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Nat Commun. 2018 Sep 4;9(1):3476. doi: 10.1038/s41467-018-05914-x.

The prognostic effects of somatic mutations in ER-positive breast cancer.

Author information

1
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, 63108, MO, USA.
2
Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, 63110, MO, USA.
3
Siteman Cancer Center, Washington University School of Medicine, St. Louis, 63110, MO, USA.
4
Department of Genetics, Washington University School of Medicine, St. Louis, 63110, MO, USA.
5
Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, 77030, TX, USA.
6
Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030, TX, USA.
7
Division of Biostatistics, Washington University School of Medicine, St. Louis, 63110, MO, USA.
8
Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, V6H 3Z6, Canada.
9
Institute of Cancer Research, London, SM2 5NG, UK.
10
Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, 43205, OH, USA.
11
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, 63108, MO, USA. elaine.mardis@nationwidechildrens.org.
12
Siteman Cancer Center, Washington University School of Medicine, St. Louis, 63110, MO, USA. elaine.mardis@nationwidechildrens.org.
13
Department of Genetics, Washington University School of Medicine, St. Louis, 63110, MO, USA. elaine.mardis@nationwidechildrens.org.
14
Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, 43205, OH, USA. elaine.mardis@nationwidechildrens.org.
15
Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, 77030, TX, USA. mjellis@bcm.edu.
16
Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030, TX, USA. mjellis@bcm.edu.

Abstract

Here we report targeted sequencing of 83 genes using DNA from primary breast cancer samples from 625 postmenopausal (UBC-TAM series) and 328 premenopausal (MA12 trial) hormone receptor-positive (HR+) patients to determine interactions between somatic mutation and prognosis. Independent validation of prognostic interactions was achieved using data from the METABRIC study. Previously established associations between MAP3K1 and PIK3CA mutations with luminal A status/favorable prognosis and TP53 mutations with Luminal B/non-luminal tumors/poor prognosis were observed, validating the methodological approach. In UBC-TAM, NF1 frame-shift nonsense (FS/NS) mutations were also a poor outcome driver that was validated in METABRIC. For MA12, poor outcome associated with PIK3R1 mutation was also reproducible. DDR1 mutations were strongly associated with poor prognosis in UBC-TAM despite stringent false discovery correction (q = 0.0003). In conclusion, uncommon recurrent somatic mutations should be further explored to create a more complete explanation of the highly variable outcomes that typifies ER+ breast cancer.

PMID:
30181556
PMCID:
PMC6123466
DOI:
10.1038/s41467-018-05914-x
[Indexed for MEDLINE]
Free PMC Article

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