Mutation Analysis (MutSig v2.0)
Pancreatic Adenocarcinoma (Primary solid tumor)
Due to issues with GAF 3.0, we strongly advise caution in the use of these results.
23 September 2013  |  analyses__2013_09_23
Maintainer Information
Citation Information
doi:10.7908/C12V2DG9
Maintained by Dan DiCara (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2013): Mutation Analysis (MutSig v2.0). Broad Institute of MIT and Harvard. doi:10.7908/C12V2DG9
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: 57

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

  • Significantly mutated genes (q ≤ 0.1): 481

  • Mutations seen in COSMIC: 148

  • Significantly mutated genes in COSMIC territory: 10

  • Genes with clustered mutations (≤ 3 aa apart): 119

  • Significantly mutated genesets: 20

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

Mutation Preprocessing

  • Read 57 MAFs of type "Broad"

  • Total number of mutations in input MAFs: 27745

  • After removing 95 mutations outside chr1-24: 27650

  • After removing 630 noncoding mutations: 27020

  • After collapsing adjacent/redundant mutations: 26916

Mutation Filtering

  • Number of mutations before filtering: 26916

  • After removing 1108 mutations outside gene set: 25808

  • After removing 158 mutations outside category set: 25650

  • After removing 2 "impossible" mutations in

  • gene-patient-category bins of zero coverage: 24382

Results
Breakdown of Mutations by Type

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

type count
Frame_Shift_Del 1629
Frame_Shift_Ins 529
In_Frame_Del 2155
In_Frame_Ins 48
Missense_Mutation 13980
Nonsense_Mutation 870
Nonstop_Mutation 5
Silent 5585
Splice_Site 839
Translation_Start_Site 10
Total 25650
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 4336 98986159 0.000044 44 3.8 2.1
*Cp(A/C/T)->T 3471 788202097 4.4e-06 4.4 0.38 1.7
C->(G/A) 3395 887188256 3.8e-06 3.8 0.33 4.7
A->mut 2777 841595742 3.3e-06 3.3 0.28 3.9
indel+null 5939 1728783998 3.4e-06 3.4 0.3 NaN
double_null 145 1728783998 8.4e-08 0.084 0.0072 NaN
Total 20063 1728783998 0.000012 12 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).

