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

Obi L. Griffith; Nicholas C. Spies; Meenakshi Anurag; Malachi Griffith; Jingqin Rosy Luo; Dongsheng Tu; Belinda Jane Yeo; Jason Kunisaki; Christopher A. Miller; Kilannin Krysiak; Jasreet Hundal; Benjamin J. Ainscough; Zachary L. Skidmore; Katie Marie Campbell; Runjun D. Kumar; Catrina C. Fronick; Lisa Cook; Jacqueline Snider; Sherri R. Davies; Shyam M. Kavuri; Eric C. Chang; Vincent J. Magrini; David E. Larson; Robert S. Fulton; Shuzhen Liu; Samuel C. Y. Leung; David K. Voduc; Ron Bose; Mitch Dowsett; Richard K. Wilson

doi:10.1038/s41467-018-05914-x

GenomicsNature CommunicationsAug 22, 2018

Peer-reviewed journal article

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

Obi L. Griffith iD, Nicholas C. Spies iD, Meenakshi Anurag iD, Malachi Griffith iD, Jingqin Rosy Luo iD, Dongsheng Tu iD, Belinda Jane Yeo iD, Jason Kunisaki iD, Christopher A. Miller iD, Kilannin Krysiak iD, Jasreet Hundal iD, Benjamin J. Ainscough iD, Zachary L. Skidmore iD, Katie Marie Campbell iD, Runjun D. Kumar iD, Catrina C. Fronick iD, Lisa Cook, Jacqueline Snider, Sherri R. Davies iD, Shyam M. Kavuri iD, Eric C. Chang iD, Vincent J. Magrini iD, David E. Larson iD, Robert S. Fulton iD, Shuzhen Liu iD, , Matthew J. Ellis iD

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Abstract

More than 50 genes are recurrently affected by somatic mutation in estrogen receptor positive (ER+) breast cancer but prognostic effects have not been definitively established. Primary tumor DNA was therefore subjected to targeted sequencing from 625 postmenopausal (UBC-TAM series) and 328 premenopausal (MA12 trial) hormone receptor-positive (HR+) patients. Independent validation of prognostic interactions was achieved using independent data from the METABRIC study. Associations between MAP3K1 and PIK3CA with luminal A status and TP53 mutations with Luminal B/non-luminal tumors were observed, validating the methodological approach. In UBC-TAM, NF1 frame-shift nonsense (FS/NS) mutation was validated as a poor outcome driver. For MA12, poor outcome associated with PIK3R1 mutation was similarly validated. 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 typify ER+ breast cancer.