Mutation Analysis (MutSig v2.0)
Head and Neck Squamous Cell Carcinoma (Primary solid tumor)
16 April 2014  |  analyses__2014_04_16
Maintainer Information
Citation Information
doi:10.7908/C18S4NJ1
Maintained by Dan DiCara (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2014): Mutation Analysis (MutSig v2.0). Broad Institute of MIT and Harvard. doi:10.7908/C18S4NJ1
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: HNSC-TP

  • Number of patients in set: 306

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:HNSC-TP.final_analysis_set.maf

  • Blacklist used for this analysis: pancan_mutation_blacklist.v14.hg19.txt

  • Significantly mutated genes (q ≤ 0.1): 65

  • Mutations seen in COSMIC: 472

  • Significantly mutated genes in COSMIC territory: 6

  • Significantly mutated genesets: 68

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

Mutation Preprocessing

  • Read 306 MAFs of type "Broad"

  • Total number of mutations in input MAFs: 74008

  • After removing 10 mutations outside chr1-24: 73998

  • After removing 3058 blacklisted mutations: 70940

  • After removing 4120 noncoding mutations: 66820

  • After collapsing adjacent/redundant mutations: 56803

Mutation Filtering

  • Number of mutations before filtering: 56803

  • After removing 732 mutations outside gene set: 56071

  • After removing 53 mutations outside category set: 56018

Results
Breakdown of Mutations by Type

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

type count
Frame_Shift_Del 1236
Frame_Shift_Ins 524
In_Frame_Del 276
In_Frame_Ins 34
Missense_Mutation 36006
Nonsense_Mutation 2883
Nonstop_Mutation 53
Silent 14010
Splice_Site 907
Translation_Start_Site 89
Total 56018
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 5934 498919062 0.000012 12 2.5 2.1
*Cp(A/C/T)->T 9078 4084447193 2.2e-06 2.2 0.48 1.7
C->(G/A) 14129 4583366255 3.1e-06 3.1 0.66 4.8
A->mut 6948 4404728973 1.6e-06 1.6 0.34 3.9
indel+null 5868 8988095228 6.5e-07 0.65 0.14 NaN
double_null 51 8988095228 5.7e-09 0.0057 0.0012 NaN
Total 42008 8988095228 4.7e-06 4.7 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). If the figure is unpopulated, then full coverage is assumed (e.g. MutSig CV doesn't use WIGs and assumes full coverage).

Figure 1. 

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

Figure 2.  Patients counts and rates file used to generate this plot: HNSC-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: C->(G/A)

