Mutation Analysis (MutSig v1.5)
Thyroid Adenocarcinoma (Primary solid tumor)
15 January 2014 | analyses__2014_01_15
Maintainer Information
Citation Information
doi:10.7908/C1FN14PN
Maintained by Dan DiCara (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2014): Mutation Analysis (MutSig v1.5). Broad Institute of MIT and Harvard. doi:10.7908/C1FN14PN
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: THCA-TP

- Number of patients in set: 401

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:THCA-TP.final_analysis_set.maf

- Significantly mutated genes (q ≤ 0.1): 8

- Mutations seen in COSMIC: 312

- Significantly mutated genes in COSMIC territory: 9

- Significantly mutated genesets: 91

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

Mutation Preprocessing

- Read 401 MAFs of type "Broad"

- Total number of mutations in input MAFs: 7430

- After removing 2 mutations outside chr1-24: 7428

- After removing 23 blacklisted mutations: 7405

- After removing 61 noncoding mutations: 7344

- After collapsing adjacent/redundant mutations: 6975

Mutation Filtering

- Number of mutations before filtering: 6975

- After removing 256 mutations outside gene set: 6719

- After removing 3 mutations outside category set: 6716

Results
Breakdown of Mutations by Type

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

type | count
--- | ---
Frame_Shift_Del | 196
Frame_Shift_Ins | 33
In_Frame_Del | 27
In_Frame_Ins | 6
Missense_Mutation | 4350
Nonsense_Mutation | 240
Nonstop_Mutation | 5
Silent | 1644
Splice_Site | 215
Total | 6716

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 | 810 | 651888269 | 1.2e-06 | 1.2 | 2.9 | 2.1
*Cp(A/C/T)->T | 1012 | 5343350203 | 1.9e-07 | 0.19 | 0.44 | 1.7
A->G | 816 | 5758499319 | 1.4e-07 | 0.14 | 0.33 | 2.3
transver | 1712 | 11753737791 | 1.5e-07 | 0.15 | 0.34 | 5
indel+null | 719 | 11753737791 | 6.1e-08 | 0.061 | 0.14 | NaN
double_null | 3 | 11753737791 | 2.6e-10 | 0.00026 | 0.00059 | NaN
Total | 5072 | 11753737791 | 4.3e-07 | 0.43 | 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: THCA-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: A->G