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: 481. 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 HRCT1 histidine rich carboxyl terminus 1 18823 10 10 2 0 0 0 0 2 8 0 8.6e-15 0.6 0.000013 0.93 0.000073 0.000 0.000
2 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) 56371 13 13 11 0 0 1 1 0 11 0 7.9e-15 0.31 0.0056 0.0041 0.0014 4.44e-16 1.84e-13
3 TP53 tumor protein p53 71159 37 37 33 0 9 1 7 7 13 0 1.9e-15 0.00024 1.2e-06 0.00033 0 <1.00e-15 <1.84e-13
4 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 39758 33 33 4 0 0 14 15 4 0 0 2.6e-15 0.0011 0 0.0024 0 <1.00e-15 <1.84e-13
5 NOS1AP nitric oxide synthase 1 (neuronal) adaptor protein 90538 12 12 2 0 1 0 0 0 11 0 2.8e-10 0.61 0 0.21 0 <1.00e-15 <1.84e-13
6 PASD1 PAS domain containing 1 125210 12 12 2 0 0 0 1 0 11 0 2.4e-10 0.88 0 0.47 0 <1.00e-15 <1.84e-13
7 RANGAP1 Ran GTPase activating protein 1 97483 13 12 3 1 1 0 1 0 11 0 7.3e-12 0.85 0 1 0 <1.00e-15 <1.84e-13
8 CDC27 cell division cycle 27 homolog (S. cerevisiae) 139960 11 11 1 0 0 0 0 0 11 0 4.1e-12 1 0 0.0072 0 <1.00e-15 <1.84e-13
9 FOXN3 forkhead box N3 85125 11 11 1 0 0 0 0 0 11 0 4.3e-11 1 0 0.3 0 <1.00e-15 <1.84e-13
10 FUZ fuzzy homolog (Drosophila) 51398 11 11 1 0 0 0 0 0 11 0 1.2e-12 1 0 0.99 0 <1.00e-15 <1.84e-13
11 HOXA1 homeobox A1 57912 12 11 2 0 1 0 0 0 11 0 2.7e-13 0.62 0 1 0 <1.00e-15 <1.84e-13
12 SF3A1 splicing factor 3a, subunit 1, 120kDa 131051 11 11 1 1 0 0 0 0 11 0 2.5e-10 1 0 1 0 <1.00e-15 <1.84e-13
13 ATP6V1C2 ATPase, H+ transporting, lysosomal 42kDa, V1 subunit C2 75337 10 10 2 1 0 0 1 0 9 0 1.7e-10 0.93 0 0.22 0 <1.00e-15 <1.84e-13
14 C16orf62 chromosome 16 open reading frame 62 171296 10 10 2 1 1 0 0 0 9 0 2.7e-06 0.87 0 0.17 0 <1.00e-15 <1.84e-13
15 CNKSR2 connector enhancer of kinase suppressor of Ras 2 180682 10 10 2 0 0 0 1 0 9 0 8.6e-07 0.87 0 1 0 <1.00e-15 <1.84e-13
16 FXR2 fragile X mental retardation, autosomal homolog 2 96461 10 10 2 1 1 0 0 0 9 0 4.1e-08 0.97 0 0.016 0 <1.00e-15 <1.84e-13
17 LILRB1 leukocyte immunoglobulin-like receptor, subfamily B (with TM and ITIM domains), member 1 113805 10 10 2 0 1 0 0 0 9 0 2.1e-09 0.64 0 0.62 0 <1.00e-15 <1.84e-13
18 LRP10 low density lipoprotein receptor-related protein 10 123645 10 10 2 1 0 0 1 0 9 0 3.1e-08 0.96 0 0.98 0 <1.00e-15 <1.84e-13
19 RBM25 RNA binding motif protein 25 145518 10 10 2 0 1 0 0 0 9 0 1.1e-07 0.91 0 1 0 <1.00e-15 <1.84e-13
20 RSPH6A radial spoke head 6 homolog A (Chlamydomonas) 122308 11 10 3 0 0 0 0 0 11 0 5.6e-10 1 0 0.097 0 <1.00e-15 <1.84e-13
21 TREML2 triggering receptor expressed on myeloid cells-like 2 54923 10 10 2 0 0 0 1 0 9 0 4.6e-10 0.78 0 0.73 0 <1.00e-15 <1.84e-13
22 ADAD1 adenosine deaminase domain containing 1 (testis-specific) 101070 9 9 2 0 0 1 0 0 8 0 2.1e-07 0.74 0 1 0 <1.00e-15 <1.84e-13
23 APBB1 amyloid beta (A4) precursor protein-binding, family B, member 1 (Fe65) 118301 9 9 2 2 1 0 0 0 8 0 6.5e-06 0.97 2e-07 0.33 0 <1.00e-15 <1.84e-13
24 C14orf49 chromosome 14 open reading frame 49 162141 9 9 1 1 0 0 0 0 9 0 2.6e-06 1 0 0.98 0 <1.00e-15 <1.84e-13
25 IL32 interleukin 32 32630 9 9 2 0 0 1 0 0 8 0 1e-14 0.61 0 0.98 0 <1.00e-15 <1.84e-13
26 KIF3B kinesin family member 3B 129525 9 9 1 0 0 0 0 0 9 0 2e-06 1 0 2e-07 0 <1.00e-15 <1.84e-13
27 KRTAP4-1 keratin associated protein 4-1 22336 9 9 1 0 0 0 0 0 9 0 1e-14 1 0 0.98 0 <1.00e-15 <1.84e-13
28 LNP1 leukemia NUP98 fusion partner 1 31289 9 9 1 1 0 0 0 0 9 0 4.8e-11 1 0 0.58 0 <1.00e-15 <1.84e-13
29 OR10A7 olfactory receptor, family 10, subfamily A, member 7 54378 9 9 1 0 0 0 0 0 9 0 4.5e-09 1 0 0.92 0 <1.00e-15 <1.84e-13
30 OR2T2 olfactory receptor, family 2, subfamily T, member 2 55358 9 9 1 0 0 0 0 0 9 0 4.8e-12 1 0 0.54 0 <1.00e-15 <1.84e-13
31 OTOP1 otopetrin 1 96428 9 9 2 2 0 0 0 0 9 0 1.8e-09 1 6e-07 0.000048 0 <1.00e-15 <1.84e-13
32 PTTG1IP pituitary tumor-transforming 1 interacting protein 25535 9 9 1 0 0 0 0 0 9 0 7.2e-12 1 0 0 0 <1.00e-15 <1.84e-13
33 TMEM40 transmembrane protein 40 40250 9 9 2 0 0 0 0 0 9 0 8.1e-11 1 0 0.56 0 <1.00e-15 <1.84e-13
34 ADAMTSL4 ADAMTS-like 4 189621 8 8 3 1 1 0 0 0 7 0 3e-05 0.83 0.0012 1.6e-06 0 <1.00e-15 <1.84e-13
35 HAMP hepcidin antimicrobial peptide 15219 8 8 1 0 0 0 0 0 8 0 2.9e-13 1 0 0.26 0 <1.00e-15 <1.84e-13
HRCT1