  • n4 = number of nonsilent mutations of type: A->mut

  • 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: 65. 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 NOTCH1 Notch homolog 1, translocation-associated (Drosophila) 1904576 62 57 62 5 10 10 10 6 26 0 3.22e-15 2.72e-05 0.00018 0.6 0.0005 1.11e-16 2.01e-12
2 TP53 tumor protein p53 375773 244 213 152 5 41 26 39 40 91 7 <1.00e-15 <1.00e-15 0 0 0 <1.00e-15 <3.02e-12
3 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) 255389 65 65 31 0 2 2 2 6 52 1 <1.00e-15 6.52e-08 0 0 0 <1.00e-15 <3.02e-12
4 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 1003706 65 64 24 0 1 40 6 17 1 0 4.66e-15 6.29e-09 0 0.000073 0 <1.00e-15 <3.02e-12
5 NFE2L2 nuclear factor (erythroid-derived 2)-like 2 546479 18 17 13 0 0 4 10 4 0 0 3.57e-11 0.0282 0 2e-07 0 <1.00e-15 <3.02e-12
6 HRAS v-Ha-ras Harvey rat sarcoma viral oncogene homolog 198292 11 10 6 0 2 2 6 1 0 0 2.12e-08 0.0221 0 0.00082 0 <1.00e-15 <3.02e-12
7 FAT1 FAT tumor suppressor homolog 1 (Drosophila) 4166666 77 69 77 2 1 5 7 6 50 8 8.33e-15 3.65e-06 0.31 0.0046 0.024 7.44e-15 1.92e-11
8 CASP8 caspase 8, apoptosis-related cysteine peptidase 533487 27 27 24 0 1 4 2 5 15 0 7.77e-15 0.000959 0.49 0.015 0.078 2.19e-14 4.95e-11
9 JUB jub, ajuba homolog (Xenopus laevis) 357659 19 18 19 1 1 2 0 2 14 0 4.66e-15 0.0729 0.19 0.33 0.28 4.52e-14 9.09e-11
10 MLL2 myeloid/lymphoid or mixed-lineage leukemia 2 4343439 55 53 55 3 4 7 7 2 32 3 5.95e-13 0.000398 0.2 0.074 0.17 3.10e-12 5.62e-09
11 FBXW7 F-box and WD repeat domain containing 7 757876 16 15 14 1 2 2 5 3 4 0 5.97e-08 0.179 3.2e-06 0.58 0.000012 2.08e-11 3.42e-08
12 NSD1 nuclear receptor binding SET domain protein 1 2490988 36 33 36 1 0 2 8 4 20 2 9.96e-10 0.0169 0.0051 0.041 0.007 1.86e-10 2.80e-07
13 BAGE2 B melanoma antigen family, member 2 105801 8 8 7 1 0 4 2 0 2 0 2.52e-08 0.167 0.036 0.0016 0.0056 3.34e-09 4.65e-06
14 ZNF750 zinc finger protein 750 666533 15 13 14 1 1 2 2 2 8 0 1.30e-05 0.133 0.00053 0.0097 4e-05 1.16e-08 1.49e-05
15 RHOA ras homolog gene family, member A 182942 4 4 1 0 0 0 4 0 0 0 0.00280 0.486 1.2e-06 0.058 2.2e-06 1.23e-07 0.000148
16 POM121L12 POM121 transmembrane nucleoporin-like 12 264068 15 14 15 2 4 2 4 3 2 0 7.33e-08 0.104 0.18 0.11 0.11 1.54e-07 0.000174
17 EP300 E1A binding protein p300 2248955 24 24 21 1 3 7 4 4 6 0 4.62e-06 0.00938 0.0017 0.1 0.0022 2.02e-07 0.000215
18 B2M beta-2-microglobulin 113810 7 7 6 0 0 1 1 1 4 0 4.21e-08 0.355 0.37 0.21 0.44 3.47e-07 0.000348
19 POTEC POTE ankyrin domain family, member C 471221 13 13 13 1 2 3 4 3 1 0 6.82e-08 0.111 0.18 0.79 0.33 4.20e-07 0.000400
20 ZNF804B zinc finger protein 804B 1240408 22 21 22 2 4 5 6 5 2 0 3.05e-07 0.0640 0.52 0.034 0.17 9.05e-07 0.000806
21 RAC1 ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) 189570 10 9 8 0 2 3 2 3 0 0 1.58e-07 0.0351 0.4 0.3 0.34 9.48e-07 0.000806
22 KCNT2 potassium channel, subfamily T, member 2 1040701 17 17 16 1 2 1 6 3 5 0 1.46e-06 0.142 0.023 0.48 0.038 9.80e-07 0.000806
23 RASA1 RAS p21 protein activator (GTPase activating protein) 1 928769 14 14 12 0 2 0 3 2 7 0 1.77e-06 0.0560 0.054 0.036 0.036 1.11e-06 0.000876
24 CNTNAP5 contactin associated protein-like 5 1072749 18 15 18 1 0 5 7 4 2 0 9.78e-05 0.0342 0.00099 0.22 0.0017 2.72e-06 0.00205
25 PRIM2 primase, DNA, polypeptide 2 (58kDa) 381394 9 9 9 1 0 2 3 1 3 0 3.65e-05 0.396 0.0023 1 0.0056 3.34e-06 0.00236
26 ZNF99 zinc finger protein 99 949165 26 22 26 4 0 4 10 6 6 0 3.05e-06 0.461 0.12 0.043 0.068 3.40e-06 0.00236
27 CDH10 cadherin 10, type 2 (T2-cadherin) 736566 24 23 24 4 0 3 12 8 1 0 1.08e-06 0.344 0.14 0.27 0.22 3.80e-06 0.00255
28 POTEG POTE ankyrin domain family, member G 366329 11 10 11 0 1 2 6 0 2 0 1.31e-05 0.113 0.01 0.59 0.023 4.77e-06 0.00308
29 REG1A regenerating islet-derived 1 alpha (pancreatic stone protein, pancreatic thread protein) 159337 8 8 8 0 0 1 5 2 0 0 3.24e-06 0.151 0.073 0.26 0.15 7.44e-06 0.00464
30 PABPC5 poly(A) binding protein, cytoplasmic 5 340988 9 9 8 1 1 3 5 0 0 0 2.30e-05 0.217 0.014 0.28 0.031 1.08e-05 0.00654
31 LRFN5 leucine rich repeat and fibronectin type III domain containing 5 664309 15 13 14 1 0 2 8 4 1 0 1.05e-05 0.134 0.049 0.74 0.091 1.41e-05 0.00823
32 ASXL3 additional sex combs like 3 (Drosophila) 1877229 24 21 24 2 2 5 9 4 3 1 0.000137 0.0573 0.6 0.0024 0.0078 1.59e-05 0.00899
33 LCP1 lymphocyte cytosolic protein 1 (L-plastin) 593980 12 12 12 0 3 1 3 4 1 0 1.46e-06 0.0391 0.94 0.53 0.86 1.83e-05 0.00958
34 PEG3 paternally expressed 3 1345043 26 23 26 2 0 6 11 6 3 0 2.89e-06 0.0764 0.26 0.98 0.43 1.83e-05 0.00958
35 FCRL4 Fc receptor-like 4 485362 14 13 14 1 1 2 7 3 1 0 3.45e-06 0.140 0.21 0.95 0.37 1.85e-05 0.00958
NOTCH1