- n4 = number of nonsilent mutations of type: transver

- 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: 8. 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 | BRAF | v-raf murine sarcoma viral oncogene homolog B1 | 891836 | 240 | 240 | 6 | 1 | 0 | 1 | 1 | 234 | 4 | 0 | <1.00e-15 | <1.00e-15 | <1.81e-11
2 | NRAS | neuroblastoma RAS viral (v-ras) oncogene homolog | 234967 | 34 | 34 | 2 | 0 | 0 | 0 | 27 | 7 | 0 | 0 | 8.81e-06 | 3.00e-15 | 2.71e-11
3 | HRAS | v-Ha-ras Harvey rat sarcoma viral oncogene homolog | 260071 | 14 | 14 | 2 | 0 | 0 | 0 | 11 | 3 | 0 | 0 | 0.0940 | 1.60e-14 | 9.64e-11
4 | EIF1AX | eukaryotic translation initiation factor 1A, X-linked | 176670 | 6 | 6 | 5 | 0 | 0 | 3 | 0 | 1 | 2 | 0 | 0.235 | 2.92e-11 | 1.32e-07
5 | PPM1D | protein phosphatase 1D magnesium-dependent, delta isoform | 625741 | 5 | 5 | 5 | 0 | 0 | 1 | 0 | 0 | 4 | 0 | 0.700 | 4.70e-07 | 0.00170
6 | KRAS | v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog | 275782 | 4 | 4 | 3 | 0 | 0 | 0 | 1 | 3 | 0 | 0 | 0.414 | 3.07e-06 | 0.00926
7 | CHEK2 | CHK2 checkpoint homolog (S. pombe) | 635291 | 5 | 5 | 5 | 0 | 0 | 0 | 1 | 3 | 1 | 0 | 0.333 | 5.54e-06 | 0.0143
8 | S100A7 | S100 calcium binding protein A7 | 125914 | 3 | 3 | 3 | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 0.679 | 1.49e-05 | 0.0336
9 | TMSB15A | thymosin beta 15a | 58475 | 2 | 2 | 2 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0.592 | 5.07e-05 | 0.102
10 | MSI1 | musashi homolog 1 (Drosophila) | 314023 | 3 | 3 | 3 | 0 | 1 | 0 | 0 | 1 | 1 | 0 | 0.502 | 0.000112 | 0.193
11 | SLA | Src-like-adaptor | 331456 | 3 | 3 | 3 | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 0.755 | 0.000120 | 0.193
12 | NUP93 | nucleoporin 93kDa | 1019335 | 4 | 4 | 2 | 0 | 0 | 1 | 0 | 0 | 3 | 0 | 0.118 | 0.000128 | 0.193
13 | ADO | 2-aminoethanethiol (cysteamine) dioxygenase | 142942 | 2 | 2 | 2 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0.648 | 0.000143 | 0.199
14 | EFCAB1 | EF-hand calcium binding domain 1 | 258650 | 2 | 2 | 2 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0.730 | 0.000175 | 0.213
15 | SLC25A45 | solute carrier family 25, member 45 | 357268 | 3 | 3 | 3 | 1 | 1 | 1 | 1 | 0 | 0 | 0 | 0.704 | 0.000193 | 0.213
16 | BRIX1 | BRX1, biogenesis of ribosomes, homolog (S. cerevisiae) | 362700 | 3 | 3 | 3 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 0.411 | 0.000197 | 0.213
17 | SAMD1 | sterile alpha motif domain containing 1 | 179200 | 2 | 2 | 2 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0.451 | 0.000209 | 0.213
18 | C11orf87 | chromosome 11 open reading frame 87 | 235195 | 3 | 3 | 3 | 0 | 2 | 0 | 0 | 1 | 0 | 0 | 0.301 | 0.000212 | 0.213
19 | DNAH9 | dynein, axonemal, heavy chain 9 | 5321094 | 9 | 9 | 9 | 1 | 2 | 3 | 1 | 3 | 0 | 0 | 0.139 | 0.000333 | 0.305
20 | CDH8 | cadherin 8, type 2 | 977851 | 4 | 4 | 4 | 1 | 1 | 0 | 0 | 3 | 0 | 0 | 0.658 | 0.000337 | 0.305
21 | CD163 | CD163 molecule | 1404730 | 4 | 4 | 4 | 0 | 2 | 1 | 1 | 0 | 0 | 0 | 0.228 | 0.000364 | 0.311
22 | SLC12A4 | solute carrier family 12 (potassium/chloride transporters), member 4 | 1294711 | 5 | 5 | 5 | 0 | 2 | 1 | 0 | 2 | 0 | 0 | 0.184 | 0.000405 | 0.311
23 | RPRD1A | regulation of nuclear pre-mRNA domain containing 1A | 348091 | 3 | 3 | 3 | 0 | 1 | 0 | 0 | 1 | 1 | 0 | 0.491 | 0.000414 | 0.311
24 | BAGE | B melanoma antigen | 50513 | 1 | 1 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0.500 | 0.000416 | 0.311
25 | SPTA1 | spectrin, alpha, erythrocytic 1 (elliptocytosis 2) | 2989128 | 6 | 6 | 6 | 0 | 0 | 3 | 0 | 1 | 2 | 0 | 0.0708 | 0.000430 | 0.311
26 | PLP1 | proteolipid protein 1 (Pelizaeus-Merzbacher disease, spastic paraplegia 2, uncomplicated) | 345054 | 2 | 2 | 2 | 1 | 2 | 0 | 0 | 0 | 0 | 0 | 0.644 | 0.000524 | 0.353
27 | COL5A3 | collagen, type V, alpha 3 | 1951789 | 5 | 5 | 5 | 0 | 2 | 1 | 0 | 2 | 0 | 0 | 0.191 | 0.000526 | 0.353
28 | DNASE2 | deoxyribonuclease II, lysosomal | 407482 | 3 | 3 | 3 | 0 | 0 | 2 | 1 | 0 | 0 | 0 | 0.269 | 0.000555 | 0.358
29 | IL7R | interleukin 7 receptor | 565326 | 3 | 3 | 3 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0.489 | 0.000602 | 0.376
30 | SNRNP70 | small nuclear ribonucleoprotein 70kDa (U1) | 278831 | 2 | 2 | 2 | 1 | 0 | 1 | 0 | 0 | 1 | 0 | 0.908 | 0.000694 | 0.408
31 | TBC1D7 | TBC1 domain family, member 7 | 363943 | 2 | 2 | 2 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0.548 | 0.000700 | 0.408
32 | CYB5R2 | cytochrome b5 reductase 2 | 335914 | 2 | 2 | 2 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0.503 | 0.000722 | 0.408
33 | MED31 | mediator complex subunit 31 | 162836 | 2 | 2 | 2 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0.587 | 0.000838 | 0.456
34 | OR5T2 | olfactory receptor, family 5, subfamily T, member 2 | 431047 | 2 | 2 | 2 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0.393 | 0.000857 | 0.456
35 | SH2D6 | SH2 domain containing 6 | 169733 | 2 | 2 | 2 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0.473 | 0.000882 | 0.456

