Mutation Analysis (MutSig v1.5)
Ovarian Serous Cystadenocarcinoma (Primary solid tumor)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C18W3CC4
Maintained by David Heiman (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2015): Mutation Analysis (MutSig v1.5). Broad Institute of MIT and Harvard. doi:10.7908/C18W3CC4
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 v1.5 was used to generate the results found in this report.

  • Working with individual set: OV-TP

  • Number of patients in set: 466

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:OV-TP.final_analysis_set.maf

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

  • Significantly mutated genes (q ≤ 0.1): 24

  • Mutations seen in COSMIC: 525

  • Significantly mutated genes in COSMIC territory: 40

  • Significantly mutated genesets: 32

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

Mutation Preprocessing

  • Read 148 MAFs of type "Broad"

  • Read 234 MAFs of type "WashU"

  • Read 91 MAFs of type "Baylor-SOLiD"

  • Total number of mutations in input MAFs: 28038

  • After removing 112 mutations outside chr1-24: 27926

  • After removing 933 noncoding mutations: 26993

  • After collapsing adjacent/redundant mutations: 26731

Mutation Filtering

  • Number of mutations before filtering: 26731

  • After removing 55 mutations outside patient set: 26676

  • After removing 1398 mutations outside gene set: 25278

  • After removing 11 mutations outside category set: 25267

  • After removing 6 "impossible" mutations in

  • gene-patient-category bins of zero coverage: 23797

Results
Breakdown of Mutations by Type

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

type count
Frame_Shift_Del 576
Frame_Shift_Ins 172
In_Frame_Del 201
In_Frame_Ins 44
Missense_Mutation 17116
Nonsense_Mutation 1063
Nonstop_Mutation 20
Silent 5503
Splice_Site 566
Splice_Site_SNP 5
Translation_Start_Site 1
Total 25267
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 2611 599277488 4.4e-06 4.4 2.7 2.2
*Cp(A/C/T)->T 2787 5454735038 5.1e-07 0.51 0.31 1.7
C->(G/A) 6832 6054012526 1.1e-06 1.1 0.69 5
A->mut 4880 6101008844 8e-07 0.8 0.49 3.8
indel+null 2637 12155021370 2.2e-07 0.22 0.13 NaN
double_null 11 12155021370 9e-10 0.0009 0.00056 NaN
Total 19758 12155021370 1.6e-06 1.6 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: OV-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_ns_s = p-value for the observed nonsilent/silent ratio being elevated in this gene

