Whole―genome analysis informs breast cancer response to aromatase inhibition

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 significa...

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Bibliographic Details
Published in:	Nature (London) 2012-06, Vol.486 (7403), p.353-360
Main Authors:	ELLIS, Matthew J, LI DING, NG, Sam, LI LIN, CROWDER, Robert, SNIDER, Jacqueline, BALLMAN, Karla, WEBER, Jason, KEN CHEN, KOBOLDT, Daniel C, KANDOTH, Cyriac, SCHIERDING, William S, DONG SHEN, MCMICHAEL, Joshua F, MILLER, Christopher A, LU, Charles, HARRIS, Christopher C, MCLELLAN, Michael D, WENDL, Michael C, DESCHRYVER, Katherine, CRAIG ALLRED, D, ESSERMAN, Laura, UNZEITIG, Gary, JINGQIN LUO, MARGENTHALER, Julie, BABIERA, G. V, KELLY MARCOM, P, GUENTHER, J. M, LEITCH, Marilyn, HUNT, Kelly, OLSON, John, YU TAO, MAHER, Christopher A, FULTON, Lucinda L, SUMAN, Vera J, FULTON, Robert S, HARRISON, Michelle, OBERKFELL, Ben, FEIYU DU, DEMETER, Ryan, VICKERY, TammiL, ELHAMMALI, Adnan, PIWNICA-WORMS, Helen, MCDONALD, Sandra, WATSON, Mark, WALLIS, John W, DOOLING, David J, OTA, David, CHANG, Li-Wei, BOSE, Ron, LEY, Timothy J, PIWNICA-WORMS, David, STUART, Joshua M, WILSON, Richard K, MARDIS, Elaine R, VAN TINE, Brian A, HOOG, Jeremy, GOIFFON, Reece J, GOLDSTEIN, Theodore C
Format:	Article
Language:	eng
Subjects:	Anastrozole Androstadienes - pharmacology Androstadienes - therapeutic use Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Aromatase - metabolism Aromatase Inhibitors - therapeutic use Binding sites Biological and medical sciences Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Classical genetics, quantitative genetics, hybrids DNA Repair Drug therapy Exome - genetics Exons - genetics Female Fundamental and applied biological sciences. Psychology Gene expression Gene mutations Genetic aspects Genetic Variation - genetics Genetics Genetics of eukaryotes. Biological and molecular evolution Genome, Human - genetics Genomes Health aspects Human Humans Kinases Letrozole MAP Kinase Kinase 4 - genetics MAP Kinase Kinase Kinase 1 - genetics Mutation Mutation - genetics Nitriles - pharmacology Nitriles - therapeutic use Receptors, Estrogen - metabolism Surgical outcomes Treatment Outcome Triazoles - pharmacology Triazoles - therapeutic use Tumors
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Summary:	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.
ISSN:	0028-0836 1476-4687