Mutation Analysis (MutSig v2.0)
Cholangiocarcinoma (Primary solid tumor)
21 August 2015  |  analyses__2015_08_21
Maintainer Information
Citation Information
doi:10.7908/C1416W7T
Maintained by David Heiman (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2015): Mutation Analysis (MutSig v2.0). Broad Institute of MIT and Harvard. doi:10.7908/C1416W7T
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: CHOL-TP

  • Number of patients in set: 35

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:CHOL-TP.final_analysis_set.maf

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

  • Significantly mutated genes (q ≤ 0.1): 16

  • Mutations seen in COSMIC: 43

  • Significantly mutated genes in COSMIC territory: 7

  • Significantly mutated genesets: 17

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

Mutation Preprocessing

  • Read 35 MAFs of type "maf1"

  • Total number of mutations in input MAFs: 6755

  • After removing 48 mutations outside chr1-24: 6707

  • After removing 211 blacklisted mutations: 6496

  • After removing 911 noncoding mutations: 5585

  • After collapsing adjacent/redundant mutations: 5584

Mutation Filtering

  • Number of mutations before filtering: 5584

  • After removing 327 mutations outside gene set: 5257

  • After removing 12 mutations outside category set: 5245

Results
Breakdown of Mutations by Type

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

type count
De_novo_Start_InFrame 2
De_novo_Start_OutOfFrame 5
Frame_Shift_Del 89
Frame_Shift_Ins 21
In_Frame_Del 42
In_Frame_Ins 4
Missense_Mutation 3411
Nonsense_Mutation 281
Nonstop_Mutation 3
Silent 1159
Splice_Site 226
Start_Codon_SNP 2
Total 5245
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) 702 55014621 0.000013 13 3.2 2.1
*Cp(A/C/T)->(A/T) 1715 462273375 3.7e-06 3.7 0.93 2.7
A->(C/G) 649 504890172 1.3e-06 1.3 0.32 3.3
flip 347 1022178168 3.4e-07 0.34 0.085 5.3
indel+null 662 1022178168 6.5e-07 0.65 0.16 NaN
double_null 11 1022178168 1.1e-08 0.011 0.0027 NaN
Total 4086 1022178168 4e-06 4 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: CHOL-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->(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: 16. 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 SPTA1 spectrin, alpha, erythrocytic 1 (elliptocytosis 2) 257252 2 2 2 0 0 1 0 0 1 0 0.12 0.57 0.43 0 0 <1.00e-15 <9.20e-12
2 PCF11 PCF11, cleavage and polyadenylation factor subunit, homolog (S. cerevisiae) 164707 6 1 6 0 0 0 5 0 1 0 0.39 0.097 0 0.41 0 <1.00e-15 <9.20e-12
3 DDHD1 DDHD domain containing 1 83718 4 4 1 0 0 0 4 0 0 0 0.000016 0.3 1.2e-06 1 0.000027 9.58e-09 5.88e-05
4 TP53 tumor protein p53 38052 5 5 5 0 1 2 1 0 0 1 1.2e-08 0.29 0.039 0.31 0.055 1.40e-08 6.44e-05
5 PBRM1 polybromo 1 164472 8 8 8 0 0 0 0 0 8 0 1.5e-08 0.26 0.034 0.8 0.064 2.12e-08 7.74e-05
6 BAP1 BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) 50481 7 6 7 1 0 0 1 0 6 0 2e-09 0.68 0.44 0.67 0.6 2.60e-08 7.74e-05
7 IDH1 isocitrate dehydrogenase 1 (NADP+), soluble 44126 4 4 1 0 4 0 0 0 0 0 1e-06 0.3 0.00018 0.72 0.0014 2.95e-08 7.74e-05
