Mutation Analysis (MutSig v2.0)
Glioblastoma Multiforme (Primary solid tumor)
23 September 2013  |  analyses__2013_09_23
Maintainer Information
Citation Information
doi:10.7908/C1DZ06M0
Maintained by Dan DiCara (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2013): Mutation Analysis (MutSig v2.0). Broad Institute of MIT and Harvard. doi:10.7908/C1DZ06M0
Overview
Introduction

This report serves to describe the mutational landscape and properties of a given individual set, as well as rank genes and genesets according to mutational significance. MutSig v2.0 was used to generate the results found in this report.

  • Working with individual set: GBM-TP

  • Number of patients in set: 283

Input

The input for this pipeline is a set of individuals with the following files associated for each:

  1. An annotated .maf file describing the mutations called for the respective individual, and their properties.

  2. A .wig file that contains information about the coverage of the sample.

Summary

  • MAF used for this analysis:GBM-TP.final_analysis_set.maf

  • Significantly mutated genes (q ≤ 0.1): 92

  • Mutations seen in COSMIC: 470

  • Significantly mutated genes in COSMIC territory: 74

  • Genes with clustered mutations (≤ 3 aa apart): 273

  • Significantly mutated genesets: 118

  • Significantly mutated genesets: (excluding sig. mutated genes):0

Mutation Preprocessing

  • Read 283 MAFs of type "Broad"

  • Total number of mutations in input MAFs: 21510

Mutation Filtering

  • Number of mutations before filtering: 21510

  • After removing 589 mutations outside gene set: 20921

  • After removing 12 mutations outside category set: 20909

Results
Breakdown of Mutations by Type

Table 1.  Get Full Table Table representing breakdown of mutations by type.

type count
Frame_Shift_Del 534
Frame_Shift_Ins 206
In_Frame_Del 205
In_Frame_Ins 27
Missense_Mutation 13483
Nonsense_Mutation 808
Nonstop_Mutation 11
Silent 5240
Splice_Site 342
Translation_Start_Site 53
Total 20909
Breakdown of Mutation Rates by Category Type

Table 2.  Get Full Table A breakdown of mutation rates per category discovered for this individual set.

category n N rate rate_per_mb relative_rate exp_ns_s_ratio
*CpG->T 5501 471456280 0.000012 12 6.3 2.1
*Cp(A/C/T)->T 2408 3846173156 6.3e-07 0.63 0.34 1.7
A->G 1689 4141354039 4.1e-07 0.41 0.22 2.3
transver 3937 8458983475 4.7e-07 0.47 0.25 5
indel+null 2122 8458983475 2.5e-07 0.25 0.14 NaN
double_null 12 8458983475 1.4e-09 0.0014 0.00077 NaN
Total 15669 8458983475 1.9e-06 1.9 1 3.5
Target Coverage for Each Individual

The x axis represents the samples. The y axis represents the exons, one row per exon, and they are sorted by average coverage across samples. For exons with exactly the same average coverage, they are sorted next by the %GC of the exon. (The secondary sort is especially useful for the zero-coverage exons at the bottom).

Figure 1. 

Distribution of Mutation Counts, Coverage, and Mutation Rates Across Samples

Figure 2.  Patients counts and rates file used to generate this plot: GBM-TP.patients.counts_and_rates.txt

Lego Plots

The mutation spectrum is depicted in the lego plots below in which the 96 possible mutation types are subdivided into six large blocks, color-coded to reflect the base substitution type. Each large block is further subdivided into the 16 possible pairs of 5' and 3' neighbors, as listed in the 4x4 trinucleotide context legend. The height of each block corresponds to the mutation frequency for that kind of mutation (counts of mutations normalized by the base coverage in a given bin). The shape of the spectrum is a signature for dominant mutational mechanisms in different tumor types.

Figure 3.  Get High-res Image SNV Mutation rate lego plot for entire set. Each bin is normalized by base coverage for that bin. Colors represent the six SNV types on the upper right. The three-base context for each mutation is labeled in the 4x4 legend on the lower right. The fractional breakdown of SNV counts is shown in the pie chart on the upper left. If this figure is blank, not enough information was provided in the MAF to generate it.

