Mutation Analysis (MutSig v2.0)
Pancreatic Adenocarcinoma (Primary solid tumor)
28 January 2016  |  analyses__2016_01_28
Maintainer Information
Citation Information
doi:10.7908/C18P5ZZG
Maintained by David Heiman (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2016): Mutation Analysis (MutSig v2.0). Broad Institute of MIT and Harvard. doi:10.7908/C18P5ZZG
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: PAAD-TP

  • Number of patients in set: 184

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:PAAD-TP.final_analysis_set.maf

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

  • Significantly mutated genes (q ≤ 0.1): 700

  • Mutations seen in COSMIC: 440

  • Significantly mutated genes in COSMIC territory: 16

  • Significantly mutated genesets: 45

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

Mutation Preprocessing

  • Read 184 MAFs of type "maf1"

  • Total number of mutations in input MAFs: 69765

  • After removing 45 mutations outside chr1-24: 69720

  • After removing 16448 blacklisted mutations: 53272

  • After removing 5561 noncoding mutations: 47711

  • After collapsing adjacent/redundant mutations: 47052

Mutation Filtering

  • Number of mutations before filtering: 47052

  • After removing 2661 mutations outside gene set: 44391

  • After removing 196 mutations outside category set: 44195

Results
Breakdown of Mutations by Type

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

type count
De_novo_Start_InFrame 24
De_novo_Start_OutOfFrame 53
Frame_Shift_Del 3256
Frame_Shift_Ins 1323
In_Frame_Del 3266
In_Frame_Ins 74
Missense_Mutation 23777
Nonsense_Mutation 1487
Nonstop_Mutation 17
Silent 9502
Splice_Site 1369
Start_Codon_Del 34
Start_Codon_Ins 4
Start_Codon_SNP 9
Total 44195
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 8462 322053823 0.000026 26 4.3 2.1
*Cp(A/C/T)->T 5536 2558116678 2.2e-06 2.2 0.35 1.7
C->(G/A) 5478 2880170501 1.9e-06 1.9 0.31 4.7
A->mut 4310 2732464530 1.6e-06 1.6 0.26 3.9
indel+null 10730 5612635031 1.9e-06 1.9 0.31 NaN
double_null 177 5612635031 3.2e-08 0.032 0.0051 NaN
Total 34693 5612635031 6.2e-06 6.2 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: PAAD-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_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: 700. 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 MAGEC1 melanoma antigen family C, 1 629615 35 29 11 3 0 1 2 5 27 0 5.00e-15 0.54 2e-07 0.98 3.4e-06 0.000 0.000
2 KCNA4 potassium voltage-gated channel, shaker-related subfamily, member 4 361710 22 19 8 1 3 2 1 0 16 0 <1.00e-15 0.4 4e-07 0.96 5.2e-06 <0.000 <0.000
3 SMAD4 SMAD family member 4 313258 41 40 36 0 7 1 3 6 24 0 4.11e-15 0.00092 0.0059 0.02 0.0013 2.22e-16 7.11e-14
4 ZNF626 zinc finger protein 626 301310 15 14 7 1 1 1 0 11 2 0 6.76e-14 0.16 0.000025 0.31 0.000086 2.22e-16 7.11e-14
5 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 129359 142 139 4 1 0 62 72 8 0 0 <1.00e-15 1.7e-11 0 0 0 <1.00e-15 <7.11e-14
6 TP53 tumor protein p53 232372 119 118 86 0 29 12 14 19 45 0 <1.00e-15 6e-13 0 0 0 <1.00e-15 <7.11e-14
7 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) 181775 43 42 25 1 0 5 2 2 34 0 5.77e-15 0.016 0.000023 2.6e-06 0 <1.00e-15 <7.11e-14
