Mutation Analysis (MutSig v2.0)
Esophageal Carcinoma (Primary solid tumor)
28 January 2016  |  analyses__2016_01_28
Maintainer Information
Citation Information
doi:10.7908/C1GM86NN
Maintained by David Heiman (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2016): Mutation Analysis (MutSig v2.0). Broad Institute of MIT and Harvard. doi:10.7908/C1GM86NN
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: ESCA-TP

  • Number of patients in set: 185

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:ESCA-TP.final_analysis_set.maf

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

  • Significantly mutated genes (q ≤ 0.1): 56

  • Mutations seen in COSMIC: 358

  • Significantly mutated genes in COSMIC territory: 17

  • Significantly mutated genesets: 30

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

Mutation Preprocessing

  • Read 185 MAFs of type "maf1"

  • Total number of mutations in input MAFs: 58419

  • After removing 185 mutations outside chr1-24: 58234

  • After removing 1049 blacklisted mutations: 57185

  • After removing 8556 noncoding mutations: 48629

  • After collapsing adjacent/redundant mutations: 47397

Mutation Filtering

  • Number of mutations before filtering: 47397

  • After removing 3268 mutations outside gene set: 44129

  • After removing 58 mutations outside category set: 44071

  • After removing 2 "impossible" mutations in

  • gene-patient-category bins of zero coverage: 40743

Results
Breakdown of Mutations by Type

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

type count
De_novo_Start_InFrame 7
De_novo_Start_OutOfFrame 19
Frame_Shift_Del 1450
Frame_Shift_Ins 530
In_Frame_Del 329
In_Frame_Ins 48
Missense_Mutation 28340
Nonsense_Mutation 2220
Nonstop_Mutation 31
Silent 9493
Splice_Site 1560
Start_Codon_Ins 6
Start_Codon_SNP 35
Stop_Codon_Del 3
Total 44071
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->(A/T) 7092 315474250 0.000022 22 3.7 2.1
*Cp(A/C/T)->(A/T) 12091 2573710473 4.7e-06 4.7 0.77 2.7
A->(C/G) 4922 2762123896 1.8e-06 1.8 0.29 3.4
flip 4270 5651308619 7.6e-07 0.76 0.12 5.3
indel+null 6148 5651308619 1.1e-06 1.1 0.18 NaN
double_null 55 5651308619 9.7e-09 0.0097 0.0016 NaN
Total 34578 5651308619 6.1e-06 6.1 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: ESCA-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.

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->(A/T)

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

  • n3 = number of nonsilent mutations of type: A->(C/G)