Figure 4.  Get High-res Image SNV Mutation rate lego plots for 4 slices of mutation allele fraction (0<=AF<0.1, 0.1<=AF<0.25, 0.25<=AF<0.5, & 0.5<=AF) . The color code and three-base context legends are the same as the previous figure. If this figure is blank, not enough information was provided in the MAF to generate it.

CoMut Plot

Figure 5.  Get High-res Image The matrix in the center of the figure represents individual mutations in patient samples, color-coded by type of mutation, for the significantly mutated genes. The rate of synonymous and non-synonymous mutations is displayed at the top of the matrix. The barplot on the left of the matrix shows the number of mutations in each gene. The percentages represent the fraction of tumors with at least one mutation in the specified gene. The barplot to the right of the matrix displays the q-values for the most significantly mutated genes. The purple boxplots below the matrix (only displayed if required columns are present in the provided MAF) represent the distributions of allelic fractions observed in each sample. The plot at the bottom represents the base substitution distribution of individual samples, using the same categories that were used to calculate significance.

Significantly Mutated Genes

Column Descriptions:

  • N = number of sequenced bases in this gene across the individual set

  • n = number of (nonsilent) mutations in this gene across the individual set

  • npat = number of patients (individuals) with at least one nonsilent mutation

  • nsite = number of unique sites having a non-silent mutation

  • nsil = number of silent mutations in this gene across the individual set

  • n1 = number of nonsilent mutations of type: *CpG->T

  • n2 = number of nonsilent mutations of type: *Cp(A/C/T)->T

  • n3 = number of nonsilent mutations of type: A->G

  • n4 = number of nonsilent mutations of type: transver

  • n5 = number of nonsilent mutations of type: indel+null

  • n6 = number of nonsilent mutations of type: double_null

  • p_classic = p-value for the observed amount of nonsilent mutations being elevated in this gene

  • p_ns_s = p-value for the observed nonsilent/silent ratio being elevated in this gene

  • p_cons = p-value for enrichment of mutations at evolutionarily most-conserved sites in gene

  • p_joint = p-value for clustering + conservation

  • p = p-value (overall)

  • q = q-value, False Discovery Rate (Benjamini-Hochberg procedure)

Table 3.  Get Full Table A Ranked List of Significantly Mutated Genes. Number of significant genes found: 92. Number of genes displayed: 35. Click on a gene name to display its stick figure depicting the distribution of mutations and mutation types across the chosen gene (this feature may not be available for all significant genes).