BRAF

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

NRAS

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

HRAS

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

EIF1AX

Figure S4. This figure depicts the distribution of mutations and mutation types across the EIF1AX significant gene.

PPM1D

Figure S5. This figure depicts the distribution of mutations and mutation types across the PPM1D significant gene.

KRAS

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

CHEK2

Figure S7. This figure depicts the distribution of mutations and mutation types across the CHEK2 significant gene.

S100A7

Figure S8. This figure depicts the distribution of mutations and mutation types across the S100A7 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: 9. Number of genes displayed: 10

rank | gene | description | n | cos | n_cos | N_cos | cos_ev | p | q
--- | --- | --- | --- | --- | --- | --- | --- | --- | ---
1 | HRAS | v-Ha-ras Harvey rat sarcoma viral oncogene homolog | 14 | 19 | 14 | 7619 | 2912 | 2.9e-13 | 1.1e-09
2 | NRAS | neuroblastoma RAS viral (v-ras) oncogene homolog | 34 | 33 | 34 | 13233 | 44132 | 5e-13 | 1.1e-09
3 | BRAF | v-raf murine sarcoma viral oncogene homolog B1 | 240 | 89 | 238 | 35689 | 3392099 | 1.3e-12 | 2e-09
4 | KRAS | v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog | 4 | 52 | 4 | 20852 | 15018 | 2.7e-10 | 3.1e-07
5 | C4BPA | complement component 4 binding protein, alpha | 1 | 1 | 1 | 401 | 1 | 0.00017 | 0.087
6 | PCGF2 | polycomb group ring finger 2 | 2 | 1 | 1 | 401 | 1 | 0.00017 | 0.087
7 | SEZ6L | seizure related 6 homolog (mouse)-like | 2 | 1 | 1 | 401 | 1 | 0.00017 | 0.087
8 | SMC3 | structural maintenance of chromosomes 3 | 1 | 1 | 1 | 401 | 1 | 0.00017 | 0.087
9 | TNS1 | tensin 1 | 3 | 1 | 1 | 401 | 1 | 0.00017 | 0.087
10 | DCC | deleted in colorectal carcinoma | 2 | 3 | 1 | 1203 | 1 | 0.00052 | 0.21