  • 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: 24. 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_ns_s p q
1 TP53 tumor protein p53 589258 391 387 175 2 63 54 55 86 133 0 <1.00e-15 <1.00e-15 <1.73e-11
2 RB1 retinoblastoma 1 (including osteosarcoma) 1230770 15 15 15 0 0 1 4 0 10 0 0.134 1.39e-10 1.20e-06
3 NF1 neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease) 3889455 26 24 26 0 1 0 2 4 19 0 0.0453 3.36e-10 1.94e-06
4 BRCA1 breast cancer 1, early onset 2651883 19 19 19 0 0 0 1 1 17 0 0.118 1.87e-09 8.07e-06
5 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 324777 5 5 2 0 0 0 5 0 0 0 0.650 5.78e-06 0.0200
6 FAM171B family with sequence similarity 171, member B 1106888 9 9 9 1 2 1 3 1 2 0 0.358 1.10e-05 0.0257
7 IL21R interleukin 21 receptor 683909 8 8 8 0 1 1 1 2 3 0 0.120 1.13e-05 0.0257
8 TAS2R1 taste receptor, type 2, member 1 400943 6 6 6 0 0 0 3 2 1 0 0.291 1.19e-05 0.0257
9 SLCO1C1 solute carrier organic anion transporter family, member 1C1 1055932 9 9 9 0 0 2 5 2 0 0 0.164 1.38e-05 0.0265
10 GABRA6 gamma-aminobutyric acid (GABA) A receptor, alpha 6 636553 7 7 7 1 1 3 1 2 0 0 0.306 1.54e-05 0.0265
11 CYP11B1 cytochrome P450, family 11, subfamily B, polypeptide 1 674440 8 8 8 0 2 0 4 2 0 0 0.138 3.15e-05 0.0494
12 ANKRD35 ankyrin repeat domain 35 1167148 9 9 9 0 1 3 1 3 1 0 0.0474 4.21e-05 0.0606
13 CYP7B1 cytochrome P450, family 7, subfamily B, polypeptide 1 632888 6 6 6 0 0 4 2 0 0 0 0.149 6.02e-05 0.0799
14 PECAM1 platelet/endothelial cell adhesion molecule (CD31 antigen) 14209 2 2 2 1 0 1 0 0 1 0 0.889 7.05e-05 0.0839
15 SNTG1 syntrophin, gamma 1 730950 7 7 7 1 0 1 2 1 3 0 0.472 7.66e-05 0.0839
16 PROKR2 prokineticin receptor 2 519909 6 6 6 1 3 0 0 3 0 0 0.439 7.78e-05 0.0839
17 EFEMP1 EGF-containing fibulin-like extracellular matrix protein 1 684901 7 7 7 0 1 0 4 0 2 0 0.310 9.06e-05 0.0885
18 DEFB118 defensin, beta 118 172530 4 4 4 0 0 1 1 0 2 0 0.307 9.33e-05 0.0885
19 ACTRT1 actin-related protein T1 510897 6 6 6 0 2 0 3 1 0 0 0.207 9.99e-05 0.0885
20 NRAS neuroblastoma RAS viral (v-ras) oncogene homolog 272817 4 4 3 0 0 1 0 2 1 0 0.320 0.000103 0.0885
21 ZNF479 zinc finger protein 479 564331 6 6 6 1 0 2 2 2 0 0 0.512 0.000110 0.0903
22 AIM2 absent in melanoma 2 487784 6 6 6 0 0 0 2 4 0 0 0.280 0.000116 0.0903
23 C4orf35 chromosome 4 open reading frame 35 538306 6 6 6 0 0 0 4 2 0 0 0.321 0.000120 0.0903
24 SPAM1 sperm adhesion molecule 1 (PH-20 hyaluronidase, zona pellucida binding) 722468 6 6 6 1 1 1 0 4 0 0 0.423 0.000126 0.0904
25 PODN podocan 515002 6 6 6 0 3 1 0 1 1 0 0.122 0.000164 0.111
26 EIF2B5 eukaryotic translation initiation factor 2B, subunit 5 epsilon, 82kDa 936424 7 7 7 1 3 1 1 1 1 0 0.369 0.000171 0.111
27 OR5V1 olfactory receptor, family 5, subfamily V, member 1 439234 5 5 5 1 1 1 2 1 0 0 0.481 0.000174 0.111
28 RGS7 regulator of G-protein signaling 7 695598 6 6 6 1 1 2 0 3 0 0 0.379 0.000208 0.127
29 PCDHB9 protocadherin beta 9 785018 7 7 7 1 1 2 4 0 0 0 0.370 0.000217 0.127
30 PPM1F protein phosphatase 1F (PP2C domain containing) 346726 5 5 4 0 0 1 3 1 0 0 0.241 0.000221 0.127
31 YSK4 yeast Sps1/Ste20-related kinase 4 (S. cerevisiae) 1860054 10 10 10 0 0 2 3 4 1 0 0.0936 0.000227 0.127
32 OR4N2 olfactory receptor, family 4, subfamily N, member 2 411912 5 5 5 0 1 2 1 1 0 0 0.148 0.000250 0.135
33 CLEC4F C-type lectin domain family 4, member F 818750 7 7 7 0 0 0 2 5 0 0 0.241 0.000303 0.159
34 MARCH4 membrane-associated ring finger (C3HC4) 4 413664 5 5 5 0 2 0 2 1 0 0 0.248 0.000339 0.172
35 TFAP2D transcription factor AP-2 delta (activating enhancer binding protein 2 delta) 627111 6 6 6 1 2 0 3 1 0 0 0.450 0.000368 0.181
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: 40. Number of genes displayed: 10