rank gene description N n npat nsite nsil n1 n2 n3 n4 n5 n6 p_classic p_ns_s p_clust p_cons p_joint p q
1 PIK3R1 phosphoinositide-3-kinase, regulatory subunit 1 (alpha) 668244 33 32 27 0 0 3 4 7 19 0 3.00e-15 0.0059 3.6e-06 0.085 4.8e-06 0.000 0.000
2 PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1) 337830 90 87 73 0 5 20 10 13 42 0 <1.00e-15 1.9e-09 0.0045 0.39 0.014 <5.55e-16 <2.88e-12
3 TP53 tumor protein p53 358092 96 79 59 1 29 15 11 23 18 0 <1.00e-15 2.8e-11 0 0 0 <1.00e-15 <2.88e-12
4 EGFR epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian) 1131442 92 74 44 7 10 44 2 32 4 0 2.89e-15 1.1e-08 0 0 0 <1.00e-15 <2.88e-12
5 IDH1 isocitrate dehydrogenase 1 (NADP+), soluble 361231 14 14 2 0 13 0 0 1 0 0 1.92e-14 0.0076 0 0.83 0 <1.00e-15 <2.88e-12
6 BRAF v-raf murine sarcoma viral oncogene homolog B1 631073 6 6 2 1 0 1 0 5 0 0 0.000315 0.62 0 0.08 0 <1.00e-15 <2.88e-12
7 RB1 retinoblastoma 1 (including osteosarcoma) 752003 26 25 24 1 1 0 0 2 22 1 1.78e-15 0.074 0.044 0.023 0.017 1.11e-15 2.88e-12
8 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 924699 33 30 28 0 5 8 7 6 7 0 2.33e-15 0.00033 0.012 0.17 0.014 1.33e-15 3.02e-12
9 NF1 neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease) 2457594 30 29 30 1 0 2 1 1 21 5 5.22e-15 0.011 0.16 0.95 0.26 4.71e-14 9.48e-11
10 SPTA1 spectrin, alpha, erythrocytic 1 (elliptocytosis 2) 2111845 28 26 27 0 11 4 1 9 3 0 3.33e-15 0.0016 0.53 0.4 0.72 8.26e-14 1.50e-10
11 KRTAP4-11 keratin associated protein 4-11 148621 13 13 8 1 1 4 2 6 0 0 1.68e-14 0.092 0.07 1 0.16 9.09e-14 1.50e-10
12 GABRA6 gamma-aminobutyric acid (GABA) A receptor, alpha 6 395438 11 11 10 1 4 2 1 4 0 0 2.86e-11 0.11 0.73 0.34 0.76 5.53e-10 8.36e-07
13 KEL Kell blood group, metallo-endopeptidase 639794 15 15 12 2 8 0 1 3 3 0 2.13e-10 0.19 0.45 0.88 0.61 3.07e-09 4.28e-06
14 PRB2 proline-rich protein BstNI subfamily 2 357375 6 6 2 0 0 0 0 0 6 0 1.10e-06 1 0.00042 0.57 0.0015 3.54e-08 4.58e-05
15 CDH18 cadherin 18, type 2 682827 11 11 10 0 3 3 0 4 1 0 1.35e-08 0.048 0.073 0.71 0.14 4.00e-08 4.83e-05
16 SEMG1 semenogelin I 395351 9 9 8 0 6 0 2 0 1 0 6.37e-09 0.087 0.42 0.29 0.52 6.86e-08 7.77e-05
17 RPL5 ribosomal protein L5 261806 7 7 7 0 0 1 1 0 5 0 1.99e-08 0.28 0.44 0.072 0.19 7.65e-08 8.16e-05
18 SEMA3C sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3C 654951 11 11 11 1 3 0 2 5 1 0 8.99e-09 0.22 0.44 0.52 0.59 1.07e-07 0.000108
19 TPTE2 transmembrane phosphoinositide 3-phosphatase and tensin homolog 2 464692 8 8 6 0 2 1 0 2 3 0 3.53e-07 0.1 0.028 0.021 0.02 1.37e-07 0.000130
20 KRTAP4-9 keratin associated protein 4-9 147031 6 6 3 1 0 0 1 5 0 0 6.68e-08 0.62 0.079 0.96 0.17 2.17e-07 0.000197
21 ZNF844 zinc finger protein 844 435135 6 6 3 1 0 0 2 4 0 0 3.84e-05 0.5 0.000066 1 0.00036 2.65e-07 0.000229
22 OR5AR1 olfactory receptor, family 5, subfamily AR, member 1 264117 7 7 7 0 3 0 2 2 0 0 8.67e-08 0.18 0.38 0.077 0.18 2.99e-07 0.000239
23 ZNF814 zinc finger protein 814 588092 11 11 3 3 0 2 0 9 0 0 0.00149 0.85 2.8e-06 1 0.000011 3.15e-07 0.000239
24 OR8K3 olfactory receptor, family 8, subfamily K, member 3 265683 7 7 7 1 2 2 0 2 1 0 2.52e-08 0.32 0.48 0.93 0.66 3.17e-07 0.000239
25 STAG2 stromal antigen 2 1110411 12 12 12 0 0 0 0 2 10 0 4.89e-08 0.19 0.29 0.59 0.45 4.14e-07 0.000300
26 ANKRD36 ankyrin repeat domain 36 660121 5 5 1 0 0 0 0 5 0 0 0.00408 0.42 0 0.86 7e-06 5.24e-07 0.000366
27 CDC27 cell division cycle 27 homolog (S. cerevisiae) 715613 7 6 3 0 0 0 1 0 6 0 0.000210 0.61 0.00028 0.036 0.00025 9.50e-07 0.000638
28 PDGFRA platelet-derived growth factor receptor, alpha polypeptide 950298 13 11 12 1 0 5 2 4 2 0 6.34e-07 0.096 0.086 0.25 0.14 1.50e-06 0.000972
29 ADAM29 ADAM metallopeptidase domain 29 698127 9 9 8 1 6 0 0 2 1 0 4.29e-07 0.34 0.35 0.58 0.51 3.57e-06 0.00223
30 WNT2 wingless-type MMTV integration site family member 2 311956 5 5 5 0 3 0 0 1 1 0 0.000378 0.2 0.003 0.03 0.00066 4.06e-06 0.00245
31 SULT1B1 sulfotransferase family, cytosolic, 1B, member 1 257699 7 6 7 1 0 2 1 3 1 0 1.03e-06 0.36 0.16 0.86 0.27 4.52e-06 0.00265
32 NLRP5 NLR family, pyrin domain containing 5 962338 12 12 11 2 9 0 1 2 0 0 3.56e-06 0.11 0.35 0.035 0.089 5.06e-06 0.00281
33 ABCC9 ATP-binding cassette, sub-family C (CFTR/MRP), member 9 1396433 14 11 14 1 4 0 3 5 2 0 7.89e-06 0.1 0.02 0.36 0.041 5.11e-06 0.00281
34 MUC4 mucin 4, cell surface associated 927343 14 13 10 2 5 2 1 6 0 0 7.00e-07 0.12 0.72 0.54 0.68 7.36e-06 0.00392
35 LZTR1 leucine-zipper-like transcription regulator 1 647961 10 10 10 0 4 0 1 4 1 0 3.96e-06 0.08 0.29 0.18 0.24 1.43e-05 0.00741
PIK3R1