Figure S1.  This figure depicts the distribution of mutations and mutation types across the NOTCH1 significant gene.

TP53

Figure S2.  This figure depicts the distribution of mutations and mutation types across the TP53 significant gene.

CDKN2A

Figure S3.  This figure depicts the distribution of mutations and mutation types across the CDKN2A significant gene.

PIK3CA

Figure S4.  This figure depicts the distribution of mutations and mutation types across the PIK3CA significant gene.

NFE2L2

Figure S5.  This figure depicts the distribution of mutations and mutation types across the NFE2L2 significant gene.

HRAS

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

FAT1

Figure S7.  This figure depicts the distribution of mutations and mutation types across the FAT1 significant gene.

JUB

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

MLL2

Figure S9.  This figure depicts the distribution of mutations and mutation types across the MLL2 significant gene.

FBXW7

Figure S10.  This figure depicts the distribution of mutations and mutation types across the FBXW7 significant gene.

NSD1

Figure S11.  This figure depicts the distribution of mutations and mutation types across the NSD1 significant gene.

ZNF750

Figure S12.  This figure depicts the distribution of mutations and mutation types across the ZNF750 significant gene.

RHOA

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

POM121L12

Figure S14.  This figure depicts the distribution of mutations and mutation types across the POM121L12 significant gene.

EP300

Figure S15.  This figure depicts the distribution of mutations and mutation types across the EP300 significant gene.

B2M

Figure S16.  This figure depicts the distribution of mutations and mutation types across the B2M significant gene.

POTEC

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

ZNF804B

Figure S18.  This figure depicts the distribution of mutations and mutation types across the ZNF804B significant gene.

RAC1

Figure S19.  This figure depicts the distribution of mutations and mutation types across the RAC1 significant gene.

KCNT2

Figure S20.  This figure depicts the distribution of mutations and mutation types across the KCNT2 significant gene.

RASA1

Figure S21.  This figure depicts the distribution of mutations and mutation types across the RASA1 significant gene.

CNTNAP5

Figure S22.  This figure depicts the distribution of mutations and mutation types across the CNTNAP5 significant gene.

PRIM2

Figure S23.  This figure depicts the distribution of mutations and mutation types across the PRIM2 significant gene.

CDH10

Figure S24.  This figure depicts the distribution of mutations and mutation types across the CDH10 significant gene.

POTEG

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

REG1A

Figure S26.  This figure depicts the distribution of mutations and mutation types across the REG1A significant gene.

PABPC5

Figure S27.  This figure depicts the distribution of mutations and mutation types across the PABPC5 significant gene.

LRFN5

Figure S28.  This figure depicts the distribution of mutations and mutation types across the LRFN5 significant gene.

ASXL3

Figure S29.  This figure depicts the distribution of mutations and mutation types across the ASXL3 significant gene.

LCP1

Figure S30.  This figure depicts the distribution of mutations and mutation types across the LCP1 significant gene.