rank gene description n cos n_cos N_cos cos_ev p q
1 TP53 tumor protein p53 391 824 390 383984 98562 0 0
2 RB1 retinoblastoma 1 (including osteosarcoma) 15 267 12 124422 30 0 0
3 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 5 52 5 24232 72780 7.6e-10 1.1e-06
4 NF1 neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease) 26 285 7 132810 8 3.6e-09 3.9e-06
5 MYO3A myosin IIIA 9 14 3 6524 3 2e-07 0.00017
6 CDC27 cell division cycle 27 homolog (S. cerevisiae) 5 3 2 1398 2 2.6e-06 0.0019
7 ERBB2 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) 5 42 3 19572 5 5.2e-06 0.0033
8 NIPBL Nipped-B homolog (Drosophila) 10 7 2 3262 2 0.000014 0.0077
9 NRAS neuroblastoma RAS viral (v-ras) oncogene homolog 4 33 2 15378 2596 0.00031 0.083
10 PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1) 5 767 5 357422 98 0.00034 0.083

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: 32. 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 HSA04110_CELL_CYCLE Genes involved in cell cycle ABL1, ANAPC1, ANAPC10, ANAPC11, ANAPC2, ANAPC4, ANAPC5, ANAPC7, ATM, ATR, BUB1, BUB1B, BUB3, CCNA1, CCNA2, CCNB1, CCNB2, CCNB3, CCND1, CCND2, CCND3, CCNE1, CCNE2, CCNH, CDC14A, CDC14B, CDC16, CDC2, CDC20, CDC23, CDC25A, CDC25B, CDC25C, CDC26, CDC27, CDC45L, CDC6, CDC7, CDK2, CDK4, CDK6, CDK7, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2B, CDKN2C, CDKN2D, CHEK1, CHEK2, CREBBP, CUL1, DBF4, E2F1, E2F2, E2F3, EP300, ESPL1, FZR1, GADD45A, GADD45B, GADD45G, GSK3B, hCG_1982709, HDAC1, HDAC2, LOC440917, LOC728919, MAD1L1, MAD2L1, MAD2L2, MCM2, MCM3, MCM4, MCM5, MCM6, MCM7, MDM2, ORC1L, ORC2L, ORC3L, ORC4L, ORC5L, ORC6L, PCNA, PKMYT1, PLK1, PRKDC, PTTG1, PTTG2, RB1, RBL1, RBL2, RBX1, SFN, SKP1, SKP2, SMAD2, SMAD3, SMAD4, SMC1A, SMC1B, TFDP1, TGFB1, TGFB2, TGFB3, TP53, WEE1, YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ, YWHAZ 107 ABL1(1), ANAPC1(1), ANAPC2(1), ANAPC4(1), ANAPC5(1), ATM(8), ATR(3), BUB1(2), BUB1B(1), BUB3(1), CCNA1(2), CCNA2(1), CCNB3(4), CCNH(1), CDC14A(1), CDC16(2), CDC20(4), CDC23(1), CDC25A(1), CDC25B(2), CDC27(5), CDC6(1), CDC7(1), CDKN1A(1), CDKN1B(1), CDKN2C(2), CHEK2(3), CREBBP(11), CUL1(2), DBF4(3), E2F2(2), E2F3(1), EP300(2), ESPL1(3), GADD45B(1), HDAC1(1), MAD1L1(1), MAD2L2(1), MCM2(3), MCM3(1), MCM4(2), MCM5(1), MCM6(1), ORC1L(2), ORC2L(2), PLK1(2), PRKDC(7), RB1(15), RBL1(1), RBL2(3), SKP2(2), SMAD4(1), SMC1A(5), SMC1B(4), TFDP1(3), TGFB2(1), TP53(391), YWHAB(1), YWHAE(2), YWHAG(1) 87823394 532 403 316 32 84 70 99 113 166 0 <1.00e-15 <1.00e-15 <3.08e-14