Figure S1.  This figure depicts the distribution of mutations and mutation types across the PIK3R1 significant gene.

PTEN

Figure S2.  This figure depicts the distribution of mutations and mutation types across the PTEN significant gene.

TP53

Figure S3.  This figure depicts the distribution of mutations and mutation types across the TP53 significant gene.

EGFR

Figure S4.  This figure depicts the distribution of mutations and mutation types across the EGFR significant gene.

IDH1

Figure S5.  This figure depicts the distribution of mutations and mutation types across the IDH1 significant gene.

BRAF

Figure S6.  This figure depicts the distribution of mutations and mutation types across the BRAF significant gene.

RB1

Figure S7.  This figure depicts the distribution of mutations and mutation types across the RB1 significant gene.

PIK3CA

Figure S8.  This figure depicts the distribution of mutations and mutation types across the PIK3CA significant gene.

NF1

Figure S9.  This figure depicts the distribution of mutations and mutation types across the NF1 significant gene.

SPTA1

Figure S10.  This figure depicts the distribution of mutations and mutation types across the SPTA1 significant gene.

KRTAP4-11

Figure S11.  This figure depicts the distribution of mutations and mutation types across the KRTAP4-11 significant gene.

GABRA6

Figure S12.  This figure depicts the distribution of mutations and mutation types across the GABRA6 significant gene.

KEL

Figure S13.  This figure depicts the distribution of mutations and mutation types across the KEL significant gene.

CDH18

Figure S14.  This figure depicts the distribution of mutations and mutation types across the CDH18 significant gene.

SEMG1

Figure S15.  This figure depicts the distribution of mutations and mutation types across the SEMG1 significant gene.

RPL5

Figure S16.  This figure depicts the distribution of mutations and mutation types across the RPL5 significant gene.

SEMA3C

Figure S17.  This figure depicts the distribution of mutations and mutation types across the SEMA3C significant gene.

TPTE2

Figure S18.  This figure depicts the distribution of mutations and mutation types across the TPTE2 significant gene.

KRTAP4-9

Figure S19.  This figure depicts the distribution of mutations and mutation types across the KRTAP4-9 significant gene.

ZNF844

Figure S20.  This figure depicts the distribution of mutations and mutation types across the ZNF844 significant gene.

OR5AR1

Figure S21.  This figure depicts the distribution of mutations and mutation types across the OR5AR1 significant gene.

ZNF814

Figure S22.  This figure depicts the distribution of mutations and mutation types across the ZNF814 significant gene.

OR8K3

Figure S23.  This figure depicts the distribution of mutations and mutation types across the OR8K3 significant gene.

STAG2

Figure S24.  This figure depicts the distribution of mutations and mutation types across the STAG2 significant gene.

ANKRD36

Figure S25.  This figure depicts the distribution of mutations and mutation types across the ANKRD36 significant gene.

CDC27

Figure S26.  This figure depicts the distribution of mutations and mutation types across the CDC27 significant gene.

