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

Obi L. Griffith, Nicholas C. Spies, Meenakshi Anurag, Malachi Griffith, Jingqin Luo, Dongsheng Tu, Belinda Yeo, Jason Kunisaki, Christopher A Miller, Kilannin Krysiak, Jasreet Hundal, Benjamin J Ainscough, Zachary L. Skidmore, Katie Campbell, Runjun Kumar, Catrina Fronick, Lisa Cook, Jacqueline E. Snider, Sherri Davies, Shyam M. Kavuri, Eric C. Chang, Vincent Magrini, David E. Larson, Robert S Fulton, Shuzhen Liu, Samuel Leung, David Voduc, Ron Bose, Mitch Dowsett, Richard K. Wilson, Torsten O. Nielsen, Elaine R Mardis () and Matthew J. Ellis ()
Additional contact information
Obi L. Griffith: Washington University School of Medicine
Nicholas C. Spies: Washington University School of Medicine
Meenakshi Anurag: Baylor College of Medicine
Malachi Griffith: Washington University School of Medicine
Jingqin Luo: Washington University School of Medicine
Dongsheng Tu: University of British Columbia
Belinda Yeo: Institute of Cancer Research
Jason Kunisaki: Washington University School of Medicine
Christopher A Miller: Washington University School of Medicine
Kilannin Krysiak: Washington University School of Medicine
Jasreet Hundal: Washington University School of Medicine
Benjamin J Ainscough: Washington University School of Medicine
Zachary L. Skidmore: Washington University School of Medicine
Katie Campbell: Washington University School of Medicine
Runjun Kumar: Washington University School of Medicine
Catrina Fronick: Washington University School of Medicine
Lisa Cook: Washington University School of Medicine
Jacqueline E. Snider: Washington University School of Medicine
Sherri Davies: Washington University School of Medicine
Shyam M. Kavuri: Baylor College of Medicine
Eric C. Chang: Baylor College of Medicine
Vincent Magrini: Washington University School of Medicine
David E. Larson: Washington University School of Medicine
Robert S Fulton: Washington University School of Medicine
Shuzhen Liu: University of British Columbia
Samuel Leung: University of British Columbia
David Voduc: University of British Columbia
Ron Bose: Washington University School of Medicine
Mitch Dowsett: Institute of Cancer Research
Richard K. Wilson: Washington University School of Medicine
Torsten O. Nielsen: University of British Columbia
Elaine R Mardis: Washington University School of Medicine
Matthew J. Ellis: Baylor College of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05914-x

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