8 CDC27 cell division cycle 27 homolog (S. cerevisiae) 88485 5 5 5 0 2 2 1 0 0 0 1.2e-06 0.22 0.028 0.57 0.034 7.15e-07 0.00152
9 FTH1 ferritin, heavy polypeptide 1 19740 3 3 1 0 0 3 0 0 0 0 0.000037 0.33 0.00017 0.057 0.0011 7.42e-07 0.00152
10 HLA-B major histocompatibility complex, class I, B 34635 5 5 3 0 0 5 0 0 0 0 5.5e-07 0.16 0.15 0.94 0.26 2.37e-06 0.00436
11 ZNF676 zinc finger protein 676 62249 3 3 2 0 0 0 0 3 0 0 0.000088 0.68 0.000087 0.98 0.0036 5.09e-06 0.00851
12 MUC2 mucin 2, oligomeric mucus/gel-forming 257402 8 7 7 2 1 4 1 2 0 0 0.0009 0.46 0.00013 0.69 0.00047 6.64e-06 0.0102
13 ARID1A AT rich interactive domain 1A (SWI-like) 167004 6 5 6 1 0 1 0 0 5 0 0.000055 0.94 0.12 0.021 0.034 2.62e-05 0.0371
14 OTOP1 otopetrin 1 48900 4 4 3 0 2 1 1 0 0 0 4.1e-06 0.25 0.45 0.54 0.72 4.05e-05 0.0532
15 RNPC3 RNA-binding region (RNP1, RRM) containing 3 15649 2 2 2 0 0 0 1 1 0 0 0.000046 0.57 NaN NaN NaN 4.62e-05 0.0567
16 EPHA2 EPH receptor A2 70989 4 4 4 0 0 0 0 2 2 0 0.000012 0.56 0.93 0.17 0.45 7.26e-05 0.0835
17 CLIP4 CAP-GLY domain containing linker protein family, member 4 75868 4 4 4 0 0 1 1 0 2 0 2e-05 0.47 0.47 0.77 0.7 0.000167 0.181
18 LCE4A late cornified envelope 4A 10574 2 2 2 0 0 0 1 1 0 0 0.000027 0.64 0.12 0.5 0.6 0.000192 0.196
19 DBNDD2 dysbindin (dystrobrevin binding protein 1) domain containing 2 14960 2 2 2 0 1 0 1 0 0 0 0.00021 0.49 NaN NaN NaN 0.000210 0.203
20 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) 20395 2 2 2 0 1 0 0 1 0 0 0.00046 0.53 0.24 0.063 0.051 0.000275 0.253
21 GXYLT1 glucoside xylosyltransferase 1 39085 3 3 3 0 0 1 0 2 0 0 0.000082 0.64 0.13 0.62 0.33 0.000312 0.273
22 XKR4 XK, Kell blood group complex subunit-related family, member 4 56312 3 2 3 0 0 1 1 1 0 0 0.024 0.48 0.0012 0.82 0.0017 0.000440 0.368
23 NF2 neurofibromin 2 (merlin) 60982 3 3 3 0 1 0 0 0 2 0 0.00036 0.39 0.08 0.94 0.13 0.000515 0.412
24 PLEKHH3 pleckstrin homology domain containing, family H (with MyTH4 domain) member 3 63339 3 3 3 0 1 1 0 0 1 0 0.0029 0.35 0.006 0.32 0.018 0.000551 0.422
25 PAXIP1 PAX interacting (with transcription-activation domain) protein 1 109239 4 4 4 0 0 3 0 0 1 0 0.00052 0.31 0.57 0.025 0.12 0.000685 0.504
26 TRAF4 TNF receptor-associated factor 4 39328 3 3 3 0 0 1 2 0 0 0 7e-05 0.45 0.88 0.57 1 0.000742 0.520
27 MUC21 mucin 21, cell surface associated 59701 3 3 2 0 0 3 0 0 0 0 0.00092 0.33 0.019 0.82 0.078 0.000764 0.520
28 TCHH trichohyalin 182773 5 5 4 0 1 1 1 2 0 0 0.00016 0.36 0.38 0.94 0.52 0.000845 0.556
29 ZNF100 zinc finger protein 100 57713 3 3 3 0 0 1 1 1 0 0 0.00019 0.52 0.39 0.46 0.48 0.000929 0.590
30 NAP1L1 nucleosome assembly protein 1-like 1 42885 3 3 3 0 0 1 1 1 0 0 0.00017 0.55 0.54 0.8 0.66 0.00112 0.672
31 RPS21 ribosomal protein S21 9287 1 1 1 0 0 0 1 0 0 0 0.0012 0.84 NaN NaN NaN 0.00116 0.672
32 NBN nibrin 81480 2 2 1 0 0 2 0 0 0 0 0.021 0.7 0.01 0.0055 0.0055 0.00117 0.672
33 SIGLEC10 sialic acid binding Ig-like lectin 10 73566 2 2 2 0 1 0 0 1 0 0 0.005 0.52 0.16 0.031 0.025 0.00125 0.677
34 ZNF345 zinc finger protein 345 51389 3 3 3 1 0 0 1 2 0 0 0.00034 0.83 0.15 0.9 0.37 0.00126 0.677
35 PLXNA4 plexin A4 198712 5 5 5 0 2 2 0 1 0 0 0.00051 0.16 0.19 0.99 0.27 0.00136 0.677
SPTA1