8 OR10A7 olfactory receptor, family 10, subfamily A, member 7 175522 41 41 2 0 0 0 0 0 41 0 <1.00e-15 1 0 1 0 <1.00e-15 <7.11e-14
9 OTUD4 OTU domain containing 4 585142 43 41 4 3 0 1 0 1 41 0 1.67e-15 0.98 0 1 0 <1.00e-15 <7.11e-14
10 TMC4 transmembrane channel-like 4 363646 37 37 3 1 1 0 0 1 35 0 3.66e-15 0.82 0 0.0035 0 <1.00e-15 <7.11e-14
11 MED15 mediator complex subunit 15 443121 40 35 6 1 0 0 1 2 37 0 4.77e-15 0.78 0 0.98 0 <1.00e-15 <7.11e-14
12 IPP intracisternal A particle-promoted polypeptide 328744 34 34 2 0 0 0 0 0 33 1 3.44e-15 0.85 0 1 0 <1.00e-15 <7.11e-14
13 MYH10 myosin, heavy chain 10, non-muscle 1120339 38 34 7 2 3 0 1 0 34 0 9.77e-15 0.86 0 1 0 <1.00e-15 <7.11e-14
14 THBS4 thrombospondin 4 525737 34 34 6 0 0 3 0 0 31 0 6.44e-15 0.23 0 1 0 <1.00e-15 <7.11e-14
15 EDC4 enhancer of mRNA decapping 4 776929 32 31 3 3 0 1 0 0 31 0 7.11e-15 0.97 0 1 0 <1.00e-15 <7.11e-14
16 GAS2L2 growth arrest-specific 2 like 2 487734 30 30 5 0 1 0 0 3 26 0 9.66e-15 0.33 0 0.38 0 <1.00e-15 <7.11e-14
17 NFAT5 nuclear factor of activated T-cells 5, tonicity-responsive 858371 31 30 5 1 0 2 1 0 28 0 6.66e-15 0.66 0 1 0 <1.00e-15 <7.11e-14
18 PRDM8 PR domain containing 8 240638 30 30 2 0 0 0 1 0 29 0 7.55e-15 0.79 0 1 0 <1.00e-15 <7.11e-14
19 QRICH1 glutamine-rich 1 435521 30 30 3 2 1 0 0 1 28 0 5.33e-15 0.92 0 0.000017 0 <1.00e-15 <7.11e-14
20 SETD1A SET domain containing 1A 885901 30 30 6 0 1 1 1 0 27 0 3.44e-15 0.33 0 0.9 0 <1.00e-15 <7.11e-14
21 CACNA1D calcium channel, voltage-dependent, L type, alpha 1D subunit 1229774 35 29 12 0 4 2 1 1 26 1 3.73e-13 0.026 0 1 0 <1.00e-15 <7.11e-14
22 IRS1 insulin receptor substrate 1 686789 30 29 7 4 2 1 1 1 25 0 4.55e-15 0.94 0 1 0 <1.00e-15 <7.11e-14
23 DHX57 DEAH (Asp-Glu-Ala-Asp/His) box polypeptide 57 782407 31 28 4 2 1 0 1 0 29 0 7.77e-15 0.92 0 0.87 0 <1.00e-15 <7.11e-14
24 OTOF otoferlin 1141449 30 28 9 0 4 2 2 0 22 0 1.05e-11 0.035 0 1 0 <1.00e-15 <7.11e-14
25 PDZD2 PDZ domain containing 2 1584773 32 28 6 1 2 0 0 0 30 0 6.59e-09 0.71 0 1 0 <1.00e-15 <7.11e-14
26 SORBS2 sorbin and SH3 domain containing 2 654762 29 28 7 3 0 7 0 0 22 0 6.41e-14 0.53 0 0.22 0 <1.00e-15 <7.11e-14
27 TNFSF9 tumor necrosis factor (ligand) superfamily, member 9 117231 28 28 1 2 0 0 0 0 28 0 6.00e-15 1 0 0.69 0 <1.00e-15 <7.11e-14
28 CDH10 cadherin 10, type 2 (T2-cadherin) 443419 30 27 10 0 2 1 2 3 22 0 5.33e-15 0.12 0 0.0018 0 <1.00e-15 <7.11e-14
29 FOXP2 forkhead box P2 430556 27 27 6 17 0 0 1 0 26 0 1.000 1 0 0.84 0 <1.00e-15 <7.11e-14
30 WRN Werner syndrome 813278 27 27 4 1 1 2 0 1 23 0 7.33e-15 0.59 0 0.59 0 <1.00e-15 <7.11e-14
31 SRP14 signal recognition particle 14kDa (homologous Alu RNA binding protein) 78837 26 26 1 0 0 0 0 0 26 0 6.99e-15 1 0 1 0 <1.00e-15 <7.11e-14
32 BRDT bromodomain, testis-specific 535477 25 25 2 0 0 0 1 0 24 0 8.99e-15 0.92 0 0.084 0 <1.00e-15 <7.11e-14
33 ERF Ets2 repressor factor 299153 28 25 7 0 2 0 2 0 24 0 7.33e-15 0.27 0 0.65 0 <1.00e-15 <7.11e-14
34 MAMLD1 mastermind-like domain containing 1 438575 25 25 3 2 1 0 0 2 22 0 4.88e-15 0.89 0 0.48 0 <1.00e-15 <7.11e-14
35 MEPCE methylphosphate capping enzyme 319033 27 25 5 1 1 0 1 0 25 0 6.33e-15 0.7 0 1 0 <1.00e-15 <7.11e-14
MAGEC1

