Whole-genome analysis informs breast cancer response to aromatase inhibition

著者: Matthew J. Ellis, Li Ding, Dong Shen, Jingqin Luo, Vera J. Suman, John W. Wallis, Brian Andrew Van Tine, Jeremy Hoog, Reece Goiffon, Theodore C. Goldstein, Sam Ng, Lin Li, Robert J. Crowder, Jacqueline Snider, Karla V. Ballman, Jason D. Weber, Ken Chen, Daniel C. Koboldt, Cyriac Kandoth, William Schierding, Joshua F. McMichael, Christopher A. Miller, Charles Lu, Christopher Harris, Michael D. McLellan, Michael C. Wendl, Katherine DeSchryver, D. Craig Allred, Laura J. Esserman, Gary Unzeitig, Julie A. Margenthaler, Gildy V. Babiera, P. Kelly Marcom, J. Michael Guenther, Marilyn Leitch, Kelly K. Hunt, John A. Olson, Tao Yu, Christopher A. Maher, Lucinda Fulton, Robert S. Fulton, Michelle Harrison, Ben Oberkfell, Feiyu Du, Ryan Demeter, Tammi L. Vickery, Adnan Elhammali, Helen Piwnica‐Worms, Sandra McDonald, Mark A. Watson, David J. Dooling, David M. Ota, Li-Wei Chang, Ron Bose, Timothy J. Ley, David Piwnica‐Worms, Joshua M. Stuart, Richard K. Wilson, Elaine R. Mardis - Nature 2012 被引用: 1,035

To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing. Whole-genome analysis of oestrogen-receptor-positive tumours in patients treated with aromatase inhibitors show that distinct phenotypes are associated with specific patterns of somatic mutations; however, most recurrent mutations are relatively infrequent so prospective clinical trials will require comprehensive sequencing and large study populations. Elaine Mardis and colleagues use whole-genome sequencing to gain insight into the mutational landscape of tissue samples from patients with oestrogen-receptor-positive (ER+) breast cancer treated with a neoadjuvant aromatase inhibitor. They identify a number of disease-linked mutations that specifically correlate with tumour-cell histology, proliferation rates and response to treatment. Such information could be used to determine which patients will benefit from aromatase-inhibitor therapy.