PDGFRA

Figure S27.  This figure depicts the distribution of mutations and mutation types across the PDGFRA significant gene.

ADAM29

Figure S28.  This figure depicts the distribution of mutations and mutation types across the ADAM29 significant gene.

WNT2

Figure S29.  This figure depicts the distribution of mutations and mutation types across the WNT2 significant gene.

SULT1B1

Figure S30.  This figure depicts the distribution of mutations and mutation types across the SULT1B1 significant gene.

NLRP5

Figure S31.  This figure depicts the distribution of mutations and mutation types across the NLRP5 significant gene.

ABCC9

Figure S32.  This figure depicts the distribution of mutations and mutation types across the ABCC9 significant gene.

MUC4

Figure S33.  This figure depicts the distribution of mutations and mutation types across the MUC4 significant gene.

COSMIC analyses

In this analysis, COSMIC is used as a filter to increase power by restricting the territory of each gene. Cosmic version: v48.

Table 4.  Get Full Table Significantly mutated genes (COSMIC territory only). To access the database please go to: COSMIC. Number of significant genes found: 74. Number of genes displayed: 10

rank gene description n cos n_cos N_cos cos_ev p q
1 TP53 tumor protein p53 96 356 92 100748 26305 0 0
2 PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1) 90 767 88 217061 3057 0 0
3 IDH1 isocitrate dehydrogenase 1 (NADP+), soluble 14 5 14 1415 20888 5.8e-14 8.7e-11
4 PIK3R1 phosphoinositide-3-kinase, regulatory subunit 1 (alpha) 33 33 13 9339 25 3.7e-13 4.2e-10
5 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 33 220 25 62260 5654 2.3e-12 1.6e-09
6 RB1 retinoblastoma 1 (including osteosarcoma) 26 267 17 75561 60 2.7e-12 1.6e-09
7 NF1 neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease) 30 285 11 80655 23 2.8e-12 1.6e-09
8 EGFR epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian) 92 293 70 82919 1144 2.9e-12 1.6e-09
9 BRAF v-raf murine sarcoma viral oncogene homolog B1 6 89 6 25187 71896 1.5e-11 7.4e-09
10 CHEK2 CHK2 checkpoint homolog (S. pombe) 4 2 3 566 3 1.9e-10 8.6e-08

Note:

n - number of (nonsilent) mutations in this gene across the individual set.

cos = number of unique mutated sites in this gene in COSMIC

n_cos = overlap between n and cos.

N_cos = number of individuals times cos.

cos_ev = total evidence: number of reports in COSMIC for mutations seen in this gene.

p = p-value for seeing the observed amount of overlap in this gene)

q = q-value, False Discovery Rate (Benjamini-Hochberg procedure)

Clustered Mutations

Table 5.  Get Full Table Genes with Clustered Mutations

num gene desc n mindist nmuts0 nmuts3 nmuts12 npairs0 npairs3 npairs12
2106 EGFR epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian) 92 0 304 377 411 304 377 411
7180 TP53 tumor protein p53 96 0 91 215 526 91 215 526
3142 IDH1 isocitrate dehydrogenase 1 (NADP+), soluble 14 0 91 91 91 91 91 91
5657 PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1) 90 0 37 94 222 37 94 222
7961 ZNF814 zinc finger protein 814 11 0 36 36 36 36 36 36
4407 NBPF10 neuroblastoma breakpoint family, member 10 16 0 21 21 21 21 21 21
5474 POTEC POTE ankyrin domain family, member C 12 0 12 12 12 12 12 12
5305 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 33 0 11 32 44 11 32 44
5308 PIK3R1 phosphoinositide-3-kinase, regulatory subunit 1 (alpha) 33 0 11 26 34 11 26 34
4290 MUC4 mucin 4, cell surface associated 14 0 10 10 23 10 10 23

Note:

n - number of mutations in this gene in the individual set.

mindist - distance (in aa) between closest pair of mutations in this gene

npairs3 - how many pairs of mutations are within 3 aa of each other.

npairs12 - how many pairs of mutations are within 12 aa of each other.