Figure S1.  This figure depicts the distribution of mutations and mutation types across the MAGEC1 significant gene.

KCNA4

Figure S2.  This figure depicts the distribution of mutations and mutation types across the KCNA4 significant gene.

SMAD4

Figure S3.  This figure depicts the distribution of mutations and mutation types across the SMAD4 significant gene.

ZNF626

Figure S4.  This figure depicts the distribution of mutations and mutation types across the ZNF626 significant gene.

KRAS

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

TP53

Figure S6.  This figure depicts the distribution of mutations and mutation types across the TP53 significant gene.

CDKN2A

Figure S7.  This figure depicts the distribution of mutations and mutation types across the CDKN2A significant gene.

OR10A7

Figure S8.  This figure depicts the distribution of mutations and mutation types across the OR10A7 significant gene.

OTUD4

Figure S9.  This figure depicts the distribution of mutations and mutation types across the OTUD4 significant gene.

TMC4

Figure S10.  This figure depicts the distribution of mutations and mutation types across the TMC4 significant gene.

MED15

Figure S11.  This figure depicts the distribution of mutations and mutation types across the MED15 significant gene.

IPP

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

MYH10

Figure S13.  This figure depicts the distribution of mutations and mutation types across the MYH10 significant gene.

THBS4

Figure S14.  This figure depicts the distribution of mutations and mutation types across the THBS4 significant gene.

EDC4

Figure S15.  This figure depicts the distribution of mutations and mutation types across the EDC4 significant gene.

GAS2L2

Figure S16.  This figure depicts the distribution of mutations and mutation types across the GAS2L2 significant gene.

NFAT5

Figure S17.  This figure depicts the distribution of mutations and mutation types across the NFAT5 significant gene.

PRDM8

Figure S18.  This figure depicts the distribution of mutations and mutation types across the PRDM8 significant gene.

QRICH1

Figure S19.  This figure depicts the distribution of mutations and mutation types across the QRICH1 significant gene.

SETD1A

Figure S20.  This figure depicts the distribution of mutations and mutation types across the SETD1A significant gene.

CACNA1D

Figure S21.  This figure depicts the distribution of mutations and mutation types across the CACNA1D significant gene.

IRS1

Figure S22.  This figure depicts the distribution of mutations and mutation types across the IRS1 significant gene.

DHX57

Figure S23.  This figure depicts the distribution of mutations and mutation types across the DHX57 significant gene.