  • n4 = number of nonsilent mutations of type: flip

  • 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: 56. 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 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) 99243 19 19 18 1 3 4 1 0 11 0 4.8e-15 0.0618 0.21 0.0007 0.0034 6.66e-16 4.62e-12
2 TP53 tumor protein p53 230983 174 153 104 1 46 28 17 16 64 3 1.4e-15 <1.00e-15 0 0 0 <1.00e-15 <4.62e-12
3 NFE2L2 nuclear factor (erythroid-derived 2)-like 2 324938 18 16 14 0 0 6 4 6 2 0 5e-13 0.0300 0 1.8e-06 0 <1.00e-15 <4.62e-12
4 SERPING1 serpin peptidase inhibitor, clade G (C1 inhibitor), member 1, (angioedema, hereditary) 274401 2 2 2 1 0 1 0 0 1 0 0.3 0.744 0.66 0 0 <1.00e-15 <4.62e-12
5 DCDC1 doublecortin domain containing 1 197249 18 16 18 2 1 5 5 3 4 0 6.7e-14 0.156 0.22 0.5 0.32 7.08e-13 2.62e-09
6 IVL involucrin 324427 16 15 16 0 1 3 8 3 1 0 8.6e-11 0.0347 0.00077 0.46 0.0018 4.77e-12 1.47e-08
7 TGFBR2 transforming growth factor, beta receptor II (70/80kDa) 273237 15 15 12 1 3 3 2 1 6 0 5e-11 0.181 0.04 0.0052 0.0099 1.45e-11 3.84e-08
8 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 600336 21 19 13 0 0 13 3 4 1 0 1.6e-10 0.0111 0.051 0.09 0.031 1.32e-10 3.05e-07
9 ZNF804B zinc finger protein 804B 666910 24 21 24 1 2 6 10 5 1 0 8e-12 0.0138 0.63 0.89 0.82 1.76e-10 3.62e-07
10 FBXW7 F-box and WD repeat domain containing 7 462539 14 13 12 0 2 1 2 3 6 0 2.1e-07 0.0778 0.0055 0.11 0.0088 3.87e-08 7.16e-05
11 SMAD4 SMAD family member 4 308138 14 13 13 1 2 5 0 1 6 0 7.7e-09 0.143 0.2 0.52 0.3 4.83e-08 8.11e-05
12 EIF4EBP2 eukaryotic translation initiation factor 4E binding protein 2 42039 3 3 1 0 0 3 0 0 0 0 0.002 0.377 0.00054 0.002 0.000011 3.96e-07 0.000609
13 CDH11 cadherin 11, type 2, OB-cadherin (osteoblast) 435666 16 14 16 1 3 2 7 4 0 0 1.6e-07 0.0582 0.75 0.08 0.33 9.09e-07 0.00129
14 ZNF268 zinc finger protein 268 88052 7 7 7 1 0 5 0 1 1 0 1e-06 0.514 NaN NaN NaN 9.95e-07 0.00131
15 ZNF750 zinc finger protein 750 401233 10 10 10 0 1 1 1 0 7 0 0.000056 0.105 0.039 0.0051 0.0014 1.41e-06 0.00174
16 SOX11 SRY (sex determining region Y)-box 11 144176 8 8 7 1 0 1 4 0 3 0 9.3e-07 0.778 0.49 0.11 0.35 5.17e-06 0.00596
17 LRFN5 leucine rich repeat and fibronectin type III domain containing 5 395063 12 12 12 0 3 5 1 2 1 0 3.8e-07 0.0420 0.79 0.57 1 5.92e-06 0.00644
18 NLGN1 neuroligin 1 445078 10 10 10 0 1 2 5 0 2 0 0.000029 0.0544 0.012 0.2 0.016 7.06e-06 0.00725
19 ANKRD30A ankyrin repeat domain 30A 695013 15 15 15 1 2 3 7 1 2 0 2.5e-06 0.0757 0.22 0.28 0.26 9.99e-06 0.00962
20 OR4C16 olfactory receptor, family 4, subfamily C, member 16 167332 8 8 8 1 0 1 6 1 0 0 3.3e-06 0.357 0.12 0.96 0.21 1.04e-05 0.00962
21 OR5D13 olfactory receptor, family 5, subfamily D, member 13 173801 8 8 7 0 0 4 3 0 1 0 2.4e-06 0.0826 0.18 1 0.41 1.43e-05 0.0125
22 CSMD1 CUB and Sushi multiple domains 1 1927495 31 27 31 0 7 5 8 1 10 0 5.3e-06 0.000125 0.14 0.39 0.2 1.57e-05 0.0131
23 CCDC7 coiled-coil domain containing 7 265749 12 10 12 0 0 7 1 1 3 0 2.3e-06 0.1000 0.24 0.84 0.51 1.69e-05 0.0136
24 MMP16 matrix metallopeptidase 16 (membrane-inserted) 368206 11 11 11 1 3 5 0 3 0 0 1.8e-06 0.258 0.56 0.8 0.77 2.00e-05 0.0154
25 DPP10 dipeptidyl-peptidase 10 463302 14 12 14 1 1 4 3 2 4 0 3.4e-06 0.108 0.35 0.8 0.47 2.28e-05 0.0168
26 FOXG1 forkhead box G1 195289 10 10 9 1 4 1 5 0 0 0 3.3e-06 0.194 0.25 0.58 0.54 2.53e-05 0.0179
27 GRXCR1 glutaredoxin, cysteine rich 1 162015 7 7 7 0 2 0 1 0 4 0 7.5e-06 0.106 0.79 0.078 0.26 2.71e-05 0.0181
28 TPTE transmembrane phosphatase with tensin homology 321398 10 10 10 0 1 2 2 1 4 0 5.4e-06 0.110 0.21 0.24 0.36 2.74e-05 0.0181
29 UNC13C unc-13 homolog C (C. elegans) 1176742 23 21 23 2 2 5 10 3 3 0 9.6e-06 0.0696 0.13 0.38 0.23 3.13e-05 0.0200
30 ARHGEF38 Rho guanine nucleotide exchange factor (GEF) 38 119380 6 6 6 0 1 2 1 1 1 0 0.000036 0.165 NaN NaN NaN 3.61e-05 0.0222
31 ERBB4 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) 737882 17 17 17 1 2 7 3 0 5 0 3e-06 0.0686 0.86 0.8 1 4.05e-05 0.0235
32 OR5L2 olfactory receptor, family 5, subfamily L, member 2 170098 8 8 8 1 0 2 4 1 1 0 3.1e-06 0.265 0.94 0.75 1 4.25e-05 0.0235
33 CHRM2 cholinergic receptor, muscarinic 2 244493 8 8 7 1 0 1 4 2 1 0 8.5e-06 0.387 0.3 0.44 0.37 4.28e-05 0.0235
34 SETBP1 SET binding protein 1 675684 13 13 13 1 5 1 3 2 2 0 0.00015 0.115 0.62 0.0044 0.022 4.32e-05 0.0235
35 CNTNAP5 contactin associated protein-like 5 731250 19 19 19 3 4 7 5 2 1 0 0.000014 0.122 0.12 0.88 0.24 4.69e-05 0.0248
CDKN2A