Figure S1.  This figure depicts the distribution of mutations and mutation types across the SPTA1 significant gene.

PCF11

Figure S2.  This figure depicts the distribution of mutations and mutation types across the PCF11 significant gene.

DDHD1

Figure S3.  This figure depicts the distribution of mutations and mutation types across the DDHD1 significant gene.

TP53

Figure S4.  This figure depicts the distribution of mutations and mutation types across the TP53 significant gene.

PBRM1

Figure S5.  This figure depicts the distribution of mutations and mutation types across the PBRM1 significant gene.

BAP1

Figure S6.  This figure depicts the distribution of mutations and mutation types across the BAP1 significant gene.

IDH1

Figure S7.  This figure depicts the distribution of mutations and mutation types across the IDH1 significant gene.

CDC27

Figure S8.  This figure depicts the distribution of mutations and mutation types across the CDC27 significant gene.

FTH1

Figure S9.  This figure depicts the distribution of mutations and mutation types across the FTH1 significant gene.

HLA-B

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

ZNF676

Figure S11.  This figure depicts the distribution of mutations and mutation types across the ZNF676 significant gene.

MUC2

Figure S12.  This figure depicts the distribution of mutations and mutation types across the MUC2 significant gene.

ARID1A

Figure S13.  This figure depicts the distribution of mutations and mutation types across the ARID1A significant gene.

OTOP1

Figure S14.  This figure depicts the distribution of mutations and mutation types across the OTOP1 significant gene.

RNPC3

Figure S15.  This figure depicts the distribution of mutations and mutation types across the RNPC3 significant gene.

EPHA2

Figure S16.  This figure depicts the distribution of mutations and mutation types across the EPHA2 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: 7. Number of genes displayed: 10

rank gene description n cos n_cos N_cos cos_ev p q
1 IDH1 isocitrate dehydrogenase 1 (NADP+), soluble 4 5 4 175 5968 3.7e-15 1.7e-11
2 TP53 tumor protein p53 5 356 5 12460 1178 2.4e-09 5.5e-06
3 IDH2 isocitrate dehydrogenase 2 (NADP+), mitochondrial 2 6 2 210 166 3.5e-07 0.00053
4 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 2 52 2 1820 14472 0.000026 0.03
5 PDGFD platelet derived growth factor D 2 1 1 35 1 0.00014 0.09
6 TBX20 T-box 20 2 1 1 35 1 0.00014 0.09
7 ZDHHC4 zinc finger, DHHC-type containing 4 1 1 1 35 1 0.00014 0.09
8 APC adenomatous polyposis coli 4 839 3 29365 34 0.00025 0.11
9 CHD1L chromodomain helicase DNA binding protein 1-like 1 2 1 70 1 0.00028 0.11
10 IMP4 IMP4, U3 small nucleolar ribonucleoprotein, homolog (yeast) 1 2 1 70 1 0.00028 0.11

