Oncogenic pathway signatures in human cancers as a guide to targeted therapies.
The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.
Bild
Andrea H
AH
Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina 27708, USA.
Yao
Guang
G
Chang
Jeffrey T
JT
Wang
Quanli
Q
Potti
Anil
A
Chasse
Dawn
D
Joshi
Mary-Beth
MB
Harpole
David
D
Lancaster
Johnathan M
JM
Berchuck
Andrew
A
Olson
John A
JA
Marks
Jeffrey R
JR
Dressman
Holly K
HK
West
Mike
M
Nevins
Joseph R
JR
D000818:Animals; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015195:Drug Design; D004847:Epithelial Cells / Q000166:cytology / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy; D051379:Mice; D009369:Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes / Q000235:genetics* / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy; D010597:Pharmacogenetics / Q000379:methods; D015203:Reproducibility of Results; D015398:Signal Transduction; D016019:Survival Analysis