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Previous GWAS hits in relation to young-onset breast cancer

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

Abstract

Purpose

Genome-wide association studies (GWAS) have identified dozens of single-nucleotide polymorphisms (SNPs) associated with breast cancer. Few studies focused on young-onset breast cancer, which exhibits etiologic and tumor-type differences from older-onset disease. Possible confounding by prenatal effects of the maternal genome has also not been considered.

Methods

Using a family-based design for breast cancer before age 50, we assessed the relationship between breast cancer and 77 GWAS-identified breast cancer risk SNPs. We estimated relative risks (RR) for inherited and maternally mediated genetic effects. We also used published RR estimates to calculate genetic risk scores and model joint effects.

Results

Seventeen of the candidate SNPs were nominally associated with young-onset breast cancer in our 1296 non-Hispanic white affected families (uncorrected p value <0.05). Top-ranked SNPs included rs3803662-A (TOX3, RR = 1.39; p = 7.0 × 10−6), rs12662670-G (ESR1, RR = 1.56; p = 5.7 × 10−4), rs2981579-A (FGFR2, RR = 1.24; p = 0.002), and rs999737-G (RAD51B, RR = 1.37; p = 0.003). No maternally mediated effects were found. A risk score based on all 77 SNPs indicated that their overall relationship to young-onset breast cancer risk was more than additive (additive-fit p = 2.2 × 10−7) and consistent with a multiplicative joint effect (multiplicative-fit p = 0.27). With the multiplicative formulation, the case sister’s genetic risk score exceeded that of her unaffected sister in 59% of families.

Conclusions

The results of this family-based study indicate that no effects of previously identified risk SNPs were explained by prenatal effects of maternal variants. Many of the known breast cancer risk variants were associated with young-onset breast cancer, with evidence that TOX3, ESR1, FGFR2, and RAD51B are important for young-onset disease.

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Abbreviations

CI:

Confidence interval

ER:

Estrogen receptor

GWAS:

Genome-wide association study

LD:

Linkage disequilibrium

OR:

Odds ratio

RR:

Relative risk

SNP:

Single-nucleotide polymorphism

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Acknowledgements

The authors would like to thank Stephanie London and Sophia Harlid for their comments on an early draft of this paper. Genotyping, quality control analysis, and imputation were completed at the Center for Inherited Disease Research, the Genetics Coordinating Center at the University of Washington (Cecelia Laurie, Quenna Wong, Sarah Nelson, and Cathy Laurie).

Funding

This work was supported by the Intramural Research Program of the NIH, the National Institute of Environmental Health Sciences (project Z01-ES044005 to DPS and project Z01-ES102245 to CRW) and Susan G. Komen for the Cure (grant FAS0703856 to CRW).

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    Authors and Affiliations

    1. Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, 111 TW Alexander Dr, Research Triangle Park, Durham, NC, 27709, USA

      Min Shi, Katie M. O’Brien, Dmitri V. Zaykin & Clarice R. Weinberg

    2. Epidemiology Branch, National Institute of Environmental Health Sciences, 111 TW Alexander Fr, Research Triangle Park, Durham, NC, 27709, USA

      Dale P. Sandler & Jack A. Taylor

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    All participants provided written or verbal consent, and the study was approved by the National Institute of Environmental Health Sciences and the Copernicus Group Institutional Review Boards. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable clinical standards.

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    Min Shi and Katie M. O’Brien have contributed equally to this work.

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    Shi, M., O’Brien, K.M., Sandler, D.P. et al. Previous GWAS hits in relation to young-onset breast cancer. Breast Cancer Res Treat 161, 333–344 (2017). https://doi.org/10.1007/s10549-016-4053-z

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