PEG3

Figure S31.  This figure depicts the distribution of mutations and mutation types across the PEG3 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: 6. Number of genes displayed: 10

rank gene description n cos n_cos N_cos cos_ev p q
1 TP53 tumor protein p53 244 356 223 108936 45566 0 0
2 HRAS v-Ha-ras Harvey rat sarcoma viral oncogene homolog 11 19 11 5814 2979 0 0
3 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 65 220 55 67320 26369 0 0
4 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) 65 332 63 101592 2920 0 0
5 FBXW7 F-box and WD repeat domain containing 7 16 91 10 27846 183 0 0
6 PIK3R1 phosphoinositide-3-kinase, regulatory subunit 1 (alpha) 6 33 4 10098 3 2e-07 0.00015
7 PTCH1 patched homolog 1 (Drosophila) 11 256 4 78336 5 0.00056 0.22
8 RB1 retinoblastoma 1 (including osteosarcoma) 10 267 4 81702 5 0.00065 0.22
9 ASMT acetylserotonin O-methyltransferase 2 1 1 306 1 0.0014 0.22
10 CHN1 chimerin (chimaerin) 1 3 1 1 306 1 0.0014 0.22

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)

Geneset Analyses

Table 5.  Get Full Table A Ranked List of Significantly Mutated Genesets. (Source: MSigDB GSEA Cannonical Pathway Set).Number of significant genesets found: 68. 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 APOPTOSIS APAF1, BAD, BAK1, BCL2L7P1, BAX, BCL2, BCL2L1, BCL2L11, BID, BIRC2, BIRC3, BIRC4, BIRC5, BNIP3L, CASP1, CASP10, CASP1, COPl, CASP2, CASP3, CASP4, CASP6, CASP7, CASP8, CASP9, CHUK, CYCS, DFFA, DFFB, FADD, FAS, FASLG, GZMB, HELLS, HRK, IKBKB, IKBKG, IRF1, IRF2, IRF3, IRF4, IRF5, IRF6, IRF7, JUN, LTA, MAP2K4, MAP3K1, MAPK10, MDM2, MYC, NFKB1, NFKBIA, NFKBIB, NFKBIE, PRF1, RELA, RIPK1, TNF, TNFRSF10B, TNFRSF1A, TNFRSF1B, TNFRSF21, TNFRSF25, TNFRSF25, PLEKHG5, TNFSF10, TP53, TP73, TRADD, TRAF1, TRAF2, TRAF3 66 APAF1(9), BAD(1), BAX(1), BCL2(1), BCL2L1(2), BCL2L11(1), BID(2), BIRC2(1), BIRC3(1), CASP1(2), CASP10(2), CASP3(1), CASP4(1), CASP6(2), CASP7(1), CASP8(27), CHUK(3), FADD(1), FAS(1), FASLG(1), GZMB(1), HELLS(4), IKBKB(5), IRF1(5), IRF2(2), IRF3(1), IRF4(2), IRF5(1), IRF6(4), IRF7(2), LTA(1), MAP2K4(1), MAP3K1(3), MAPK10(3), MDM2(2), MYC(3), NFKB1(2), NFKBIB(1), PLEKHG5(4), PRF1(3), RELA(1), RIPK1(2), TNFRSF10B(1), TNFRSF21(2), TNFRSF25(2), TP53(244), TRAF2(1), TRAF3(3) 26196004 367 241 272 32 61 53 65 60 121 7 <1.00e-15 <1.00e-15 <8.36e-14
2 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 APAF1(9), BAX(1), BCL2(1), BCL2L1(2), BID(2), BIRC2(1), BIRC3(1), CASP3(1), CASP6(2), CASP7(1), CASP8(27), FADD(1), FAS(1), FASLG(1), GZMB(1), MAP2K4(1), MAP3K1(3), MAP3K14(2), MAPK10(3), MCL1(1), MDM2(2), MYC(3), NFKB1(2), PARP1(3), PRF1(3), RELA(1), RIPK1(2), TP53(244), TRAF2(1) 17088240 323 235 228 21 53 40 56 55 112 7 <1.00e-15 <1.00e-15 <8.36e-14
3 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(2), APAF1(9), ATM(9), BAD(1), BAX(1), BCL2(1), BCL2L1(2), BID(2), CASP3(1), CASP6(2), CASP7(1), EIF2S1(1), PRKCA(2), PTK2(5), PXN(1), STAT1(5), TLN1(13), TP53(244) 12480574 302 232 210 26 48 39 58 51 99 7 1.27e-11 <1.00e-15 <8.36e-14
4 SA_G1_AND_S_PHASES Cdk2, 4, and 6 bind cyclin D in G1, while cdk2/cyclin E promotes the G1/S transition. ARF1, ARF3, CCND1, CDK2, CDK4, CDKN1A, CDKN1B, CDKN2A, CFL1, E2F1, E2F2, MDM2, NXT1, PRB1, TP53 15 CCND1(2), CDK4(4), CDKN1B(2), CDKN2A(65), CFL1(2), E2F2(3), MDM2(2), PRB1(8), TP53(244) 3842593 332 222 205 12 44 33 49 50 148 8 <1.00e-15 <1.00e-15 <8.36e-14