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: 91. 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 | HSA04010_MAPK_SIGNALING_PATHWAY | Genes involved in MAPK signaling pathway | ACVR1B, ACVR1C, AKT1, AKT2, AKT3, ARRB1, ARRB2, ATF2, ATF4, BDNF, BRAF, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1, CACNB2, CACNB3, CACNB4, CACNG1, CACNG2, CACNG3, CACNG4, CACNG5, CACNG6, CACNG7, CACNG8, CASP3, CD14, CDC25B, CDC42, CHP, CHUK, CRK, CRKL, DAXX, DDIT3, DUSP1, DUSP10, DUSP14, DUSP16, DUSP2, DUSP3, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8, DUSP9, ECSIT, EGF, EGFR, ELK1, ELK4, EVI1, FAS, FASLG, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGFR1, FGFR2, FGFR3, FGFR4, FLNA, FLNB, FLNC, FOS, GADD45A, GADD45B, GADD45G, GNA12, GNG12, GRB2, HRAS, IKBKB, IKBKG, IL1A, IL1B, IL1R1, IL1R2, JUN, JUND, KRAS, LOC653852, MAP2K1, MAP2K1IP1, MAP2K2, MAP2K3, MAP2K4, MAP2K5, MAP2K6, MAP2K7, MAP3K1, MAP3K10, MAP3K12, MAP3K13, MAP3K14, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7, MAP3K7IP1, MAP3K7IP2, MAP3K8, MAP4K1, MAP4K2, MAP4K3, MAP4K4, MAPK1, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK3, MAPK7, MAPK8, MAPK8IP1, MAPK8IP2, MAPK8IP3, MAPK9, MAPKAPK2, MAPKAPK3, MAPKAPK5, MAPT, MAX, MEF2C, MKNK1, MKNK2, MOS, MRAS, MYC, NF1, NFATC2, NFATC4, NFKB1, NFKB2, NGFB, NLK, NR4A1, NRAS, NTF3, NTF5, NTRK1, NTRK2, PAK1, PAK2, PDGFA, PDGFB, PDGFRA, PDGFRB, PLA2G10, PLA2G12A, PLA2G12B, PLA2G1B, PLA2G2A, PLA2G2D, PLA2G2E, PLA2G2F, PLA2G3, PLA2G4A, PLA2G5, PLA2G6, PPM1A, PPM1B, PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, PPP5C, PRKACA, PRKACB, PRKACG, PRKCA, PRKCB1, PRKCG, PRKX, PRKY, PTPN5, PTPN7, PTPRR, RAC1, RAC2, RAC3, RAF1, RAP1A, RAP1B, RAPGEF2, RASA1, RASA2, RASGRF1, RASGRF2, RASGRP1, RASGRP2, RASGRP3, RASGRP4, RPS6KA1, RPS6KA2, RPS6KA3, RPS6KA4, RPS6KA5, RPS6KA6, RRAS, RRAS2, SOS1, SOS2, SRF, STK3, STK4, STMN1, TAOK1, TAOK2, TAOK3, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, TNF, TNFRSF1A, TP53, TRAF2, TRAF6, ZAK | 247 | AKT1(3), AKT2(2), ARRB1(1), BRAF(240), CACNA1A(2), CACNA1B(2), CACNA1C(1), CACNA1D(2), CACNA1E(5), CACNA1G(3), CACNA1S(1), CACNA2D1(2), CACNA2D3(1), CACNA2D4(2), CACNB3(1), CACNG7(1), CASP3(1), CDC42(1), DUSP5(1), DUSP7(1), ECSIT(1), FGF20(1), FGF5(1), FGF7(1), FGFR2(1), FLNA(1), FLNC(3), HRAS(14), IL1R1(2), JUN(1), KRAS(4), MAP2K6(1), MAP3K1(2), MAP3K3(3), MAP3K6(1), MAP4K4(1), MAPK10(1), MAPK8IP2(1), MAPKAPK3(1), MYC(1), NF1(2), NFATC4(3), NRAS(34), PDGFRB(1), PLA2G2A(1), PLA2G5(1), PPP3R2(1), PTPRR(1), RAP1A(1), RASA1(1), RASGRF2(2), RASGRP1(1), SOS1(1), TGFBR2(1), TP53(3) | 170374057 | 369 | 311 | 89 | 27 | 13 | 23 | 51 | 266 | 16 | 0 | 4.33e-15 | <1.00e-15 | <6.16e-14