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: 17. 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 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 CDK2(1), CDKN1A(1), CDKN2A(2), MDM2(1), TP53(5) 401952 10 9 10 0 2 2 1 1 3 1 0.087 8.2e-07 0.0003
2 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(5), ATR(1), CDC25C(1), CHEK1(1), CHEK2(2), TP53(5) 825226 15 12 15 0 2 6 2 1 3 1 0.025 9.7e-07 0.0003
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 ATM(5), BRCA1(1), CDKN1A(1), CHEK1(1), CHEK2(2), MDM2(1), RAD50(1), TP53(5) 1482189 17 14 17 1 2 5 3 1 5 1 0.076 0.000013 0.0026
4 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(1), ATM(5), CDK2(1), CDKN1A(1), MDM2(1), TIMP3(1), TP53(5) 939238 15 11 15 1 1 5 1 1 6 1 0.12 0.000026 0.0033
5 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 CDKN2A(2), MDM2(1), PIK3CA(2), PIK3R1(2), TP53(5) 1017333 12 11 12 0 2 4 2 2 1 1 0.042 0.000027 0.0033
6 P53HYPOXIAPATHWAY Hypoxia induces p53 accumulation and consequent apoptosis with p53-mediated cell cycle arrest, which is present under conditions of DNA damage. ABCB1, AKT1, ATM, BAX, CDKN1A, CPB2, CSNK1A1, CSNK1D, FHL2, GADD45A, HIC1, HIF1A, HSPA1A, HSPCA, IGFBP3, MAPK8, MDM2, NFKBIB, NQO1, TP53 19 ABCB1(1), ATM(5), CDKN1A(1), MDM2(1), TP53(5) 1064878 13 11 13 0 2 3 1 1 5 1 0.047 0.000067 0.0068
7 G2PATHWAY Activated Cdc2-cyclin B kinase regulates the G2/M transition; DNA damage stimulates the DNA-PK/ATM/ATR kinases, which inactivate Cdc2. ATM, ATR, BRCA1, CCNB1, CDC2, CDC25A, CDC25B, CDC25C, CDC34, CDKN1A, CDKN2D, CHEK1, CHEK2, EP300, GADD45A, MDM2, MYT1, PLK, PRKDC, RPS6KA1, TP53, WEE1, YWHAH, YWHAQ 22 ATM(5), ATR(1), BRCA1(1), CDC25C(1), CDKN1A(1), CHEK1(1), CHEK2(2), EP300(3), MDM2(1), PRKDC(2), TP53(5) 2178745 23 15 23 0 2 9 3 2 6 1 0.0034 0.00012 0.0095
8 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(5), CDC25C(1), CDK2(1), CHEK1(1), TP53(5) 903263 13 10 13 0 1 5 1 1 4 1 0.038 0.00012 0.0095
9 GLUTATHIONE_METABOLISM ANPEP, G6PD, GCLC, GCLM, GGT1, GPX1, GPX2, GPX3, GPX4, GPX5, GSS, GSTA1, GSTA2, GSTA3, GSTA4, GSTM1, GSTM2, GSTM3, GSTM4, GSTM5, GSTO2, GSTP1, GSTT1, GSTT2, GSTZ1, IDH1, IDH2, MGST1, MGST2, MGST3, PGD 30 ANPEP(1), GPX2(1), IDH1(4), IDH2(2), MGST1(1), PGD(2) 910815 11 11 8 1 5 4 0 1 1 0 0.089 0.00025 0.017
10 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 ATM(5), ATR(1), CDK2(1), CDKN1A(1), CDKN2A(2), TP53(5) 1539151 15 12 15 1 2 4 1 2 5 1 0.11 0.0004 0.023

