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.
Source: 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 &
Elaine R. Mardis. Nature (2012)
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