2 CELL_CYCLE_KEGG ABL1, ASK, ATM, BUB1, BUB1B, BUB3, CCNA1, CCNA2, CCNB1, CCNB2, CCNB3, CCND2, CCND3, CCNE1, CCNE2, CCNH, CDAN1, CDC14A, CDC14B, CDC14B, CDC14C, CDC2, CDC20, CDC25A, CDC25B, CDC25C, CDC45L, CDC6, CDC7, CDH1, CDK2, CDK4, CDKN1A, CDKN2A, CHEK1, CHEK2, DTX4, E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, EP300, ESPL1, FLJ14001, GADD45A, GSK3B, HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7A, HDAC8, MAD1L1, MAD2L1, MAD2L2, MCM2, MCM3, MCM4, MCM5, MCM6, MCM7, MDM2, MPEG1, MPL, ORC1L, ORC2L, ORC3L, ORC4L, ORC5L, ORC6L, PCNA, PLK1, PRKDC, PTPRA, PTTG1, PTTG2, PTTG3, RB1, RBL1, SKP2, SMAD4, SMC1L1, TBC1D8, TFDP1, TGFB1, TP53, WEE1 82 ABL1(1), ATM(8), BUB1(2), BUB1B(1), BUB3(1), CCNA1(2), CCNA2(1), CCNB3(4), CCNH(1), CDAN1(3), CDC14A(1), CDC20(4), CDC25A(1), CDC25B(2), CDC6(1), CDC7(1), CDH1(2), CDKN1A(1), CHEK2(3), DTX4(2), E2F2(2), E2F3(1), E2F4(1), E2F5(3), EP300(2), ESPL1(3), HDAC1(1), HDAC3(2), HDAC4(1), HDAC5(1), HDAC6(3), MAD1L1(1), MAD2L2(1), MCM2(3), MCM3(1), MCM4(2), MCM5(1), MCM6(1), MPEG1(1), MPL(1), ORC1L(2), ORC2L(2), PLK1(2), PRKDC(7), RB1(15), RBL1(1), SKP2(2), SMAD4(1), TBC1D8(4), TFDP1(3), TP53(391) 72494429 504 399 288 27 82 68 86 109 159 0 <1.00e-15 <1.00e-15 <3.08e-14
3 HSA04310_WNT_SIGNALING_PATHWAY Genes involved in Wnt signaling pathway APC, APC2, AXIN1, AXIN2, BTRC, CACYBP, CAMK2A, CAMK2B, CAMK2D, CAMK2G, CCND1, CCND2, CCND3, CER1, CHD8, CHP, CREBBP, CSNK1A1, CSNK1A1L, CSNK1E, CSNK2A1, CSNK2A2, CSNK2B, CTBP1, CTBP2, CTNNB1, CTNNBIP1, CUL1, CXXC4, DAAM1, DAAM2, DKK1, DKK2, DKK4, DVL1, DVL2, DVL3, EP300, FBXW11, FOSL1, FRAT1, FRAT2, FZD1, FZD10, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, GSK3B, JUN, LEF1, LOC652788, LRP5, LRP6, MAP3K7, MAPK10, MAPK8, MAPK9, MMP7, MYC, NFAT5, NFATC1, NFATC2, NFATC3, NFATC4, NKD1, NKD2, NLK, PLCB1, PLCB2, PLCB3, PLCB4, PORCN, PPARD, PPP2CA, PPP2CB, PPP2R1A, PPP2R1B, PPP2R2A, PPP2R2B, PPP2R2C, PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, PRICKLE1, PRICKLE2, PRKACA, PRKACB, PRKACG, PRKCA, PRKCB1, PRKCG, PRKX, PRKY, PSEN1, RAC1, RAC2, RAC3, RBX1, RHOA, ROCK1, ROCK2, RUVBL1, SENP2, SFRP1, SFRP2, SFRP4, SFRP5, SIAH1, SKP1, SMAD2, SMAD3, SMAD4, SOX17, TBL1X, TBL1XR1, TBL1Y, TCF7, TCF7L1, TCF7L2, TP53, VANGL1, VANGL2, WIF1, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT2B, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B 