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Association of germline microRNA SNPs in pre-miRNA flanking region and breast cancer risk and survival: the Carolina Breast Cancer Study

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Abstract

Purpose

Common germline variation in the 5′ region proximal to precursor (pre-) miRNA gene sequences is evaluated for association with breast cancer risk and survival among African Americans and Caucasians.

Methods

We genotyped nine single nucleotide polymorphisms (SNPs) within six miRNA gene regions previously associated with breast cancer, in 1,972 cases and 1,776 controls. In a race-stratified analysis using unconditional logistic regression, odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated to evaluate SNP association with breast cancer risk. Additionally, hazard ratios (HRs) for breast cancer-specific mortality were estimated.

Results

Two miR-185 SNPs provided suggestive evidence of an inverse association with breast cancer risk (rs2008591, OR = 0.72 (95 % CI = 0.53–0.98, p value = 0.04) and rs887205, OR = 0.71 (95 % CI = 0.52–0.96, p value = 0.03), respectively) among African Americans. Two SNPs, miR-34b/34c (rs4938723, HR = 0.57 (95 % CI = 0.37–0.89, p value = 0.01)) and miR-206 (rs6920648, HR = 0.77 (95 % CI = 0.61–0.97, p value = 0.02)), provided evidence of association with breast cancer survival. Further adjustment for stage resulted in more modest associations with survival (HR = 0.65 [95 % CI = 0.42–1.02, p value = 0.06] and HR = 0.79 [95 % CI = 0.62–1.00, p value = 0.05, respectively]).

Conclusions

Our results suggest that germline variation in the 5′ region proximal to pre-miRNA gene sequences may be associated with breast cancer risk among African Americans and breast cancer-specific survival generally; however, further validation is needed to confirm these findings.

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Abbreviations

3′-UTR:

3′-Untranslated region

AIMs:

Ancestry informative markers

CBCS:

Carolina Breast Cancer Study

cDNA:

Complementary DNA made from an mRNA template

CI:

Confidence interval

CIS:

Breast carcinoma in situ

HR:

Hazard ratio

kb:

Kilobase

LD:

Linkage disequilibrium

MAF:

Minor allele frequency

miRNA or miR:

MicroRNA

mRNA:

Messenger RNA

nt:

Nucleotide

OR:

Odds ratio

Pol II:

Polymerase II

Pol III:

Polymerase III

pre-miRNA:

Precursor microRNA

pri-miRNA:

Primary miRNA transcript

SNP:

Single nucleotide polymorphism

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Acknowledgments

The authors would like to acknowledge the UNC BioSpecimen Processing Facility for our DNA extractions, blood processing, storage, and sample disbursement (https://genome.unc.edu/bsp) and the UNC Mammalian Genotyping Core for CBCS sample genotyping (http://mgc.unc.edu). The authors would also like to thank Amy Otto for her thorough review and editing. This work was supported by the Specialized Program of Research Excellence (SPORE) in Breast Cancer at UNC funded by National Institute of Health/National Cancer Institute [P50-CA58223] (supports JTB, CKT, and RCM); the Lineberger Comprehensive Cancer Center Core Grant funded by the National Institute of Health/National Cancer Institute [P30-CA16086] (funded manuscript preparation and submission), and by the Lineberger Comprehensive Cancer Center Cancer Control Education Program Predoctoral Fellowship [R25 CA57726] (supported SJN).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

All experiments comply with the current laws of the United States of America, where they were performed.

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Authors and Affiliations

  1. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Jeannette T. Bensen, Chiu Kit Tse, Stephen R. Cole & Robert C. Millikan

  2. Lineberger Comprehensive Cancer Center of the University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Jeannette T. Bensen & Robert C. Millikan

  3. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA

    Sarah J. Nyante

  4. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    Jill S. Barnholtz-Sloan

Authors
  1. Jeannette T. Bensen
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  2. Chiu Kit Tse
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  3. Sarah J. Nyante
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  4. Jill S. Barnholtz-Sloan
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  5. Stephen R. Cole
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  6. Robert C. Millikan
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Corresponding author

Correspondence to Jeannette T. Bensen.

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Dr. Robert C. Millikan—deceased.

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Bensen, J.T., Tse, C.K., Nyante, S.J. et al. Association of germline microRNA SNPs in pre-miRNA flanking region and breast cancer risk and survival: the Carolina Breast Cancer Study. Cancer Causes Control 24, 1099–1109 (2013). https://doi.org/10.1007/s10552-013-0187-z

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