2 | HSA04910_INSULIN_SIGNALING_PATHWAY | Genes involved in insulin signaling pathway | ACACA, ACACB, AKT1, AKT2, AKT3, ARAF, BAD, BRAF, CALM1, CALM2, CALM3, CALML3, CALML6, CBL, CBLB, CBLC, CRK, CRKL, EIF4EBP1, ELK1, EXOC7, FASN, FBP1, FBP2, FLOT1, FLOT2, FOXO1, FRAP1, G6PC, G6PC2, GCK, GRB2, GSK3B, GYS1, GYS2, HRAS, IKBKB, INPP5D, INS, INSR, IRS1, IRS2, IRS4, KIAA1303, KRAS, LIPE, MAP2K1, MAP2K2, MAPK1, MAPK10, MAPK3, MAPK8, MAPK9, MKNK1, MKNK2, NRAS, PCK1, PCK2, PDE3A, PDE3B, PDPK1, PFKL, PFKM, PFKP, PHKA1, PHKA2, PHKB, PHKG1, PHKG2, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R5, PKLR, PKM2, PPARGC1A, PPP1CA, PPP1CB, PPP1CC, PPP1R3A, PPP1R3B, PPP1R3C, PPP1R3D, PRKAA1, PRKAA2, PRKAB1, PRKAB2, PRKACA, PRKACB, PRKACG, PRKAG1, PRKAG2, PRKAG3, PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B, PRKCI, PRKCZ, PRKX, PRKY, PTPN1, PTPRF, PYGB, PYGL, PYGM, RAF1, RAPGEF1, RHEB, RHOQ, RPS6, RPS6KB1, RPS6KB2, SH2B2, SHC1, SHC2, SHC3, SHC4, SKIP, SLC2A4, SOCS1, SOCS2, SOCS3, SOCS4, SORBS1, SOS1, SOS2, SREBF1, TRIP10, TSC1, TSC2 | 131 | ACACA(1), ACACB(1), AKT1(3), AKT2(2), BRAF(240), EXOC7(1), FASN(1), FLOT1(1), FLOT2(1), GYS2(1), HRAS(14), INPP5D(1), IRS1(1), IRS2(1), KRAS(4), MAPK10(1), NRAS(34), PCK2(1), PDE3A(1), PFKP(2), PHKA2(2), PIK3CA(2), PIK3CB(1), PIK3CD(1), PIK3CG(1), PIK3R1(1), PIK3R5(3), PPARGC1A(1), PPP1R3B(1), PRKAG2(1), PRKAR2A(1), PYGB(1), RAPGEF1(2), RHOQ(2), RPS6KB2(1), SHC1(1), SOS1(1), SREBF1(1), TRIP10(1) | 95676922 | 337 | 303 | 57 | 19 | 11 | 10 | 46 | 262 | 8 | 0 | 2.11e-15 | <1.00e-15 | <6.16e-14
3 | HSA04650_NATURAL_KILLER_CELL_MEDIATED_CYTOTOXICITY | Genes involved in natural killer cell mediated cytotoxicity | ARAF, BID, BRAF, CASP3, CD244, CD247, CD48, CHP, CSF2, FAS, FASLG, FCER1G, FCGR3A, FCGR3B, FYN, GRB2, GZMB, HCST, HLA-A, HLA-B, HLA-C, HLA-E, HLA-G, HRAS, ICAM1, ICAM2, IFNA1, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA2, IFNA21, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNAR1, IFNAR2, IFNB1, IFNG, IFNGR1, IFNGR2, ITGAL, ITGB2, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5A, KIR2DS1, KIR2DS2, KIR3DL1, KIR3DL2, KLRC1, KLRC2, KLRC3, KLRD1, KLRK1, KRAS, LAT, LCK, LCP2, LOC652578, MAP2K1, MAP2K2, MAPK1, MAPK3, MICA, MICB, NCR1, NCR2, NCR3, NFAT5, NFATC1, NFATC2, NFATC3, NFATC4, NRAS, PAK1, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R5, PLCG1, PLCG2, PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, PRF1, PRKCA, PRKCB1, PRKCG, PTK2B, PTPN11, PTPN6, RAC1, RAC2, RAC3, RAF1, SH2D1A, SH2D1B, SH3BP2, SHC1, SHC2, SHC3, SHC4, SOS1, SOS2, SYK, TNF, TNFRSF10A, TNFRSF10B, TNFRSF10C, TNFRSF10D, TNFSF10, TYROBP, ULBP1, ULBP2, ULBP3, VAV1, VAV2, VAV3, ZAP70 | 126 | BRAF(240), CASP3(1), HLA-E(1), HRAS(14), IFNAR2(1), IFNGR1(1), ITGAL(4), KIR2DL1(1), KIR3DL2(2), KRAS(4), LCK(1), NCR1(1), NFAT5(2), NFATC1(1), NFATC4(3), NRAS(34), PIK3CA(2), PIK3CB(1), PIK3CD(1), PIK3CG(1), PIK3R1(1), PIK3R5(3), PPP3R2(1), PTK2B(2), SHC1(1), SOS1(1), SYK(1), ULBP1(1) | 67770272 | 327 | 300 | 48 | 15 | 9 | 9 | 43 | 258 | 8 | 0 | <1.00e-15 | <1.00e-15 | <6.16e-14
4 | HSA04012_ERBB_SIGNALING_PATHWAY | Genes involved in ErbB signaling pathway | ABL1, ABL2, AKT1, AKT2, AKT3, ARAF, AREG, BAD, BRAF, BTC, CAMK2A, CAMK2B, CAMK2D, CAMK2G, CBL, CBLB, CBLC, CDKN1A, CDKN1B, CRK, CRKL, EGF, EGFR, EIF4EBP1, ELK1, ERBB2, ERBB3, ERBB4, EREG, FRAP1, GAB1, GRB2, GSK3B, HBEGF, HRAS, JUN, KRAS, MAP2K1, MAP2K2, MAP2K4, MAP2K7, MAPK1, MAPK10, MAPK3, MAPK8, MAPK9, MYC, NCK1, NCK2, NRAS, NRG1, NRG2, NRG3, NRG4, PAK1, PAK2, PAK3, PAK4, PAK6, PAK7, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R5, PLCG1, PLCG2, PRKCA, PRKCB1, PRKCG, PTK2, RAF1, RPS6KB1, RPS6KB2, SHC1, SHC2, SHC3, SHC4, SOS1, SOS2, SRC, STAT5A, STAT5B, TGFA | 85 | ABL1(1), ABL2(1), AKT1(3), AKT2(2), BRAF(240), CAMK2A(1), CAMK2B(1), CDKN1A(1), ERBB2(1), ERBB3(1), ERBB4(2), HRAS(14), JUN(1), KRAS(4), MAPK10(1), MYC(1), NCK1(2), NRAS(34), NRG1(1), NRG2(1), PAK3(1), PAK7(2), PIK3CA(2), PIK3CB(1), PIK3CD(1), PIK3CG(1), PIK3R1(1), PIK3R5(3), RPS6KB2(1), SHC1(1), SOS1(1), SRC(1), STAT5B(1) | 61538338 | 330 | 298 | 50 | 9 | 8 | 8 | 46 | 258 | 9 | 1 | <1.00e-15 | <1.00e-15 | <6.16e-14
5 | ST_INTEGRIN_SIGNALING_PATHWAY | Integrins are transmembrane receptors that mediate cell growth, survival, and migration by binding to ligands in the extracellular matrix. | ABL1, ACK1, ACTN1, ACTR2, ACTR3, AKT1, AKT2, AKT3, ANGPTL2, ARHGEF6, ARHGEF7, BCAR1, BRAF, CAV1, CDC42, CDKN2A, CRK, CSE1L, DDEF1, DOCK1, EPHB2, FYN, GRAF, GRB2, GRB7, GRF2, GRLF1, ILK, ITGA1, ITGA10, ITGA11, ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA7, ITGA8, ITGA9, ITGB3BP, MAP2K4, MAP2K7, MAP3K11, MAPK1, MAPK10, MAPK8, MAPK8IP1, MAPK8IP2, MAPK8IP3, MAPK9, MRAS, MYLK, MYLK2, P4HB, PAK1, PAK2, PAK3, PAK4, PAK6, PAK7, PIK3CA, PIK3CB, PKLR, PLCG1, PLCG2, PTEN, PTK2, RAF1, RALA, RHO, ROCK1, ROCK2, SHC1, SOS1, SOS2, SRC, TERF2IP, TLN1, TLN2, VASP, WAS, ZYX | 78 | ABL1(1), AKT1(3), AKT2(2), ANGPTL2(1), ARHGEF6(1), ARHGEF7(1), BRAF(240), CDC42(1), GRB7(1), ITGA10(1), ITGA3(2), ITGA7(1), ITGA8(1), MAPK10(1), MAPK8IP2(1), MYLK(3), P4HB(1), PAK3(1), PAK7(2), PIK3CA(2), PIK3CB(1), PTEN(2), SHC1(1), SOS1(1), SRC(1), TLN2(2) | 72966816 | 275 | 251 | 40 | 13 | 8 | 9 | 3 | 248 | 6 | 1 | 2.26e-12 | <1.00e-15 | <6.16e-14