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 PLK3PATHWAY Active Plk3 phosphorylates CDC25c, blocking the G2/M transition, and phosphorylates p53 to induce apoptosis. ATM, ATR, CDC25C, CHEK1, CHEK2, CNK, TP53, YWHAH 6 ATM(5), ATR(1), CDC25C(1), CHEK1(1), CHEK2(2) 787174 10 9 10 0 1 4 1 1 3 0 0.075 0.00024 0.15
2 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 18 ATM(5), BRCA1(1), CDKN1A(1), CHEK1(1), CHEK2(2), MDM2(1), RAD50(1) 1444137 12 11 12 1 1 3 2 1 5 0 0.19 0.0011 0.32
3 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 15 APAF1(1), ATM(5), CDK2(1), CDKN1A(1), MDM2(1), TIMP3(1) 901186 10 8 10 1 0 3 0 1 6 0 0.29 0.0027 0.32
4 TPOPATHWAY Thrombopoietin binds to its receptor and activates cell growth through the Erk and JNK MAP kinase pathways, protein kinase C, and JAK/STAT activation. CSNK2A1, FOS, GRB2, HRAS, JAK2, JUN, MAP2K1, MAPK3, MPL, PIK3CA, PIK3R1, PLCG1, PRKCA, PRKCB1, RAF1, RASA1, SHC1, SOS1, STAT1, STAT3, STAT5A, STAT5B, THPO 22 GRB2(1), MAP2K1(1), PIK3CA(2), PIK3R1(2), PLCG1(1), PRKCA(1), RASA1(1), SOS1(1), STAT1(1), STAT5A(1), THPO(2) 1493290 14 12 14 1 1 7 2 2 2 0 0.082 0.0032 0.32
5 IGF1RPATHWAY Insulin-like growth factor receptor IGF-1R promotes cell growth and inhibits apoptosis on binding of ligands IGF-1 and 2 via Ras activation and the AKT pathway. AKT1, BAD, GRB2, HRAS, IGF1R, IRS1, MAP2K1, MAPK1, MAPK3, PIK3CA, PIK3R1, RAF1, SHC1, SOS1, YWHAH 15 BAD(1), GRB2(1), IGF1R(1), IRS1(2), MAP2K1(1), PIK3CA(2), PIK3R1(2), SOS1(1) 953052 11 9 11 1 1 7 1 2 0 0 0.15 0.0036 0.32
6 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 GRB2(1), NTRK1(1), PIK3CA(2), PIK3R1(2), PLCG1(1), PRKCA(1), SOS1(1) 773480 9 8 9 0 1 5 1 1 1 0 0.071 0.0039 0.32
7 SA_TRKA_RECEPTOR The TrkA receptor binds nerve growth factor to activate MAP kinase pathways and promote cell growth. AKT1, AKT2, AKT3, ARHA, CDKN1A, ELK1, GRB2, HRAS, MAP2K1, MAP2K2, NGFB, NGFR, NTRK1, PIK3CA, PIK3CD, SHC1, SOS1 15 CDKN1A(1), ELK1(1), GRB2(1), MAP2K1(1), NTRK1(1), PIK3CA(2), SOS1(1) 827926 8 8 8 0 1 3 0 3 1 0 0.15 0.0039 0.32
8 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 CYP2E1(1), NR1I3(2), PTGS1(1) 265148 4 4 4 0 0 0 2 0 2 0 0.46 0.0049 0.32
9 P53HYPOXIAPATHWAY Hypoxia induces p53 accumulation and consequent apoptosis with p53-mediated cell cycle arrest, which is present under conditions of DNA damage. ABCB1, AKT1, ATM, BAX, CDKN1A, CPB2, CSNK1A1, CSNK1D, FHL2, GADD45A, HIC1, HIF1A, HSPA1A, HSPCA, IGFBP3, MAPK8, MDM2, NFKBIB, NQO1, TP53 18 ABCB1(1), ATM(5), CDKN1A(1), MDM2(1) 1026826 8 8 8 0 1 1 0 1 5 0 0.15 0.005 0.32
10 G2PATHWAY Activated Cdc2-cyclin B kinase regulates the G2/M transition; DNA damage stimulates the DNA-PK/ATM/ATR kinases, which inactivate Cdc2. ATM, ATR, BRCA1, CCNB1, CDC2, CDC25A, CDC25B, CDC25C, CDC34, CDKN1A, CDKN2D, CHEK1, CHEK2, EP300, GADD45A, MDM2, MYT1, PLK, PRKDC, RPS6KA1, TP53, WEE1, YWHAH, YWHAQ 21 ATM(5), ATR(1), BRCA1(1), CDC25C(1), CDKN1A(1), CHEK1(1), CHEK2(2), EP300(3), MDM2(1), PRKDC(2) 2140693 18 12 18 0 1 7 2 2 6 0 0.011 0.0051 0.32
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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