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Breast Cancer Res Treat. 2017 Aug;164(3):707-717. doi: 10.1007/s10549-017-4287-4. Epub 2017 May 13.

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.

Author information

1
University of Chicago, Chicago, IL, USA. scannemo@uic.edu.
2
University of Illinois at Chicago, Chicago, IL, 60608-1264, USA. scannemo@uic.edu.
3
University of Illinois at Chicago, Chicago, IL, 60608-1264, USA.
4
Lunefeld-Tanenbaum Research Institute, Sinai Health System and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
5
University of Melbourne, Melbourne, Australia.
6
Deutsches Krebsforschungszentrum in der Helmholtz-Gemeinshaft, Hamburg, Germany.
7
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
8
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
9
Cancer Prevention Institute of California, Fremont, CA, USA.
10
Stanford University School of Medicine, Stanford, CA, USA.
11
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
12
Fox Chase Cancer Center, Philadelphia, PA, USA.
13
Columbia University, New York, NY, USA.
14
University of Utah, Salt Lake City, UT, USA.
15
University of Chicago, Chicago, IL, USA.

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.

KEYWORDS:

Early onset breast cancer; Gene-based tests; SKAT-O; Single nucleotide variants; Survival; Whole-genome prediction

PMID:
28503721
PMCID:
PMC5510603
DOI:
10.1007/s10549-017-4287-4
[Indexed for MEDLINE]
Free PMC Article

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