Figure S1.  This figure depicts the distribution of mutations and mutation types across the CDKN2A significant gene.

TP53

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

NFE2L2

Figure S3.  This figure depicts the distribution of mutations and mutation types across the NFE2L2 significant gene.

SERPING1

Figure S4.  This figure depicts the distribution of mutations and mutation types across the SERPING1 significant gene.

DCDC1

Figure S5.  This figure depicts the distribution of mutations and mutation types across the DCDC1 significant gene.

IVL

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

TGFBR2

Figure S7.  This figure depicts the distribution of mutations and mutation types across the TGFBR2 significant gene.

PIK3CA

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

ZNF804B

Figure S9.  This figure depicts the distribution of mutations and mutation types across the ZNF804B significant gene.

FBXW7

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

SMAD4

Figure S11.  This figure depicts the distribution of mutations and mutation types across the SMAD4 significant gene.

EIF4EBP2

Figure S12.  This figure depicts the distribution of mutations and mutation types across the EIF4EBP2 significant gene.

CDH11

Figure S13.  This figure depicts the distribution of mutations and mutation types across the CDH11 significant gene.

ZNF268

Figure S14.  This figure depicts the distribution of mutations and mutation types across the ZNF268 significant gene.

ZNF750

Figure S15.  This figure depicts the distribution of mutations and mutation types across the ZNF750 significant gene.

SOX11

Figure S16.  This figure depicts the distribution of mutations and mutation types across the SOX11 significant gene.

LRFN5

Figure S17.  This figure depicts the distribution of mutations and mutation types across the LRFN5 significant gene.

NLGN1

Figure S18.  This figure depicts the distribution of mutations and mutation types across the NLGN1 significant gene.

ANKRD30A

Figure S19.  This figure depicts the distribution of mutations and mutation types across the ANKRD30A significant gene.

OR4C16

Figure S20.  This figure depicts the distribution of mutations and mutation types across the OR4C16 significant gene.

OR5D13

Figure S21.  This figure depicts the distribution of mutations and mutation types across the OR5D13 significant gene.

CSMD1

Figure S22.  This figure depicts the distribution of mutations and mutation types across the CSMD1 significant gene.

CCDC7

Figure S23.  This figure depicts the distribution of mutations and mutation types across the CCDC7 significant gene.

MMP16

Figure S24.  This figure depicts the distribution of mutations and mutation types across the MMP16 significant gene.

DPP10

Figure S25.  This figure depicts the distribution of mutations and mutation types across the DPP10 significant gene.