5 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(1), MYC(3), SP1(1), SP3(1), TP53(244) 3219260 250 213 158 7 41 27 42 41 92 7 <1.00e-15 <1.00e-15 <8.36e-14
6 IGF1PATHWAY Growth factor IGF-1 stimulates growth and inhibits apoptosis by activating the MAP kinase pathway in a variety of cell types. CSNK2A1, ELK1, FOS, GRB2, HRAS, IGF1, IGF1R, IRS1, JUN, MAP2K1, MAPK3, MAPK8, PIK3CA, PIK3R1, PTPN11, RAF1, RASA1, SHC1, SOS1, SRF 20 CSNK2A1(6), ELK1(1), FOS(1), HRAS(11), IGF1R(7), IRS1(1), MAP2K1(4), MAPK8(4), PIK3CA(65), PIK3R1(6), PTPN11(1), RAF1(2), RASA1(14), SHC1(1), SOS1(7) 11293994 131 109 83 6 11 47 32 25 16 0 1.14e-11 <1.00e-15 <8.36e-14
7 TRKAPATHWAY Nerve growth factor (NGF) promotes neuronal survival and proliferation by binding its receptor TrkA, which activates PI3K/AKT, Ras, and the MAP kinase pathway. AKT1, DPM2, GRB2, HRAS, KLK2, NGFB, NTRK1, PIK3CA, PIK3R1, PLCG1, PRKCA, PRKCB1, SHC1, SOS1 12 AKT1(2), HRAS(11), NTRK1(3), PIK3CA(65), PIK3R1(6), PLCG1(5), PRKCA(2), SHC1(1), SOS1(7) 7103380 102 87 56 5 6 49 21 23 3 0 4.12e-10 <1.00e-15 <8.36e-14
8 TELPATHWAY Telomerase is a ribonucleotide protein that adds telomeric repeats to the 3' ends of chromosomes. AKT1, BCL2, EGFR, G22P1, HSPCA, IGF1R, KRAS2, MYC, POLR2A, PPP2CA, PRKCA, RB1, TEP1, TERF1, TERT, TNKS, TP53, XRCC5 15 AKT1(2), BCL2(1), EGFR(14), IGF1R(7), MYC(3), POLR2A(9), PRKCA(2), RB1(10), TEP1(8), TERF1(3), TERT(1), TNKS(4), TP53(244), XRCC5(2) 12869416 310 230 218 29 49 40 60 51 103 7 1.18e-13 1.11e-15 8.36e-14
9 HSA04115_P53_SIGNALING_PATHWAY Genes involved in p53 signaling pathway APAF1, ATM, ATR, BAI1, BAX, BBC3, BID, CASP3, CASP8, CASP9, CCNB1, CCNB2, CCNB3, CCND1, CCND2, CCND3, CCNE1, CCNE2, CCNG1, CCNG2, CD82, CDC2, CDK2, CDK4, CDK6, CDKN1A, CDKN2A, CHEK1, CHEK2, CYCS, DDB2, EI24, FAS, GADD45A, GADD45B, GADD45G, GTSE1, IGF1, IGFBP3, LRDD, MDM2, MDM4, P53AIP1, PERP, PMAIP1, PPM1D, PTEN, RCHY1, RFWD2, RPRM, RRM2, RRM2B, SCOTIN, SERPINB5, SERPINE1, SESN1, SESN2, SESN3, SFN, SIAH1, STEAP3, THBS1, TNFRSF10B, TP53, TP53I3, TP73, TSC2, ZMAT3 65 APAF1(9), ATM(9), ATR(18), BAI1(4), BAX(1), BID(2), CASP3(1), CASP8(27), CCNB1(3), CCNB3(5), CCND1(2), CCNE1(3), CCNE2(3), CCNG1(1), CCNG2(2), CDK4(4), CDK6(1), CDKN2A(65), CHEK2(4), DDB2(2), EI24(1), FAS(1), GADD45G(1), GTSE1(4), IGFBP3(1), LRDD(3), MDM2(2), MDM4(1), PERP(1), PMAIP1(2), PPM1D(2), PTEN(6), RCHY1(1), RFWD2(1), RRM2(1), RRM2B(1), SERPINE1(4), SESN3(1), SFN(5), SIAH1(1), STEAP3(2), THBS1(7), TNFRSF10B(1), TP53(244), TSC2(3) 29795051 463 246 334 38 57 61 72 86 179 8 <1.00e-15 1.22e-15 8.36e-14
10 ATMPATHWAY The tumor-suppressing protein kinase ATM responds to radiation-induced DNA damage by blocking cell-cycle progression and activating DNA repair. ABL1, ATM, BRCA1, CDKN1A, CHEK1, CHEK2, GADD45A, JUN, MAPK8, MDM2, MRE11A, NBS1, NFKB1, NFKBIA, RAD50, RAD51, RBBP8, RELA, TP53, TP73 19 ATM(9), BRCA1(9), CHEK2(4), MAPK8(4), MDM2(2), MRE11A(1), NFKB1(2), RAD50(5), RAD51(1), RBBP8(6), RELA(1), TP53(244) 13588317 288 223 196 20 45 39 52 49 96 7 4.41e-12 1.89e-15 8.79e-14