OTOF

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

SORBS2

Figure S25.  This figure depicts the distribution of mutations and mutation types across the SORBS2 significant gene.

TNFSF9

Figure S26.  This figure depicts the distribution of mutations and mutation types across the TNFSF9 significant gene.

CDH10

Figure S27.  This figure depicts the distribution of mutations and mutation types across the CDH10 significant gene.

FOXP2

Figure S28.  This figure depicts the distribution of mutations and mutation types across the FOXP2 significant gene.

WRN

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

SRP14

Figure S30.  This figure depicts the distribution of mutations and mutation types across the SRP14 significant gene.

BRDT

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

ERF

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

MAMLD1

Figure S33.  This figure depicts the distribution of mutations and mutation types across the MAMLD1 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: 16. Number of genes displayed: 10

rank gene description n cos n_cos N_cos cos_ev p q
1 TTK TTK protein kinase 20 2 16 368 48 1.4e-14 6.5e-11
2 GNAS GNAS complex locus 16 7 11 1288 2310 5e-14 1.1e-10
3 TNFRSF9 tumor necrosis factor receptor superfamily, member 9 7 1 4 184 4 7.4e-14 1.1e-10
4 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 142 52 142 9568 1951074 3.5e-13 4e-10
5 SMAD4 SMAD family member 4 41 159 24 29256 81 9.6e-13 8.6e-10
6 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) 43 332 43 61088 1369 1.6e-12 1.1e-09
7 TP53 tumor protein p53 119 356 113 65504 29860 1.7e-12 1.1e-09
8 ADAMTS18 ADAM metallopeptidase with thrombospondin type 1 motif, 18 12 8 3 1472 6 1.2e-07 7e-05
9 NF2 neurofibromin 2 (merlin) 8 550 8 101200 8 3.3e-07 0.00017
10 KRTAP5-5 keratin associated protein 5-5 6 1 2 184 0 6.4e-07 0.00026