Geneset Analyses

Table 6.  Get Full Table A Ranked List of Significantly Mutated Genesets. (Source: MSigDB GSEA Cannonical Pathway Set).Number of significant genesets found: 118. Number of genesets displayed: 10

rank geneset description genes N_genes mut_tally N n npat nsite nsil n1 n2 n3 n4 n5 n6 p_ns_s p q
1 MTORPATHWAY Mammalian target of rapamycin (mTOR) senses mitogenic factors and nutrients, including ATP, and induces cell proliferation. AKT1, EIF3S10, EIF4A1, EIF4A2, EIF4B, EIF4E, EIF4EBP1, EIF4G1, EIF4G2, EIF4G3, FKBP1A, FRAP1, MKNK1, PDK2, PDPK1, PIK3CA, PIK3R1, PPP2CA, PTEN, RPS6, RPS6KB1, TSC1, TSC2 21 AKT1(1), EIF4A1(1), EIF4B(1), EIF4G1(1), EIF4G3(1), PIK3CA(33), PIK3R1(33), PTEN(90), TSC2(3) 11773777 164 138 136 2 12 33 21 30 68 0 3.77e-15 <1.00e-15 <5.47e-14
2 G1PATHWAY CDK4/6-cyclin D and CDK2-cyclin E phosphorylate Rb, which allows the transcription of genes needed for the G1/S cell cycle transition. ABL1, ATM, ATR, CCNA1, CCND1, CCNE1, CDC2, CDC25A, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, DHFR, E2F1, GSK3B, HDAC1, MADH3, MADH4, RB1, SKP2, TFDP1, TGFB1, TGFB2, TGFB3, TP53 25 ABL1(2), ATM(4), ATR(4), CCNA1(1), CCNE1(1), CDKN1A(1), CDKN1B(1), CDKN2A(2), CDKN2B(2), GSK3B(1), RB1(26), SKP2(1), TFDP1(1), TP53(96) 12757976 143 103 104 4 31 18 15 34 44 1 3.44e-13 <1.00e-15 <5.47e-14
3 APOPTOSIS_GENMAPP APAF1, BAK1, BCL2L7P1, BAX, BCL2, BCL2L1, BID, BIRC2, BIRC3, BIRC4, CASP2, CASP3, CASP6, CASP7, CASP8, CASP9, CYCS, FADD, FAS, FASLG, GZMB, IKBKG, JUN, MAP2K4, MAP3K1, MAP3K14, MAPK10, MCL1, MDM2, MYC, NFKB1, NFKBIA, PARP1, PRF1, RELA, RIPK1, TNF, TNFRSF1A, TNFRSF1B, TNFSF10, TP53, TRADD, TRAF1, TRAF2 41 BCL2(2), BIRC2(1), BIRC3(1), CASP9(1), GZMB(2), MAP3K1(6), MCL1(1), MDM2(2), MYC(1), NFKB1(1), NFKBIA(1), PARP1(2), RIPK1(1), TNFRSF1A(1), TNFRSF1B(1), TNFSF10(2), TP53(96), TRAF1(1) 15966939 123 95 84 9 35 20 15 29 24 0 2.31e-09 <1.00e-15 <5.47e-14
4 PDGFPATHWAY Platelet-derived growth factor (PDGF) receptor is phosphorylated on ligand binding and promotes cell proliferation. CSNK2A1, ELK1, FOS, GRB2, HRAS, JAK1, JUN, MAP2K1, MAP2K4, MAP3K1, MAPK3, MAPK8, PDGFA, PDGFRA, PIK3CA, PIK3R1, PLCG1, PRKCA, PRKCB1, RAF1, RASA1, SHC1, SOS1, SRF, STAT1, STAT3, STAT5A 26 ELK1(2), FOS(1), JAK1(2), MAP2K1(1), MAP3K1(6), MAPK3(1), PDGFRA(13), PIK3CA(33), PIK3R1(33), PLCG1(6), PRKCA(1), RAF1(1), SOS1(3), SRF(1), STAT1(2), STAT3(1) 14833818 107 91 93 6 10 24 17 24 32 0 3.22e-07 <1.00e-15 <5.47e-14