FOXG1

Figure S26.  This figure depicts the distribution of mutations and mutation types across the FOXG1 significant gene.

GRXCR1

Figure S27.  This figure depicts the distribution of mutations and mutation types across the GRXCR1 significant gene.

TPTE

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

UNC13C

Figure S29.  This figure depicts the distribution of mutations and mutation types across the UNC13C significant gene.

ARHGEF38

Figure S30.  This figure depicts the distribution of mutations and mutation types across the ARHGEF38 significant gene.

OR5L2

Figure S31.  This figure depicts the distribution of mutations and mutation types across the OR5L2 significant gene.

CHRM2

Figure S32.  This figure depicts the distribution of mutations and mutation types across the CHRM2 significant gene.

SETBP1

Figure S33.  This figure depicts the distribution of mutations and mutation types across the SETBP1 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: 17. Number of genes displayed: 10

rank gene description n cos n_cos N_cos cos_ev p q
1 ERBB2 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) 12 42 8 7770 52 3.8e-13 1.7e-09
2 FBXW7 F-box and WD repeat domain containing 7 14 91 8 16835 123 1.1e-12 1.7e-09
3 SMAD4 SMAD family member 4 14 159 12 29415 43 1.3e-12 1.7e-09
4 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 21 220 17 40700 7996 1.6e-12 1.7e-09
5 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) 19 332 18 61420 372 2.2e-12 1.7e-09
6 TP53 tumor protein p53 174 356 161 65860 46286 2.3e-12 1.7e-09
7 APC adenomatous polyposis coli 15 839 8 155215 293 7.1e-06 0.0046
8 RIPK1 receptor (TNFRSF)-interacting serine-threonine kinase 1 2 4 2 740 2 1e-05 0.0058
9 PTCH1 patched homolog 1 (Drosophila) 13 256 5 47360 5 0.000013 0.0067
10 CTNNB1 catenin (cadherin-associated protein), beta 1, 88kDa 9 138 4 25530 733 0.000022 0.0099