137 APC(11), AXIN1(1), AXIN2(2), BTRC(1), CAMK2B(1), CAMK2D(2), CHD8(6), CHP(1), CREBBP(11), CSNK1A1L(1), CSNK1E(1), CSNK2A1(2), CTBP2(2), CTNNB1(2), CUL1(2), CXXC4(1), DAAM1(2), DAAM2(2), DKK1(1), DKK2(3), DVL3(1), EP300(2), FBXW11(1), FZD1(1), FZD3(1), FZD4(1), FZD5(2), FZD7(2), LEF1(1), LRP5(1), LRP6(3), MAP3K7(2), MAPK8(1), MAPK9(1), MMP7(1), NFAT5(4), NFATC1(1), NFATC2(3), NFATC4(2), NLK(1), PLCB1(6), PLCB2(3), PLCB3(2), PLCB4(3), PORCN(3), PPARD(3), PPP2CA(2), PPP2R1A(3), PPP2R1B(1), PPP2R2A(2), PPP2R2B(1), PPP3CA(1), PPP3CC(1), PPP3R2(1), PRICKLE1(4), PRICKLE2(4), PRKACA(1), PRKACB(1), PRKACG(1), PRKCA(2), PRKCG(2), RHOA(3), ROCK2(2), SENP2(1), SMAD4(1), TBL1X(1), TBL1XR1(2), TCF7L1(1), TCF7L2(2), TP53(391), VANGL2(1), WIF1(2), WNT11(2), WNT16(3), WNT2(1), WNT2B(3), WNT4(1), WNT6(2), WNT7A(3), WNT8A(1), WNT9A(1), WNT9B(1) 98049024 559 399 342 36 89 83 116 115 156 0 <1.00e-15 <1.00e-15 <3.08e-14
4 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 62 APAF1(2), ATM(8), ATR(3), BAI1(2), CASP8(2), CASP9(2), CCNB3(4), CCNG2(1), CD82(1), CDKN1A(1), CHEK2(3), DDB2(1), EI24(1), GADD45B(1), GTSE1(1), MDM4(1), PERP(1), PTEN(5), RCHY1(1), RFWD2(1), RRM2B(2), SERPINB5(2), SERPINE1(2), SESN1(1), STEAP3(1), THBS1(3), TP53(391), TSC2(3), ZMAT3(2) 39434553 449 396 233 15 73 62 72 101 141 0 <1.00e-15 <1.00e-15 <3.08e-14
5 HSA04210_APOPTOSIS Genes involved in apoptosis AIFM1, AKT1, AKT2, AKT3, APAF1, ATM, BAD, BAX, BCL2, BCL2L1, BID, BIRC2, BIRC3, BIRC4, CAPN1, CAPN2, CASP10, CASP3, CASP6, CASP7, CASP8, CASP9, CFLAR, CHP, CHUK, CSF2RB, CYCS, DFFA, DFFB, ENDOG, FADD, FAS, FASLG, IKBKB, IKBKG, IL1A, IL1B, IL1R1, IL1RAP, IL3, IL3RA, IRAK1, IRAK2, IRAK3, IRAK4, MAP3K14, MYD88, NFKB1, NFKB2, NFKBIA, NGFB, NTRK1, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R5, PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, PRKACA, PRKACB, PRKACG, PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B, RELA, RIPK1, TNF, TNFRSF10A, TNFRSF10B, TNFRSF10C, TNFRSF10D, TNFRSF1A, TNFSF10, TP53, TRADD, TRAF2 78 AIFM1(2), APAF1(2), ATM(8), BIRC3(2), CASP6(2), CASP7(1), CASP8(2), CASP9(2), CHP(1), CHUK(1), CSF2RB(2), DFFB(1), FADD(1), IKBKB(2), IRAK1(3), IRAK2(1), IRAK3(2), IRAK4(2), MAP3K14(1), MYD88(1), NFKB1(2), NFKBIA(2), NTRK1(2), PIK3CA(3), PIK3CB(5), PIK3CD(2), PIK3CG(3), PIK3R1(2), PIK3R2(1), PIK3R5(2), PPP3CA(1), PPP3CC(1), PPP3R2(1), PRKACA(1), PRKACB(1), PRKACG(1), PRKAR1B(1), PRKAR2A(2), PRKAR2B(1), RELA(1), TNF(1), TNFRSF10A(2), TNFRSF1A(2), TNFSF10(1), TP53(391), TRAF2(1) 52657574 472 395 256 28 72 66 84 107 143 0 <1.00e-15 <1.00e-15 <3.08e-14
