Journal Article

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

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

2018

Overview

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. Unravelling the link between somatic mutation and prognosis in estrogen positive (ER+) breast cancer requires the use of long-term follow-up data. Here, combining archival formalin-fixed paraffin embedded tissue and targeted sequencing in three cohorts of ER+ breast cancer, the authors find associations with clinical outcome for NF1 frame-shift nonsense mutations, PIK3R1 mutation, and DDR1 mutations.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/23 / 631/67/1347 / 631/67/69 / Adult / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - mortality / Cancer / Case-Control Studies / Class I Phosphatidylinositol 3-Kinases - genetics / Cohort Studies / Deoxyribonucleic acid / Discoidin Domain Receptor 1 - genetics / DNA / DNA sequencing / Female / Humanities and Social Sciences / Humans / MAP Kinase Kinase Kinase 1 - genetics / Middle Aged / multidisciplinary / Mutation / Neurofibromin 1 - genetics / p53 Protein / Phosphatidylinositol 3-Kinases - genetics / Post-menopause / Postmenopause / Prognosis / Receptors, Estrogen - metabolism / Science / Science (multidisciplinary) / Survival Analysis / Tumors