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: 30. 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 ARFPATHWAY Cyclin-dependent kinase inhibitor 2A is a tumor suppressor that induces G1 arrest and can activate the p53 pathway, leading to G2/M arrest. ABL1, CDKN2A, E2F1, MDM2, MYC, PIK3CA, PIK3R1, POLR1A, POLR1B, POLR1C, POLR1D, RAC1, RB1, TBX2, TP53, TWIST1 16 ABL1(2), CDKN2A(19), E2F1(2), MDM2(2), PIK3CA(21), PIK3R1(5), POLR1A(4), POLR1B(3), POLR1C(5), RAC1(1), RB1(8), TBX2(2), TP53(174), TWIST1(2) 5500423 250 165 171 15 53 53 23 23 95 3 1.34e-14 <1.00e-15 <6.31e-14
2 ST_JNK_MAPK_PATHWAY JNKs are MAP kinases regulated by several levels of kinases (MAPKK, MAPKKK) and phosphorylate transcription factors and regulatory proteins. AKT1, ATF2, CDC42, DLD, DUSP10, DUSP4, DUSP8, GAB1, GADD45A, GCK, IL1R1, JUN, MAP2K4, MAP2K5, MAP2K7, MAP3K1, MAP3K10, MAP3K11, MAP3K12, MAP3K13, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K7, MAP3K7IP1, MAP3K7IP2, MAP3K9, MAPK10, MAPK7, MAPK8, MAPK9, MYEF2, NFATC3, NR2C2, PAPPA, SHC1, TP53, TRAF6, ZAK 38 AKT1(4), DLD(4), DUSP10(3), DUSP4(1), GAB1(1), GCK(1), IL1R1(1), JUN(1), MAP2K4(3), MAP2K5(2), MAP3K1(8), MAP3K10(4), MAP3K11(3), MAP3K12(2), MAP3K13(2), MAP3K2(3), MAP3K3(1), MAP3K4(6), MAP3K5(8), MAP3K7(3), MAP3K9(2), MAPK10(3), MAPK7(1), MAPK8(1), MAPK9(2), MYEF2(2), NFATC3(2), NR2C2(4), PAPPA(6), TP53(174), TRAF6(1), ZAK(4) 13707275 263 163 192 23 66 56 25 27 86 3 9.94e-12 <1.00e-15 <6.31e-14
3 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 ABL1(2), ATM(22), BRCA1(6), CDKN1A(2), CHEK1(1), CHEK2(3), JUN(1), MAPK8(1), MDM2(2), MRE11A(2), NFKB1(2), RAD50(3), RAD51(3), RBBP8(3), TP53(174), TP73(3) 8026064 230 161 157 10 53 51 22 24 77 3 1.18e-14 <1.00e-15 <6.31e-14
4 TIDPATHWAY On ligand binding, interferon gamma receptors stimulate JAK2 kinase to phosphorylate STAT transcription factors, which promote expression of interferon responsive genes. DNAJA3, HSPA1A, IFNG, IFNGR1, IFNGR2, IKBKB, JAK2, LIN7A, NFKB1, NFKBIA, RB1, RELA, TIP-1, TNF, TNFRSF1A, TNFRSF1B, TP53, USH1C, WT1 18 DNAJA3(3), IFNG(1), IFNGR1(1), IKBKB(2), JAK2(2), LIN7A(2), NFKB1(2), RB1(8), TNFRSF1B(1), TP53(174), WT1(4) 5099114 200 161 130 12 52 33 19 18 75 3 8.62e-13 <1.00e-15 <6.31e-14
5 ATRBRCAPATHWAY BRCA1 and 2 block cell cycle progression in response to DNA damage and promote double-stranded break repair; mutations induce breast cancer susceptibility. ATM, ATR, BRCA1, BRCA2, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, HUS1, MRE11A, NBS1, RAD1, RAD17, RAD50, RAD51, RAD9A, TP53, TREX1 21 ATM(22), ATR(5), BRCA1(6), BRCA2(9), CHEK1(1), CHEK2(3), FANCA(5), FANCC(2), FANCD2(4), FANCF(1), FANCG(1), MRE11A(2), RAD17(4), RAD50(3), RAD51(3), TP53(174), TREX1(1) 11882135 246 160 174 14 53 52 29 26 83 3 1.64e-12 <1.00e-15 <6.31e-14
6 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(22), CDC25A(3), CDC25B(2), CDK2(1), CHEK1(1), MYT1(4), RB1(8), TP53(174), WEE1(1) 4826897 216 160 146 6 51 44 21 19 78 3 <1.00e-15 <1.00e-15 <6.31e-14
7 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 ARF1(1), CCND1(1), CDK2(1), CDKN1A(2), CDKN2A(19), CFL1(1), E2F1(2), E2F2(2), MDM2(2), NXT1(1), PRB1(2), TP53(174) 2257529 208 159 137 5 51 37 18 19 80 3 <1.00e-15 <1.00e-15 <6.31e-14