6 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(8), ATR(3), BRCA1(19), BRCA2(13), CHEK2(3), FANCA(5), FANCC(1), FANCD2(1), FANCE(1), FANCF(2), FANCG(1), HUS1(1), MRE11A(1), RAD17(1), RAD50(1), RAD51(1), TP53(391) 29545907 453 393 237 4 67 58 64 98 166 0 <1.00e-15 <1.00e-15 <3.08e-14
7 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(1), ATM(8), ATR(3), CCNA1(2), CDC25A(1), CDKN1A(1), CDKN1B(1), HDAC1(1), RB1(15), SKP2(2), TFDP1(3), TGFB2(1), TP53(391) 19838703 430 393 214 6 65 60 66 91 148 0 <1.00e-15 <1.00e-15 <3.08e-14
8 ST_FAS_SIGNALING_PATHWAY The Fas receptor induces apoptosis and NF-kB activation when bound to Fas ligand. ADPRT, ALG2, BAK1, BAX, BFAR, BIRC4, BTK, CAD, CASP10, CASP3, CASP8, CASP8AP2, CD7, CDK2AP1, CSNK1A1, DAXX, DEDD, DEDD2, DFFA, DIABLO, EGFR, EPHB2, FADD, FAF1, FAIM2, FREQ, HRB, HSPB1, IL1A, IL8, MAP2K4, MAP2K7, MAP3K1, MAP3K5, MAPK1, MAPK10, MAPK8, MAPK8IP1, MAPK8IP2, MAPK8IP3, MAPK9, MCP, MET, NFAT5, NFKB1, NFKB2, NFKBIA, NFKBIB, NFKBIE, NFKBIL1, NFKBIL2, NR0B2, PFN1, PFN2, PTPN13, RALBP1, RIPK1, ROCK1, SMPD1, TNFRSF6, TNFRSF6B, TP53, TPX2, TRAF2, TUFM, VIL2 54 ALG2(3), BFAR(2), BTK(2), CAD(6), CASP8(2), CASP8AP2(1), DAXX(3), EGFR(6), EPHB2(2), FADD(1), IL8(3), MAP2K4(2), MAP3K1(2), MAP3K5(5), MAPK8(1), MAPK8IP1(1), MAPK9(1), MET(4), NFAT5(4), NFKB1(2), NFKBIA(2), NFKBIB(1), NFKBIE(1), NFKBIL2(1), PTPN13(5), TP53(391), TPX2(1), TRAF2(1), TUFM(1) 44230141 457 393 241 17 69 69 75 100 144 0 <1.00e-15 <1.00e-15 <3.08e-14
9 P53PATHWAY p53 induces cell cycle arrest or apoptosis under conditions of DNA damage. APAF1, ATM, BAX, BCL2, CCND1, CCNE1, CDK2, CDK4, CDKN1A, E2F1, GADD45A, MDM2, PCNA, RB1, TIMP3, TP53 16 APAF1(2), ATM(8), CDKN1A(1), RB1(15), TP53(391) 11939947 417 392 201 2 65 57 61 89 145 0 <1.00e-15 <1.00e-15 <3.08e-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(8), CDC25A(1), CDC25B(2), MYT1(1), RB1(15), TP53(391) 11814157 418 392 202 4 64 56 64 88 146 0 <1.00e-15 <1.00e-15 <3.08e-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 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 LDLR(5), NR1H3(5), NR1H4(3), RXRA(2) 3418440 15 15 15 0 2 2 4 3 4 0 0.013 0.00041 0.25