5 CHEMICALPATHWAY DNA damage promotes Bid cleavage, which stimulates mitochondrial cytochrome c release and consequent caspase activation, resulting in apoptosis. ADPRT, AKT1, APAF1, ATM, BAD, BAX, BCL2, BCL2L1, BID, CASP3, CASP6, CASP7, CASP9, CYCS, EIF2S1, PRKCA, PRKCB1, PTK2, PXN, STAT1, TLN1, TP53 20 AKT1(1), ATM(4), BCL2(2), CASP9(1), PRKCA(1), PXN(1), STAT1(2), TP53(96) 11683717 108 89 71 2 30 16 13 26 23 0 1.18e-11 <1.00e-15 <5.47e-14
6 TERTPATHWAY hTERC, the RNA subunit of telomerase, and hTERT, the catalytic protein subunit, are required for telomerase activity and are overexpressed in many cancers. HDAC1, MAX, MYC, SP1, SP3, TP53, WT1, ZNF42 7 MAX(2), MYC(1), SP1(1), SP3(1), TP53(96), WT1(2) 2998025 103 84 66 3 30 17 11 25 20 0 1.64e-11 <1.00e-15 <5.47e-14
7 CREBPATHWAY CREB is a transcription factor that binds to cAMP-responsive elements (CREs) to activate transcription in response to extracellular signaling. ADCY1, AKT1, CAMK2A, CAMK2B, CAMK2D, CAMK2G, CREB1, GNAS, GRB2, HRAS, MAPK1, MAPK14, MAPK3, PIK3CA, PIK3R1, PRKACB, PRKACG, PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B, PRKCA, PRKCB1, RAC1, RPS6KA1, RPS6KA5, SOS1 26 ADCY1(3), AKT1(1), CAMK2A(1), CREB1(1), MAPK1(2), MAPK3(1), PIK3CA(33), PIK3R1(33), PRKAR1B(1), PRKAR2B(1), PRKCA(1), RPS6KA1(1), RPS6KA5(1), SOS1(3) 12403154 83 74 72 1 13 14 13 16 27 0 4.08e-08 <1.00e-15 <5.47e-14
8 NGFPATHWAY Nerve growth factor (NGF) stimulates neural survival and proliferation via the TrkA and p75 receptors, which induce DAG and IP3 production and activate Ras. CSNK2A1, DPM2, ELK1, FOS, GRB2, HRAS, JUN, KLK2, MAP2K1, MAPK3, MAPK8, NGFB, NGFR, PIK3CA, PIK3R1, PLCG1, RAF1, SHC1, SOS1 18 ELK1(2), FOS(1), MAP2K1(1), MAPK3(1), PIK3CA(33), PIK3R1(33), PLCG1(6), RAF1(1), SOS1(3) 8135723 81 72 70 1 8 13 14 18 28 0 6.60e-08 <1.00e-15 <5.47e-14
9 PLCPATHWAY Phospholipase C hydrolyzes the membrane lipid PIP2 to DAG, which activates protein kinase C, and IP3, which causes calcium influx. AKT1, PIK3CA, PIK3R1, PLCB1, PLCG1, PRKCA, PRKCB1, VAV1 7 AKT1(1), PIK3CA(33), PIK3R1(33), PLCB1(1), PLCG1(6), PRKCA(1), VAV1(4) 5434302 79 70 68 3 8 13 13 16 29 0 8.88e-06 <1.00e-15 <5.47e-14
10 RBPATHWAY The ATM protein kinase recognizes DNA damage and blocks cell cycle progression by phosphorylating chk1 and p53, which normally inhibits Rb to allow G1/S transitions. ATM, CDC2, CDC25A, CDC25B, CDC25C, CDK2, CDK4, CHEK1, MYT1, RB1, TP53, WEE1, YWHAH 12 ATM(4), CHEK1(3), RB1(26), TP53(96), WEE1(1), YWHAH(1) 7486740 131 95 92 2 31 15 14 28 42 1 6.87e-13 1.11e-15 5.47e-14