8 PMLPATHWAY Ring-shaped PML nuclear bodies regulate transcription and are required co-activators in p53- and DAXX-mediated apoptosis. CREBBP, DAXX, HRAS, PAX3, PML, PRAM-1, RARA, RB1, SIRT1, SP100, TNF, TNFRSF1A, TNFRSF1B, TNFRSF6, TNFSF6, TP53, UBL1 13 CREBBP(13), DAXX(3), HRAS(1), PML(4), RB1(8), SIRT1(5), SP100(7), TNFRSF1B(1), TP53(174) 5160329 216 157 146 6 52 37 22 20 82 3 <1.00e-15 <1.00e-15 <6.31e-14
9 PLK3PATHWAY Active Plk3 phosphorylates CDC25c, blocking the G2/M transition, and phosphorylates p53 to induce apoptosis. ATM, ATR, CDC25C, CHEK1, CHEK2, CNK, TP53, YWHAH 7 ATM(22), ATR(5), CHEK1(1), CHEK2(3), TP53(174) 4342671 205 156 135 4 50 37 22 22 71 3 <1.00e-15 <1.00e-15 <6.31e-14
10 RNAPATHWAY dsRNA-activated protein kinase phosphorylates elF2a, which generally inhibits translation, and activates NF-kB to provoke inflammation. CHUK, DNAJC3, EIF2S1, EIF2S2, MAP3K14, NFKB1, NFKBIA, PRKR, RELA, TP53 9 CHUK(5), DNAJC3(1), EIF2S1(1), NFKB1(2), TP53(174) 2784224 183 155 113 4 47 32 18 16 67 3 1.11e-15 1.22e-15 6.31e-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 SLRPPATHWAY Small leucine-rich proteoglycans (SLRPs) interact with and reorganize collagen fibers in the extracellular matrix. BGN, DCN, DSPG3, FMOD, KERA, LUM 5 BGN(1), DCN(6), FMOD(2), KERA(2), LUM(3) 981573 14 14 14 0 2 6 2 3 1 0 0.02 0.0016 1
2 PS1PATHWAY Presenilin is required for gamma-secretase activity to activate Notch signaling; presenilin also inhibits beta-catenin in the Wnt/Frizzled pathway. ADAM17, APC, AXIN1, BTRC, CTNNB1, DLL1, DVL1, FZD1, GSK3B, NOTCH1, PSEN1, RBPSUH, TCF1, WNT1 12 ADAM17(3), APC(15), AXIN1(2), BTRC(3), CTNNB1(9), DLL1(1), FZD1(4), GSK3B(3), NOTCH1(20), PSEN1(2), WNT1(1) 5943593 63 50 62 6 10 10 12 7 21 3 0.01 0.0043 1
3 NOTCHPATHWAY Proteolysis and Signaling Pathway of Notch ADAM17, DLL1, FURIN, NOTCH1, PSEN1, RBPSUH 5 ADAM17(3), DLL1(1), FURIN(2), NOTCH1(20), PSEN1(2) 2782582 28 25 28 2 5 2 3 5 11 2 0.066 0.0069 1
4 ERBB4PATHWAY ErbB4 (aka HER4) is a receptor tyrosine kinase that binds neuregulins as well as members of the EGF family, which also target EGF receptors. ADAM17, ERBB4, NRG2, NRG3, PRKCA, PRKCB1, PSEN1 5 ADAM17(3), NRG2(2), NRG3(8), PRKCA(1), PSEN1(2) 1787004 16 16 16 1 4 3 4 2 3 0 0.048 0.022 1
5 FLUMAZENILPATHWAY Flumazenil is a benzodiazepine receptor antagonist that may induce protective preconditioning in ischemic cardiomyocytes. GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6, GPX1, PRKCE, SOD1 8 GABRA1(7), GABRA3(1), GABRA4(3), GABRA5(4), GABRA6(7), PRKCE(2) 1945815 24 21 24 3 7 5 9 0 3 0 0.046 0.067 1
6 UREACYCLEPATHWAY Ammonia released from amino acid deamination is used to produce carbamoyl phosphate, which is used to convert ornithine to citrulline, from which urea is eventually formed. ARG1, ASL, ASS, CPS1, GLS, GLUD1, GOT1 6 ARG1(1), ASL(3), CPS1(11), GLS(2), GLUD1(1) 2139811 18 16 18 1 2 8 5 2 1 0 0.032 0.089 1
7 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(2), CDK2(1), CUL1(4), E2F1(2), RB1(8), TFDP1(1) 1884442 18 17 18 3 0 5 1 1 11 0 0.41 0.11 1
8 BETAOXIDATIONPATHWAY Beta-Oxidation of Fatty Acids ACADL, ACADM, ACADS, ACAT1, ECHS1, HADHA 6 ACADL(5), ACADS(2), ACAT1(3), ECHS1(1), HADHA(2) 1517471 13 12 13 0 2 6 1 0 4 0 0.068 0.12 1
9 BOTULINPATHWAY Blockade of Neurotransmitter Relase by Botulinum Toxin CHRM1, CHRNA1, SNAP25, STX1A, VAMP2 5 CHRM1(2), CHRNA1(4), SNAP25(1), STX1A(2) 881127 9 8 8 0 6 1 1 1 0 0 0.056 0.12 1
10 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(5), IFNG(1), IL12B(1) 817967 7 7 7 1 0 4 2 0 1 0 0.36 0.12 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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