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: 45. 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 TIDPATHWAY On ligand binding, interferon gamma receptors stimulate JAK2 kinase to phosphorylate STAT transcription factors, which promote expression of interferon responsive genes. DNAJA3, HSPA1A, IFNG, IFNGR1, IFNGR2, IKBKB, JAK2, LIN7A, NFKB1, NFKBIA, RB1, RELA, TIP-1, TNF, TNFRSF1A, TNFRSF1B, TP53, USH1C, WT1 18 DNAJA3(1), HSPA1A(1), IFNGR1(2), IFNGR2(17), IKBKB(4), JAK2(2), LIN7A(1), NFKBIA(2), RB1(3), RELA(3), TNFRSF1A(2), TNFRSF1B(1), TP53(119), USH1C(1) 5180987 159 125 110 11 34 15 22 22 66 0 2e-07 <1.00e-15 <1.57e-13
2 PMLPATHWAY Ring-shaped PML nuclear bodies regulate transcription and are required co-activators in p53- and DAXX-mediated apoptosis. CREBBP, DAXX, HRAS, PAX3, PML, PRAM-1, RARA, RB1, SIRT1, SP100, TNF, TNFRSF1A, TNFRSF1B, TNFRSF6, TNFSF6, TP53, UBL1 13 CREBBP(3), DAXX(6), HRAS(1), PML(2), RB1(3), SIRT1(1), SP100(5), TNFRSF1A(2), TNFRSF1B(1), TP53(119) 5380911 143 120 108 10 35 15 20 23 50 0 3.7e-08 <1.00e-15 <1.57e-13
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 16 APAF1(3), ATM(11), CCNE1(1), CDK4(2), MDM2(2), PCNA(1), RB1(3), TP53(119) 5074342 142 124 109 4 34 16 21 23 48 0 7e-11 1.44e-15 1.57e-13
4 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(7), AKT1(3), ATM(11), CSNK1A1(1), CSNK1D(1), FHL2(1), HIC1(2), HIF1A(1), HSPA1A(1), MAPK8(2), MDM2(2), NFKBIB(1), NQO1(2), TP53(119) 5853817 154 127 119 10 35 16 22 28 53 0 1.4e-08 2.00e-15 1.57e-13
5 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(11), ATR(10), BRCA1(6), CDC25A(6), CDC25B(2), CDC25C(3), CDC34(1), CHEK2(1), EP300(6), MDM2(2), MYT1(12), PRKDC(9), RPS6KA1(2), TP53(119), YWHAH(1) 11825926 191 134 149 12 42 21 26 32 70 0 6.3e-09 2.33e-15 1.57e-13
6 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(7), ATM(11), ATR(10), CCNA1(3), CCNE1(1), CDC25A(6), CDK4(2), CDK6(2), CDKN2A(43), DHFR(1), GSK3B(2), RB1(3), SKP2(3), TFDP1(1), TGFB1(1), TGFB2(2), TP53(119) 8450927 217 133 160 15 36 26 29 28 98 0 6.5e-09 2.33e-15 1.57e-13
7 ST_JNK_MAPK_PATHWAY JNKs are MAP kinases regulated by several levels of kinases (MAPKK, MAPKKK) and phosphorylate transcription factors and regulatory proteins. AKT1, ATF2, CDC42, DLD, DUSP10, DUSP4, DUSP8, GAB1, GADD45A, GCK, IL1R1, JUN, MAP2K4, MAP2K5, MAP2K7, MAP3K1, MAP3K10, MAP3K11, MAP3K12, MAP3K13, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K7, MAP3K7IP1, MAP3K7IP2, MAP3K9, MAPK10, MAPK7, MAPK8, MAPK9, MYEF2, NFATC3, NR2C2, PAPPA, SHC1, TP53, TRAF6, ZAK 38 AKT1(3), CDC42(1), DUSP10(1), DUSP8(1), GCK(1), MAP2K4(5), MAP2K7(3), MAP3K1(3), MAP3K10(4), MAP3K12(4), MAP3K13(2), MAP3K2(2), MAP3K4(2), MAP3K5(2), MAP3K7(12), MAP3K9(4), MAPK10(1), MAPK7(4), MAPK8(2), MAPK9(1), MYEF2(2), NFATC3(2), NR2C2(1), PAPPA(3), SHC1(2), TP53(119), TRAF6(1), ZAK(5) 14186800 193 133 147 17 48 20 25 28 72 0 1.1e-07 2.66e-15 1.57e-13
8 TERTPATHWAY hTERC, the RNA subunit of telomerase, and hTERT, the catalytic protein subunit, are required for telomerase activity and are overexpressed in many cancers. HDAC1, MAX, MYC, SP1, SP3, TP53, WT1, ZNF42 7 MAX(1), MYC(2), SP1(1), SP3(1), TP53(119) 1961934 124 120 91 0 30 12 15 19 48 0 6e-15 2.66e-15 1.57e-13
9 TELPATHWAY Telomerase is a ribonucleotide protein that adds telomeric repeats to the 3' ends of chromosomes. AKT1, BCL2, EGFR, G22P1, HSPCA, IGF1R, KRAS2, MYC, POLR2A, PPP2CA, PRKCA, RB1, TEP1, TERF1, TERT, TNKS, TP53, XRCC5 15 AKT1(3), EGFR(2), IGF1R(6), MYC(2), POLR2A(6), PPP2CA(1), RB1(3), TEP1(18), TERF1(9), TERT(6), TNKS(4), TP53(119), XRCC5(2) 7893165 181 130 132 14 47 18 19 26 70 1 1.5e-08 2.78e-15 1.57e-13
10 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(7), CDKN2A(43), MDM2(2), MYC(2), PIK3CA(6), PIK3R1(2), POLR1A(6), POLR1B(3), RB1(3), TBX2(2), TP53(119) 5728217 195 131 143 5 36 23 23 25 88 0 6.6e-15 2.89e-15 1.57e-13

