Gene Set Enrichment Analysis: a Knowledge-based Approach for Interpreting Genome-wide Expression Profiles

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2005 Oct 4

PMID 16199517

Citations 27789

Authors

Aravind Subramanian

Pablo Tamayo

Vamsi K Mootha

Sayan Mukherjee

Benjamin L Ebert

Michael A Gillette

Amanda Paulovich

Scott L Pomeroy

Todd R Golub

Eric S Lander

Jill P Mesirov

Affiliations

Soon will be listed here.

Abstract

Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

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References

Armstrong S, Staunton J, Silverman L, Pieters R, den Boer M, Minden M . MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 2001; 30(1):41-7. DOI: 10.1038/ng765. View

Xie X, Lu J, Kulbokas E, Golub T, Mootha V, Lindblad-Toh K . Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals. Nature. 2005; 434(7031):338-45. PMC: 2923337. DOI: 10.1038/nature03441. View

Peng T, Golub T, Sabatini D . The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol Cell Biol. 2002; 22(15):5575-84. PMC: 133939. DOI: 10.1128/MCB.22.15.5575-5584.2002. View

Beer D, Kardia S, Huang C, Giordano T, Levin A, Misek D . Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med. 2002; 8(8):816-24. DOI: 10.1038/nm733. View

Acker T, Plate K . A role for hypoxia and hypoxia-inducible transcription factors in tumor physiology. J Mol Med (Berl). 2002; 80(9):562-75. DOI: 10.1007/s00109-002-0355-1. View

Morelli C, Karayianni E, Magnanini C, Mungall A, Thorland E, Negrini M . Cloning and characterization of the common fragile site FRA6F harboring a replicative senescence gene and frequently deleted in human tumors. Oncogene. 2002; 21(47):7266-76. DOI: 10.1038/sj.onc.1205573. View

Plath K, Mlynarczyk-Evans S, Nusinow D, Panning B . Xist RNA and the mechanism of X chromosome inactivation. Annu Rev Genet. 2002; 36:233-78. DOI: 10.1146/annurev.genet.36.042902.092433. View

Doniger S, Salomonis N, Dahlquist K, Vranizan K, Lawlor S, Conklin B . MAPPFinder: using Gene Ontology and GenMAPP to create a global gene-expression profile from microarray data. Genome Biol. 2003; 4(1):R7. PMC: 151291. DOI: 10.1186/gb-2003-4-1-r7. View

Reiner A, Yekutieli D, Benjamini Y . Identifying differentially expressed genes using false discovery rate controlling procedures. Bioinformatics. 2003; 19(3):368-75. DOI: 10.1093/bioinformatics/btf877. View

10.

Barbouti A, Hoglund M, Johansson B, Lassen C, Nilsson P, Hagemeijer A . A novel gene, MSI2, encoding a putative RNA-binding protein is recurrently rearranged at disease progression of chronic myeloid leukemia and forms a fusion gene with HOXA9 as a result of the cryptic t(7;17)(p15;q23). Cancer Res. 2003; 63(6):1202-6. View

11.

Smith L, Coller H, Roberts J . Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. Nat Cell Biol. 2003; 5(5):474-9. DOI: 10.1038/ncb985. View

12.

Mootha V, Lindgren C, Eriksson K, Subramanian A, Sihag S, Lehar J . PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003; 34(3):267-73. DOI: 10.1038/ng1180. View

13.

Patti M, Butte A, Crunkhorn S, Cusi K, Berria R, Kashyap S . Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A. 2003; 100(14):8466-71. PMC: 166252. DOI: 10.1073/pnas.1032913100. View

14.

Disteche C, Filippova G, Tsuchiya K . Escape from X inactivation. Cytogenet Genome Res. 2003; 99(1-4):36-43. DOI: 10.1159/000071572. View

15.

Lamb J, Ramaswamy S, Ford H, Contreras B, Martinez R, Kittrell F . A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer. Cell. 2003; 114(3):323-34. DOI: 10.1016/s0092-8674(03)00570-1. View

16.

Fortunel N, Otu H, Ng H, Chen J, Mu X, Chevassut T . Comment on " 'Stemness': transcriptional profiling of embryonic and adult stem cells" and "a stem cell molecular signature". Science. 2003; 302(5644):393. DOI: 10.1126/science.1086384. View

17.

Berriz G, King O, Bryant B, Sander C, Roth F . Characterizing gene sets with FuncAssociate. Bioinformatics. 2003; 19(18):2502-4. DOI: 10.1093/bioinformatics/btg363. View

18.

Boffa D, Luan F, Thomas D, Yang H, Sharma V, Lagman M . Rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer. Clin Cancer Res. 2004; 10(1 Pt 1):293-300. DOI: 10.1158/1078-0432.ccr-0629-3. View

19.

Petersen K, Dufour S, Befroy D, Garcia R, Shulman G . Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med. 2004; 350(7):664-71. PMC: 2995502. DOI: 10.1056/NEJMoa031314. View

20.

Mrozek K, Heerema N, Bloomfield C . Cytogenetics in acute leukemia. Blood Rev. 2004; 18(2):115-36. DOI: 10.1016/S0268-960X(03)00040-7. View