Genetic alterations and oncogenic pathways associated with breast cancer subtypes.
Breast cancers can be divided into subtypes with important implications for prognosis and treatment. We set out to characterize the genetic alterations observed in different breast cancer subtypes and to identify specific candidate genes and pathways associated with subtype biology. mRNA expression levels of estrogen receptor, progesterone receptor, and HER2 were shown to predict marker status determined by immunohistochemistry and to be effective at assigning samples to subtypes. HER2(+) cancers were shown to have the greatest frequency of high-level amplification (independent of the ERBB2 amplicon itself), but triple-negative cancers had the highest overall frequencies of copy gain. Triple-negative cancers also were shown to have more frequent loss of phosphatase and tensin homologue and mutation of RB1, which may contribute to genomic instability. We identified and validated seven regions of copy number alteration associated with different subtypes, and used integrative bioinformatics analysis to identify candidate oncogenes and tumor suppressors, including ERBB2, GRB7, MYST2, PPM1D, CCND1, HDAC2, FOXA1, and RASA1. We tested the candidate oncogene MYST2 and showed that it enhances the anchorage-independent growth of breast cancer cells. The genome-wide and region-specific differences between subtypes suggest the differential activation of oncogenic pathways.
Department of Bioinformatics, Genentech, Inc., South San Francisco, CA, USA.
Xiaolan
X
Hu
Howard M
HM
Stern
Lin
L
Ge
Carol
C
O'Brien
Lauren
L
Haydu
Cynthia D
CD
Honchell
Peter M
PM
Haverty
Brock A
BA
Peters
Thomas D
TD
Wu
Lukas C
LC
Amler
John
J
Chant
David
D
Stokoe
Mark R
MR
Lackner
Guy
G
Cavet
D000328:Adult; D000368:Aged; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000145:classification* / Q000235:genetics* / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D018275:Carcinoma, Lobular / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D003114:Colony-Forming Units Assay; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D042822:Genomic Instability; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D034741:RNA, Small Interfering; D051548:Histone Acetyltransferases; C496553:KAT7 protein, human