6 | ST_ADRENERGIC | Adrenergic receptors respond to epinephrine and norepinephrine signaling. | AKT1, APC, AR, ASAH1, BF, BRAF, CAMP, CCL13, CCL15, CCL16, DAG1, EGFR, GAS, GNA11, GNA15, GNAI1, GNAQ, ITPKA, ITPKB, ITPR1, ITPR2, ITPR3, KCNJ3, KCNJ5, KCNJ9, MAPK1, MAPK10, MAPK14, PHKA2, PIK3CA, PIK3CD, PIK3R1, PITX2, PTX1, PTX3, RAF1, SRC | 34 | AKT1(3), APC(2), BRAF(240), ITPR1(2), ITPR2(5), MAPK10(1), PHKA2(2), PIK3CA(2), PIK3CD(1), PIK3R1(1), PITX2(2), SRC(1) | 31888074 | 262 | 246 | 27 | 6 | 5 | 5 | 1 | 244 | 7 | 0 | 9.66e-15 | <1.00e-15 | <6.16e-14
7 | HSA04150_MTOR_SIGNALING_PATHWAY | Genes involved in mTOR signaling pathway | AKT1, AKT2, AKT3, BRAF, CAB39, DDIT4, EIF4B, EIF4EBP1, FIGF, FRAP1, GBL, HIF1A, IGF1, INS, KIAA1303, LYK5, MAPK1, MAPK3, PDPK1, PGF, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R5, PRKAA1, PRKAA2, RHEB, RICTOR, RPS6, RPS6KA1, RPS6KA2, RPS6KA3, RPS6KA6, RPS6KB1, RPS6KB2, STK11, TSC1, TSC2, ULK1, ULK2, ULK3, VEGFA, VEGFB, VEGFC | 44 | AKT1(3), AKT2(2), BRAF(240), FIGF(1), HIF1A(1), PIK3CA(2), PIK3CB(1), PIK3CD(1), PIK3CG(1), PIK3R1(1), PIK3R5(3), RPS6KB2(1), ULK3(1), VEGFA(1) | 31724050 | 259 | 242 | 24 | 4 | 3 | 4 | 5 | 240 | 7 | 0 | <1.00e-15 | <1.00e-15 | <6.16e-14
8 | ST_DIFFERENTIATION_PATHWAY_IN_PC12_CELLS | Rat-derived PC12 cells respond to nerve growth factor (NGF) and PACAP to differentiate into neuronal cells. | AKT1, ASAH1, ATF1, BRAF, CAMP, CREB1, CREB3, CREB5, CREBBP, CRKL, DAG1, EGR1, EGR2, EGR3, EGR4, ELK1, FRS2, GAS, GNAQ, GRF2, JUN, MAP1B, MAP2K4, MAP2K7, MAPK1, MAPK10, MAPK3, MAPK8, MAPK8IP1, MAPK8IP2, MAPK8IP3, MAPK9, NTRK1, OPN1LW, PACAP, PIK3C2G, PIK3CA, PIK3CD, PIK3R1, PTPN11, RPS6KA3, SH2B, SHC1, SRC, TERF2IP, TH, TUBA3 | 42 | AKT1(3), BRAF(240), CREBBP(1), JUN(1), MAP1B(3), MAPK10(1), MAPK8IP2(1), PIK3C2G(1), PIK3CA(2), PIK3CD(1), PIK3R1(1), SHC1(1), SRC(1) | 30662299 | 257 | 242 | 22 | 5 | 4 | 6 | 1 | 240 | 6 | 0 | 2.00e-15 | <1.00e-15 | <6.16e-14
9 | ST_ERK1_ERK2_MAPK_PATHWAY | The Erk1 and Erk2 MAP kinase pathways are regulated by Raf, Mos, and Tpl-2. | ARAF1, ATF1, BAD, BRAF, COPEB, CREB1, CREB3, CREB5, DUSP4, DUSP6, DUSP9, EEF2K, EIF4E, GRB2, HTATIP, MAP2K1, MAP2K2, MAP3K8, MAPK1, MAPK3, MKNK1, MKNK2, MOS, NFKB1, RAP1A, RPS6KA1, RPS6KA2, RPS6KA3, SHC1, SOS1, SOS2, TRAF3 | 29 | BRAF(240), EEF2K(1), RAP1A(1), SHC1(1), SOS1(1) | 17612692 | 244 | 241 | 10 | 3 | 1 | 3 | 1 | 235 | 4 | 0 | 1.33e-15 | <1.00e-15 | <6.16e-14
10 | ST_G_ALPHA_S_PATHWAY | The G-alpha-s protein activates adenylyl cyclases, which catalyze cAMP formation. | ASAH1, BF, BFAR, BRAF, CAMP, CREB1, CREB3, CREB5, EPAC, GAS, GRF2, MAPK1, RAF1, SNX13, SRC, TERF2IP | 12 | BRAF(240), SNX13(1), SRC(1) | 6581484 | 242 | 240 | 8 | 2 | 0 | 1 | 1 | 235 | 5 | 0 | <1.00e-15 | <1.00e-15 | <6.16e-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 | 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(3), CHEK1(1), TP53(3) | 8877061 | 12 | 12 | 12 | 1 | 0 | 2 | 1 | 3 | 6 | 0 | 0.18 | 0.00033 | 0.12