2 FOLATE_BIOSYNTHESIS ALPI, ALPL, ALPP, ALPP, ALPPL2, ALPPL2, DHFR, FPGS, GCH1, GGH, SPR 9 ALPI(2), ALPL(2), ALPP(2), FPGS(1), GCH1(1), SPR(2) 3429581 10 10 10 1 3 3 2 1 1 0 0.091 0.032 1
3 SETPATHWAY Cytotoxic T cells release perforin, which to allow entry into target cells of granzyme B, which activates caspases, and granzyme A, which induces caspase-independent apoptosis. ANP32A, APEX1, CREBBP, DFFA, DFFB, GZMA, GZMB, HMGB2, NME1, PRF1, SET 11 APEX1(3), CREBBP(11), DFFB(1), GZMA(2), PRF1(1) 6668804 18 18 18 2 2 1 3 4 8 0 0.26 0.035 1
4 FOSBPATHWAY FOSB gene expression and drug abuse CDK5, FOSB, GRIA2, JUND, PPP1R1B 4 FOSB(2), GRIA2(6) 2208351 8 8 8 1 0 0 1 5 2 0 0.58 0.036 1
5 TUBBYPATHWAY Tubby is activated by phospholipase C activity and hydrolysis of PIP2, after which it enters the nucleus and regulates transcription. CHRM1, GNAQ, GNB1, GNGT1, HTR2C, PLCB1, TUB 7 GNAQ(1), HTR2C(6), PLCB1(6), TUB(1) 4745469 14 13 14 1 2 4 6 2 0 0 0.063 0.046 1
6 CARM1PATHWAY The methyltransferase CARM1 interacts with transcription factors such as CBP/p300 and methylates histones H3 and H4. CARM1, CREB1, CREBBP, EP300, NCOA3, PRKACB, PRKACG, PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B, RARA, RXRA 13 CARM1(3), CREBBP(11), EP300(2), NCOA3(5), PRKACB(1), PRKACG(1), PRKAR1B(1), PRKAR2A(2), PRKAR2B(1), RARA(1), RXRA(2) 13212238 30 29 30 2 2 2 7 8 11 0 0.041 0.052 1
7 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(4), GABRA2(3), GABRA3(2), GABRA4(4), GABRA5(2), PRKCE(1), SOD1(1) 4480716 17 16 17 3 3 0 4 6 4 0 0.28 0.057 1
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 11 CREBBP(11), DAXX(3), PAX3(5), RARA(1), SP100(7), TNF(1), TNFRSF1A(2) 10230269 30 29 30 4 3 2 10 5 10 0 0.12 0.058 1
9 TCYTOTOXICPATHWAY Cytotoxic T cells release perforin and granzyme to lyse foreign cell targets and express Fas ligand to promote Fas-induced apoptosis. CD2, CD28, CD3D, CD3E, CD3G, CD3Z, CD8A, ICAM1, ITGAL, ITGB2, PTPRC, THY1, TRA@, TRB@ 11 CD2(3), CD3E(2), CD3G(1), CD8A(1), ICAM1(1), ITGAL(6), ITGB2(2), PTPRC(3) 6899991 19 18 19 2 3 5 7 2 2 0 0.045 0.059 1
10 TCRMOLECULE T Cell Receptor and CD3 Complex CD3D, CD3E, CD3G, CD3Z, TRA@, TRB@ 3 CD3E(2), CD3G(1) 781618 3 3 3 1 0 0 2 0 1 0 0.79 0.061 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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