Paper

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

Wilson, Richard K, Dowsett, Mitch, Krysiak, Kilannin, Meenakshi Anurag, Kumar, Runjun, Ainscough, Benjamin, Fronick, Catrina, Mardis, Elaine R, Kunisaki, Jason, Spies, Nicholas C, Chang, Eric C, Bose, Ron, Luo, Jingqin, Fulton, Robert S, Campbell, Katie, Griffith, Obi L, Ellis, Matthew J, Tu, Dongsheng, Yeo, Belinda, Larson, David E, Leung, Samuel, Snider, Jacqueline E, Kavuri, Shyam M, Magrini, Vincent, Griffith, Malachi, Nielsen, Torsten O, Hundal, Jasreet, Skidmore, Zachary, Liu, Shuzen, Davies, Sherri, Cook, Lisa, Voduc, David, Miller, Christopher A

2017

Overview

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 hormonal receptor-positive (HR+) patients (MA12 trial). Independent validation of prognostic interactions were achieved with public 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) mutations were validated as poor outcome drivers. For MA12, poor outcomes associated with PIK3R1 mutation were similarly validated. DDR1 mutations were strongly associated with poor prognosis in UBC-TAM with false-discovery correction (q=0.0003). In conclusion, the tail of uncommon recurrent somatic mutations should be further explored to create a more complete explanation of the highly variable outcomes that typify ER+ breast cancer.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Breast cancer / DNA sequencing / Estrogen receptors / Genomics / Menopause / Mutation / p53 Protein / Post-menopause / Tumors