2 | 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(5), CDKN1A(1), RB1(2), TP53(3) | 10776925 | 13 | 13 | 13 | 0 | 1 | 3 | 1 | 3 | 5 | 0 | 0.038 | 0.00045 | 0.12
3 | 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(1), MYC(1), PIK3CA(2), PIK3R1(1), POLR1A(1), POLR1B(2), RB1(2), TP53(3), TWIST1(1) | 12103444 | 14 | 14 | 14 | 0 | 2 | 2 | 1 | 2 | 7 | 0 | 0.014 | 0.00067 | 0.12
4 | SA_PTEN_PATHWAY | PTEN is a tumor suppressor that dephosphorylates the lipid messenger phosphatidylinositol triphosphate. | AKT1, AKT2, AKT3, BPNT1, GRB2, ILK, MAPK1, MAPK3, PDK1, PIK3CA, PIK3CD, PIP3-E, PTEN, PTK2B, RBL2, SHC1, SOS1 | 16 | AKT1(3), AKT2(2), PIK3CA(2), PIK3CD(1), PTEN(2), PTK2B(2), RBL2(1), SHC1(1), SOS1(1) | 12167760 | 15 | 15 | 14 | 2 | 2 | 6 | 1 | 4 | 1 | 1 | 0.1 | 0.0008 | 0.12
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 | 20 | ATM(5), ATR(3), BRCA1(1), BRCA2(3), CHEK1(1), FANCD2(3), FANCF(1), FANCG(2), TP53(3), TREX1(1) | 25596031 | 23 | 22 | 23 | 2 | 0 | 5 | 4 | 5 | 9 | 0 | 0.042 | 0.0011 | 0.14
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 | AKT1(3), ATM(5), CDKN1A(1), HIF1A(1), TP53(3) | 12386329 | 13 | 13 | 12 | 1 | 0 | 3 | 2 | 4 | 4 | 0 | 0.11 | 0.0016 | 0.14
7 | 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 | ABL1(1), ATM(5), BRCA1(1), CDKN1A(1), CHEK1(1), JUN(1), TP53(3), TP73(3) | 17118506 | 16 | 16 | 16 | 0 | 1 | 6 | 2 | 3 | 4 | 0 | 0.0083 | 0.0016 | 0.14
8 | HCMVPATHWAY | Cytomegalovirus activates MAP kinase pathways in the host cell, inducing transcription of viral genes. | AKT1, CREB1, MAP2K1, MAP2K2, MAP2K3, MAP2K6, MAP3K1, MAPK1, MAPK14, MAPK3, NFKB1, PIK3CA, PIK3R1, RB1, RELA, SP1 | 16 | AKT1(3), MAP2K6(1), MAP3K1(2), PIK3CA(2), PIK3R1(1), RB1(2), SP1(1) | 11567588 | 12 | 12 | 11 | 1 | 1 | 3 | 1 | 5 | 2 | 0 | 0.12 | 0.0029 | 0.21
9 | TCAPOPTOSISPATHWAY | HIV infection upregulates Fas ligand in macrophages and CD4 in helper T cells, leading to widespread Fas-induced T cell apoptosis. | CCR5, CD28, CD3D, CD3E, CD3G, CD3Z, CD4, TNFRSF6, TNFSF6, TRA@, TRB@ | 6 | CD28(1), CD3D(1), CD3E(1), CD4(1) | 1916305 | 4 | 4 | 4 | 0 | 2 | 0 | 1 | 0 | 1 | 0 | 0.35 | 0.0036 | 0.21
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(5), CHEK1(1), RB1(2), TP53(3) | 10466190 | 11 | 11 | 11 | 0 | 1 | 3 | 1 | 2 | 4 | 0 | 0.044 | 0.0037 | 0.21

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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