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.

- Analysis Results (MD5 checksum)

- Auxiliary Data (MD5 checksum)

- MAGE-TAB File (MD5 checksum)

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