Whole-genome analysis informs breast cancer response to aromatase inhibition

Matthew J. Ellis, Li Ding, Dong Shen, Jingqin Luo, Vera J. Suman, John W. Wallis, Brian A. Van Tine, Jeremy Hoog, Reece J. Goiffon, Theodore C. Goldstein, Sam Ng, Li Lin, Robert Crowder, Jacqueline Snider, Karla Ballman, Jason Weber, Ken Chen, Daniel C. Koboldt, Cyriac Kandoth, William S. Schierding, Joshua F. McMichael, Christopher A. Miller, Charles Lu, Christopher C. Harris, Michael D. McLellan, Michael C. Wendl, Katherine DeSchryver, D. Craig Allred, Laura Esserman, Gary Unzeitig, Julie Margenthaler, G. V. Babiera, P. Kelly Marcom, J. M. Guenther, Marilyn Leitch, Kelly Hunt, John Olson, Yu Tao, Christopher A. Maher, Lucinda L. Fulton, Robert S. Fulton, Michelle Harrison, Ben Oberkfell, Feiyu Du, Ryan Demeter, Tammi L. Vickery, Adnan Elhammali, Helen Piwnica-Worms, Sandra McDonald, Mark Watson, David J. Dooling, David Ota, Li-Wei Chang, Ron Bose, Timothy J. Ley, David Piwnica-Worms, Joshua M. Stuart, Richard K. Wilson and Elaine R. Mardis
Additional contact information
Matthew J. Ellis: Washington University
Li Ding: The Genome Institute, Washington University
Dong Shen: The Genome Institute, Washington University
Jingqin Luo: Breast Cancer Program, Washington University
Vera J. Suman: ACOSOG Statistical Center, Mayo Clinic
John W. Wallis: The Genome Institute, Washington University
Brian A. Van Tine: Washington University
Jeremy Hoog: Washington University
Reece J. Goiffon: BRIGHT Institute, Washington University School of Medicine
Theodore C. Goldstein: University of California
Sam Ng: University of California
Li Lin: Washington University
Robert Crowder: Washington University
Jacqueline Snider: Washington University
Karla Ballman: ACOSOG Statistical Center, Mayo Clinic
Jason Weber: Washington University
Ken Chen: M. D. Anderson Cancer Center
Daniel C. Koboldt: The Genome Institute, Washington University
Cyriac Kandoth: The Genome Institute, Washington University
William S. Schierding: The Genome Institute, Washington University
Joshua F. McMichael: The Genome Institute, Washington University
Christopher A. Miller: The Genome Institute, Washington University
Charles Lu: The Genome Institute, Washington University
Christopher C. Harris: The Genome Institute, Washington University
Michael D. McLellan: The Genome Institute, Washington University
Michael C. Wendl: The Genome Institute, Washington University
Katherine DeSchryver: Washington University
D. Craig Allred: Breast Cancer Program, Washington University
Laura Esserman: Helen Diller Cancer Center, University of California
Gary Unzeitig: Doctors Hospital of Laredo
Julie Margenthaler: Siteman Cancer Center, Washington University
G. V. Babiera: M. D. Anderson Cancer Center
P. Kelly Marcom: Duke University Cancer Center
J. M. Guenther: Good Samaritan Hospital
Marilyn Leitch: Simmons Cancer Center, University of Texas Southwestern
Kelly Hunt: M. D. Anderson Cancer Center
John Olson: Duke University Cancer Center
Yu Tao: Washington University
Christopher A. Maher: Washington University
Lucinda L. Fulton: The Genome Institute, Washington University
Robert S. Fulton: The Genome Institute, Washington University
Michelle Harrison: The Genome Institute, Washington University
Ben Oberkfell: The Genome Institute, Washington University
Feiyu Du: The Genome Institute, Washington University
Ryan Demeter: The Genome Institute, Washington University
Tammi L. Vickery: The Genome Institute, Washington University
Adnan Elhammali: BRIGHT Institute, Washington University School of Medicine
Helen Piwnica-Worms: BRIGHT Institute, Washington University School of Medicine
Sandra McDonald: Siteman Cancer Center, Washington University
Mark Watson: Washington University
David J. Dooling: The Genome Institute, Washington University
David Ota: ACOSOG Operations Center, Duke University
Li-Wei Chang: Breast Cancer Program, Washington University
Ron Bose: Siteman Cancer Center, Washington University
Timothy J. Ley: Washington University
David Piwnica-Worms: BRIGHT Institute, Washington University School of Medicine
Joshua M. Stuart: University of California
Richard K. Wilson: Siteman Cancer Center, Washington University
Elaine R. Mardis: Siteman Cancer Center, Washington University

Nature, 2012, vol. 486, issue 7403, 353-360

Abstract: Abstract 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.

Date: 2012
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DOI: 10.1038/nature11143

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