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 RABPATHWAY Rab family GTPases regulate vesicle transport, endocytosis and exocytosis, and vesicle docking via interactions with the rabphilins. ACTA1, MEL, RAB11A, RAB1A, RAB2, RAB27A, RAB3A, RAB4A, RAB5A, RAB6A, RAB7, RAB9A 9 ACTA1(4), RAB11A(1), RAB27A(2), RAB3A(2), RAB4A(1), RAB6A(1), RAB9A(1) 1187560 12 6 12 1 5 3 2 1 1 0 0.071 0.24 1
2 HSA00550_PEPTIDOGLYCAN_BIOSYNTHESIS Genes involved in peptidoglycan biosynthesis GLUL, PGLYRP2 2 PGLYRP2(3) 515787 3 3 3 0 1 0 0 2 0 0 0.45 0.39 1
3 SLRPPATHWAY Small leucine-rich proteoglycans (SLRPs) interact with and reorganize collagen fibers in the extracellular matrix. BGN, DCN, DSPG3, FMOD, KERA, LUM 5 DCN(1), FMOD(2), KERA(2), LUM(2) 1001919 7 4 7 1 1 0 1 4 1 0 0.48 0.4 1
4 RANPATHWAY RanGEF (aka RCC1) and RanGFP regulate the GTP- or GDP-bound state of Ran, creating a Ran gradient across the nuclear membrane that is used in nuclear import. CHC1, RAN, RANBP1, RANBP2, RANGAP1 3 RANBP1(1), RANGAP1(4) 544748 5 3 5 1 2 2 1 0 0 0 0.36 0.4 1
5 CREMPATHWAY The transcription factor CREM activates a post-meiotic transcriptional cascade culminating in spermatogenesis. ADCY1, CREM, FHL5, FSHB, FSHR, GNAS, XPO1 6 ADCY1(5), FSHB(1), FSHR(4), XPO1(2) 2056757 12 7 12 1 4 1 2 3 2 0 0.16 0.48 1
6 SA_BONE_MORPHOGENETIC Bone morphogenetic protein binds to its receptor to induce ectopic bone formation and promote development of the viscera. BMP1, BMPR1A, BMPR1B, BMPR2, MADH1, MADH4, MADH6 4 BMP1(10), BMPR1A(4), BMPR2(3) 1735555 17 9 17 3 4 6 2 1 4 0 0.19 0.5 1
7 NUCLEOTIDE_GPCRS ADORA1, ADORA2A, ADORA2B, ADORA3, GPR23, LTB4R, P2RY1, P2RY2, P2RY5, P2RY6 6 ADORA2A(1), ADORA3(5), P2RY2(1), P2RY6(1) 1309771 8 6 8 1 4 2 0 0 2 0 0.12 0.51 1
8 HSA00830_RETINOL_METABOLISM Genes involved in retinol metabolism ALDH1A1, ALDH1A2, BCMO1, RDH5 4 ALDH1A1(1), ALDH1A2(1), RDH5(1) 1070904 3 3 3 0 1 1 1 0 0 0 0.34 0.54 1
9 IL18PATHWAY Pro-inflammatory IL-18 is activated in macrophages by caspase-1 cleavage and, in conjunction with IL-12, stimulates Th1 cell differentiation. CASP1, IFNG, IL12A, IL12B, IL18, IL2 6 CASP1(4), IL12B(1) 830479 5 5 4 2 0 2 0 0 3 0 0.93 0.55 1
10 SALMONELLAPATHWAY Salmonella induces membrane ruffling in infected cells via bacterial proteins including SipA, SipC, and SopE, which alter actin structure. ACTA1, ACTR2, ACTR3, ARPC1A, ARPC1B, ARPC2, ARPC3, ARPC4, CDC42, RAC1, WASF1, WASL 12 ACTA1(4), ARPC1A(2), ARPC2(1), CDC42(1), WASF1(1), WASL(6) 2248368 15 10 13 3 3 4 2 2 4 0 0.38 0.56 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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