Table 6.  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 HSA00902_MONOTERPENOID_BIOSYNTHESIS Genes involved in monoterpenoid biosynthesis CYP2C19, CYP2C9 2 CYP2C19(3), CYP2C9(5) 922599 8 8 8 0 0 3 4 1 0 0 0.087 0.051 1
2 HSA00627_1,4_DICHLOROBENZENE_DEGRADATION Genes involved in 1,4-dichlorobenzene degradation CMBL 1 CMBL(2) 231812 2 2 2 0 0 0 0 0 2 0 0.66 0.11 1
3 GSPATHWAY Activated G-protein coupled receptors stimulate cAMP production and thus activate protein kinase A, involved in a number of signal transduction pathways. ADCY1, GNAS, GNB1, GNGT1, PRKACA, PRKAR1A 6 ADCY1(12), GNAS(6), GNB1(2), PRKACA(4), PRKAR1A(2) 2991458 26 23 26 2 10 3 9 4 0 0 0.019 0.15 1
4 BLOOD_GROUP_GLYCOLIPID_BIOSYNTHESIS_NEOLACTOSERIES ABO, B3GNT1, FUT1, FUT2, FUT9, GCNT2, ST8SIA1 7 ABO(2), B3GNT1(1), FUT1(1), FUT2(2), FUT9(10), GCNT2(4), ST8SIA1(2) 2797416 22 21 22 4 2 7 10 2 1 0 0.12 0.18 1
5 ACETAMINOPHENPATHWAY Acetaminophen selectively inhibits Cox-3, which is localized to the brain, and yields the toxic metabolite NAPQI when processed by CAR in the liver. CYP1A2, CYP2E1, CYP3A, NR1I3, PTGS1, PTGS2 5 CYP1A2(4), CYP2E1(5), PTGS1(6), PTGS2(2) 2433197 17 15 17 2 2 1 9 0 5 0 0.16 0.24 1
6 FBW7PATHWAY Cyclin E interacts with cell cycle checkpoint kinase cdk2 to allow transcription of genes required for S phase, including transcription of additional cyclin E. CCNE1, CDC34, CDK2, CUL1, E2F1, FBXW7, RB1, SKP1A, TFDP1 7 CCNE1(3), CDC34(1), CUL1(6), RB1(10), TFDP1(2) 2976526 22 21 22 4 3 4 2 2 11 0 0.2 0.31 1
7 HSA00550_PEPTIDOGLYCAN_BIOSYNTHESIS Genes involved in peptidoglycan biosynthesis GLUL, PGLYRP2 2 GLUL(2), PGLYRP2(3) 829283 5 5 5 1 1 2 0 1 1 0 0.39 0.32 1
8 BETAOXIDATIONPATHWAY Beta-Oxidation of Fatty Acids ACADL, ACADM, ACADS, ACAT1, ECHS1, HADHA 6 ACADL(2), ACADM(3), ACADS(2), ECHS1(2), HADHA(3) 2467452 12 12 12 1 2 2 4 3 1 0 0.13 0.33 1
9 NUCLEOTIDE_SUGARS_METABOLISM GALE, GALT, TGDS, UGDH, UXS1 5 GALT(1), TGDS(2), UGDH(3), UXS1(2) 1758796 8 8 8 0 0 1 3 3 1 0 0.19 0.37 1
10 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(2), LDLR(3), NR0B2(1), NR1H4(5), RXRA(4) 2480469 15 15 15 1 2 2 6 1 4 0 0.1 0.38 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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