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


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.

MeSH terms

  • Adult
  • Age of Onset
  • Biomarkers, Tumor / genetics
  • Breast Neoplasms / genetics
  • Breast Neoplasms / mortality*
  • Breast Neoplasms / pathology
  • Exome Sequencing / methods*
  • Female
  • Genotyping Techniques / methods*
  • Germ-Line Mutation*
  • Humans
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis / methods*
  • Regression Analysis
  • Survival Analysis


  • Biomarkers, Tumor