Significant over-representation of pathway gene sets for a given gene list
Uveal Melanoma (Primary solid tumor)
28 January 2016 | analyses__2016_01_28
Maintainer Information
Citation Information
doi:10.7908/C10G3JPM
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2016): Significant over-representation of pathway gene sets for a given gene list. Broad Institute of MIT and Harvard. doi:10.7908/C10G3JPM
Overview
Introduction

This pipeline inspects significant overlapping pathway gene sets for a given gene list using a hypergeometric test. For the gene set database, we uses GSEA MSigDB Class2: Canonical Pathways DB as a gene set data. Further details about the MsigDB gene sets, please visit The Broad Institute GSEA MsigDB

Summary

For a given gene list, a hypergeometric test was tried to find significant overlapping canonical pathways using 1320 gene sets. In terms of FDR adjusted p.values, top 5 significant overlapping gene sets are listed as below.

- PID_ENDOTHELINPATHWAY, PID_TXA2PATHWAY, REACTOME_REGULATION_OF_INSULIN_SECRETION_BY_ACETYLCHOLINE, PID_THROMBIN_PAR4_PATHWAY, KEGG_CALCIUM_SIGNALING_PATHWAY

Results
For a given gene list, top significant overlapping canonical pathway gene sets

Table 1. Get Full Table This table shows significant gene sets in which at least one gene is found and its FDR adjusted p.value is smaller than 0.3. the hypergeometric p-value is a probability of randomly drawing x or more successes(gene overlaps in gene set database) from the population (gene universe consisting of N number of genes) in k total draws(the number of input genes). The hypergeometric test is identical to the corresponding one-tailed version of Fisher's exact test. That is, P(X=x) = f(x| N,m,k). The FDR q.value was obtained for 1320 multiple comparison.

GS(gene set) pathway name | gene.list | GS size (m) | n.NotInGS (n) | Gene universe (N) | n.drawn (k) | n.found (x) | p.value (p(X>=x)) | FDR (q.value)
--- | --- | --- | --- | --- | --- | --- | --- | ---
PID ENDOTHELINPATHWAY | gene.list | 63 | 45893 | 45956 | 10 | 3 | 2.926e-07 | 0.0001931
PID TXA2PATHWAY | gene.list | 57 | 45899 | 45956 | 10 | 3 | 2.157e-07 | 0.0001931
REACTOME REGULATION OF INSULIN SECRETION BY ACETYLCHOLINE | gene.list | 11 | 45945 | 45956 | 10 | 2 | 2.341e-06 | 0.0010300
PID THROMBIN PAR4 PATHWAY | gene.list | 15 | 45941 | 45956 | 10 | 2 | 4.468e-06 | 0.0014740
KEGG CALCIUM SIGNALING PATHWAY | gene.list | 178 | 45778 | 45956 | 10 | 3 | 6.720e-06 | 0.0015300
PID S1P META PATHWAY | gene.list | 21 | 45935 | 45956 | 10 | 2 | 8.930e-06 | 0.0015300
PID S1P S1P2 PATHWAY | gene.list | 24 | 45932 | 45956 | 10 | 2 | 1.173e-05 | 0.0015300
REACTOME GASTRIN CREB SIGNALLING PATHWAY VIA PKC AND MAPK | gene.list | 205 | 45751 | 45956 | 10 | 3 | 1.026e-05 | 0.0015300
REACTOME G ALPHA Q SIGNALLING EVENTS | gene.list | 184 | 45772 | 45956 | 10 | 3 | 7.422e-06 | 0.0015300
REACTOME ADP SIGNALLING THROUGH P2RY1 | gene.list | 25 | 45931 | 45956 | 10 | 2 | 1.275e-05 | 0.0015300
REACTOME THROMBOXANE SIGNALLING THROUGH TP RECEPTOR | gene.list | 23 | 45933 | 45956 | 10 | 2 | 1.076e-05 | 0.0015300
PID S1P S1P3 PATHWAY | gene.list | 29 | 45927 | 45956 | 10 | 2 | 1.725e-05 | 0.0018970
REACTOME SIGNAL AMPLIFICATION | gene.list | 31 | 45925 | 45956 | 10 | 2 | 1.975e-05 | 0.0019860
REACTOME THROMBIN SIGNALLING THROUGH PROTEINASE ACTIVATED RECEPTORS PARS | gene.list | 32 | 45924 | 45956 | 10 | 2 | 2.106e-05 | 0.0019860
ST ADRENERGIC | gene.list | 36 | 45920 | 45956 | 10 | 2 | 2.674e-05 | 0.0022060
PID ARF6 PATHWAY | gene.list | 35 | 45921 | 45956 | 10 | 2 | 2.526e-05 | 0.0022060
PID ER NONGENOMIC PATHWAY | gene.list | 41 | 45915 | 45956 | 10 | 2 | 3.479e-05 | 0.0027010
PID THROMBIN PAR1 PATHWAY | gene.list | 43 | 45913 | 45956 | 10 | 2 | 3.830e-05 | 0.0028090
PID LYSOPHOSPHOLIPID PATHWAY | gene.list | 66 | 45890 | 45956 | 10 | 2 | 9.073e-05 | 0.0063040
KEGG LONG TERM DEPRESSION | gene.list | 70 | 45886 | 45956 | 10 | 2 | 1.021e-04 | 0.0067390

Figure 1. Get High-res Image This figure is an event heatmap indicating gene matches across gene sets

Methods & Data
Input

- Gene set database = c2.cp.v4.0.symbols.gmt

- Input gene list = MutSig2CV.input.genenames.txt

Hypergeometric Test

For a given gene list, it uses a hypergeometric test to get a significance of each overlapping pathway gene set. The hypergeometric p-value is obtained by R library function phyper() and is defined as a probability of randomly drawing x or more successes(gene matches) from the population consisting N genes in k(the input genes) total draws.

- a cumulative p-value using the R function phyper():

- ex). a probability to see at least x genes in the group is defined as p(X>=x) = 1 - p(X<=x)= 1 - phyper(x-1, m, n, k, lower.tail=FALSE, log.p=FALSE) that is, f(x| N, m, k) = (m) C (k) * ((N-m) C (n-k)) / ((N) C (n))

- The hypergeometric test is identical to the corresponding one-tailed version of Fisher's exact test.

- ex). Fisher' exact test = matrix(c(n.Found, n.GS-n.Found, n.drawn-n.Found, n.NotGS- (n.drawn-n.Found)), nrow=2, dimnames = list(inputGenes = c("Found", "NotFound"),GeneUniverse = c("GS", "nonGS")) )

Download Results

In addition to the links below, the full results of the analysis summarized in this report can also be downloaded programmatically using firehose_get, or interactively from either the Broad GDAC website or TCGA Data Coordination Center Portal.

- Analysis Results (MD5 checksum)

- Auxiliary Data (MD5 checksum)

- MAGE-TAB File (MD5 checksum)

References
[1] Johnson, N.L., et al, Univariate Discrete Distributions, Second Edition, Wiley (1992)
[2] Berkopec, Aleš, HyperQuick algorithm for discrete hypergeometric distribution, Journal of Discrete Algorithms:341-347 (2007)
[3] Tamayo, et al, Molecular Signatures Database, MSigDB, PNAS:15545-15550 (2005)
[4] The GSEA MSigDB Compute overlaps
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