B. Ambrosone

  2. Department of Social and Preventive Medicine, University at Buffalo, Buffalo, NY, 14226, USA

    Michelle R. Roberts & Jo L. Freudenheim

  3. Department of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Stephen B. Edge

  4. Department of Pathology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Wiam Bshara

  5. Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Michael J. Higgins

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  1. Michelle R. Roberts
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Correspondence to Michelle R. Roberts.

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Roberts, M.R., Hong, CC., Edge, S.B. et al. Case-only analyses of the associations between polymorphisms in the metastasis-modifying genes BRMS1 and SIPA1 and breast tumor characteristics, lymph node metastasis, and survival. Breast Cancer Res Treat 139, 873–885 (2013). https://doi.org/10.1007/s10549-013-2601-3

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  • DOI: https://doi.org/10.1007/s10549-013-2601-3

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