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Limited influence of germline genetic variation on all-cause mortality in women with early onset breast cancer: evidence from gene-based tests, single-marker regression, and whole-genome prediction

  • Epidemiology
  • Published:
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Abstract

Purpose

Women diagnosed with breast cancer have heterogeneous survival outcomes that cannot be fully explained by known prognostic factors, and germline variation is a plausible but unconfirmed risk factor.

Methods

We used three approaches to test the hypothesis that germline variation drives some differences in survival: mortality loci identification, tumor aggressiveness loci identification, and whole-genome prediction. The 2954 study participants were women diagnosed with breast cancer before age 50, with a median follow-up of 15 years who were genotyped on an exome array. We first searched for loci in gene regions that were associated with all-cause mortality. We next searched for loci in gene regions associated with five histopathological characteristics related to tumor aggressiveness. Last, we also predicted 10-year all-cause mortality on a subset of 1903 participants (3,245,343 variants after imputation) using whole-genome prediction methods.

Results

No risk loci for mortality or tumor aggressiveness were identified. This null result persisted when restricting to women with estrogen receptor-positive tumors, when examining suggestive loci in an independent study, and when restricting to previously published risk loci. Additionally, the whole-genome prediction model also found no evidence to support an association.

Conclusion

Despite multiple complementary approaches, our study found no evidence that mortality in women with early onset breast cancer is influenced by germline variation.

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Abbreviations

AUC:

Area under the receiver operating characteristic

CADD:

Combined annotation-dependent depletion

EBI:

European Bioinformatics Institute

ER:

Estrogen receptor

GWAS:

Genome-wide association study

HER2:

Human epidermal growth factor receptor 2

NHGRI:

National Human Genome Research Institute

PR:

Progesterone receptor

QQ:

Quantile–quantile

SKAT:

Sequence kernel association test

SNV:

Single nucleotide variant

TCGA:

The Cancer Genome Atlas

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Acknowledgements

Portions of this manuscript have been included in the doctoral thesis of Molly Scannell Bryan at the University of Chicago (under embargo until 2019). The authors would like to thank Regina M. Santella of Columbia University. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. Samples from the CPIC were processed and distributed by the Coriell Institute for Medical Research. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

Funding

This study was supported by the National Institute of Health Grants R01CA122171, RC1CA145506, U01CA122171, R01CA094069, UM1CA164920, RFA-CA-95-011, UO1CA/ES66572, UO1CA66572, U19CA148065, and R25-CA057699.

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Authors and Affiliations

  1. University of Chicago, Chicago, IL, USA

    Molly Scannell Bryan, Dezheng Huo, Olofunmilayo Olopade, Farzana Jasmine, Muhammad G. Kibriya, Lin Chen & Habibul Ahsan

  2. University of Illinois at Chicago, Chicago, IL, 60608-1264, USA

    Molly Scannell Bryan & Maria Argos

  3. Lunefeld-Tanenbaum Research Institute, Sinai Health System and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    Irene L. Andrulis

  4. University of Melbourne, Melbourne, Australia

    John L. Hopper

  5. Deutsches Krebsforschungszentrum in der Helmholtz-Gemeinshaft, Hamburg, Germany

    Jenny Chang-Claude

  6. University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Jenny Chang-Claude

  7. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Kathleen Malone

  8. Cancer Prevention Institute of California, Fremont, CA, USA

    Esther M. John

  9. Stanford University School of Medicine, Stanford, CA, USA

    Esther M. John

  10. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Marilie D. Gammon

  11. Fox Chase Cancer Center, Philadelphia, PA, USA

    Mary Daly

  12. Columbia University, New York, NY, USA

    Mary Beth Terry & Jeanine M. Genkinger

  13. University of Utah, Salt Lake City, UT, USA

    Saundra S. Buys

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  1. Molly Scannell Bryan
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Corresponding author

Correspondence to Molly Scannell Bryan.

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The authors declare that they have no conflict of interest. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee, and with the 1964 Helsinki declaration and its later amendments. Informed consent was obtained from all individual participants included in the study.

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Scannell Bryan, M., Argos, M., Andrulis, I.L. et al. Limited influence of germline genetic variation on all-cause mortality in women with early onset breast cancer: evidence from gene-based tests, single-marker regression, and whole-genome prediction. Breast Cancer Res Treat 164, 707–717 (2017). https://doi.org/10.1007/s10549-017-4287-4

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  • DOI: https://doi.org/10.1007/s10549-017-4287-4

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