Table 7.  Get Full Table A Ranked List of Significantly Mutated Genesets (Excluding Significantly Mutated Genes). Number of significant genesets found: 0. Number of genesets displayed: 10

rank geneset description genes N_genes mut_tally N n npat nsite nsil n1 n2 n3 n4 n5 n6 p_ns_s p q
1 IL17PATHWAY Activated T cells secrete IL-17, which stimulates fibroblasts and other cells to secrete inflammatory and hematopoietic cytokines. CD2, CD34, CD3D, CD3E, CD3G, CD3Z, CD4, CD58, CD8A, CSF3, IL17, IL3, IL6, IL8, KITLG, TRA@, TRB@ 13 CD2(1), CD3E(2), CD3G(1), CD4(1), CD58(1), CD8A(1), IL3(1), IL6(1), KITLG(1) 2644975 10 10 10 1 3 1 1 3 2 0 0.15 0.0078 1
2 IL18PATHWAY Pro-inflammatory IL-18 is activated in macrophages by caspase-1 cleavage and, in conjunction with IL-12, stimulates Th1 cell differentiation. CASP1, IFNG, IL12A, IL12B, IL18, IL2 6 CASP1(2), IFNG(2), IL12B(2) 1269839 6 6 6 1 2 1 1 0 2 0 0.34 0.0078 1
3 IFNGPATHWAY IFN gamma signaling pathway IFNG, IFNGR1, IFNGR2, JAK1, JAK2, STAT1 6 IFNG(2), IFNGR1(1), IFNGR2(3), JAK1(2), JAK2(2), STAT1(2) 3472100 12 12 12 0 0 0 3 6 3 0 0.057 0.01 1
4 ACE_INHIBITOR_PATHWAY_PHARMGKB ACE, AGT, AGTR1, AGTR2, BDKRB2, KNG1, NOS3, REN 8 ACE(5), AGT(1), AGTR1(1), AGTR2(1), KNG1(2), NOS3(3), REN(5) 4284311 18 18 17 2 10 2 0 2 4 0 0.04 0.012 1
5 NUCLEOTIDE_SUGARS_METABOLISM GALE, GALT, TGDS, UGDH, UXS1 5 GALE(2), GALT(1), TGDS(1), UGDH(1), UXS1(2) 1665957 7 7 7 0 1 1 1 2 2 0 0.14 0.014 1
6 TCAPOPTOSISPATHWAY HIV infection upregulates Fas ligand in macrophages and CD4 in helper T cells, leading to widespread Fas-induced T cell apoptosis. CCR5, CD28, CD3D, CD3E, CD3G, CD3Z, CD4, TNFRSF6, TNFSF6, TRA@, TRB@ 6 CCR5(1), CD28(1), CD3E(2), CD3G(1), CD4(1) 1364210 6 6 6 1 3 0 1 1 1 0 0.36 0.016 1
7 TCRMOLECULE T Cell Receptor and CD3 Complex CD3D, CD3E, CD3G, CD3Z, TRA@, TRB@ 3 CD3E(2), CD3G(1) 483380 3 3 3 0 0 0 1 1 1 0 0.42 0.016 1
8 HSA00472_D_ARGININE_AND_D_ORNITHINE_METABOLISM Genes involved in D-arginine and D-ornithine metabolism DAO 1 DAO(3) 306178 3 3 3 0 2 1 0 0 0 0 0.3 0.017 1
9 FXRPATHWAY The nuclear receptor transcription factors FXR and LXR are activated by cholesterol metabolites and regulate cholesterol homeostasis. FABP6, LDLR, NR0B2, NR1H3, NR1H4, RXRA 6 FABP6(1), LDLR(3), NR0B2(1), NR1H4(3), RXRA(3) 2319597 11 11 11 2 4 2 0 4 1 0 0.24 0.022 1
10 EOSINOPHILSPATHWAY Recruitment of eosinophils in the inflammatory response observed in asthma occurs via the chemoattractant eotaxin binding to the CCR3 receptor. CCL11, CCL5, CCR3, CSF2, HLA-DRA, HLA-DRB1, IL3, IL5 8 CCR3(1), CSF2(2), HLA-DRA(1), IL3(1) 1289447 5 5 5 0 2 1 1 0 1 0 0.2 0.033 1
Methods & Data
Methods

In brief, we tabulate the number of mutations and the number of covered bases for each gene. The counts are broken down by mutation context category: four context categories that are discovered by MutSig, and one for indel and 'null' mutations, which include indels, nonsense mutations, splice-site mutations, and non-stop (read-through) mutations. For each gene, we calculate the probability of seeing the observed constellation of mutations, i.e. the product P1 x P2 x ... x Pm, or a more extreme one, given the background mutation rates calculated across the dataset. [1]

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.

References
[1] TCGA, Integrated genomic analyses of ovarian carcinoma, Nature 474:609 - 615 (2011)
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