Figure S1.  This figure depicts the distribution of mutations and mutation types across the HRCT1 significant gene.

CDKN2A

Figure S2.  This figure depicts the distribution of mutations and mutation types across the CDKN2A significant gene.

TP53

Figure S3.  This figure depicts the distribution of mutations and mutation types across the TP53 significant gene.

KRAS

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

NOS1AP

Figure S5.  This figure depicts the distribution of mutations and mutation types across the NOS1AP significant gene.

PASD1

Figure S6.  This figure depicts the distribution of mutations and mutation types across the PASD1 significant gene.

RANGAP1

Figure S7.  This figure depicts the distribution of mutations and mutation types across the RANGAP1 significant gene.

CDC27

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

FOXN3

Figure S9.  This figure depicts the distribution of mutations and mutation types across the FOXN3 significant gene.

FUZ

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

HOXA1

Figure S11.  This figure depicts the distribution of mutations and mutation types across the HOXA1 significant gene.

SF3A1

Figure S12.  This figure depicts the distribution of mutations and mutation types across the SF3A1 significant gene.

ATP6V1C2

Figure S13.  This figure depicts the distribution of mutations and mutation types across the ATP6V1C2 significant gene.

C16orf62

Figure S14.  This figure depicts the distribution of mutations and mutation types across the C16orf62 significant gene.

CNKSR2

Figure S15.  This figure depicts the distribution of mutations and mutation types across the CNKSR2 significant gene.

FXR2

Figure S16.  This figure depicts the distribution of mutations and mutation types across the FXR2 significant gene.

LILRB1

Figure S17.  This figure depicts the distribution of mutations and mutation types across the LILRB1 significant gene.

LRP10

Figure S18.  This figure depicts the distribution of mutations and mutation types across the LRP10 significant gene.

RBM25

Figure S19.  This figure depicts the distribution of mutations and mutation types across the RBM25 significant gene.

RSPH6A

Figure S20.  This figure depicts the distribution of mutations and mutation types across the RSPH6A significant gene.

TREML2

Figure S21.  This figure depicts the distribution of mutations and mutation types across the TREML2 significant gene.

ADAD1

Figure S22.  This figure depicts the distribution of mutations and mutation types across the ADAD1 significant gene.

APBB1

Figure S23.  This figure depicts the distribution of mutations and mutation types across the APBB1 significant gene.

C14orf49

Figure S24.  This figure depicts the distribution of mutations and mutation types across the C14orf49 significant gene.

IL32

Figure S25.  This figure depicts the distribution of mutations and mutation types across the IL32 significant gene.

KIF3B

Figure S26.  This figure depicts the distribution of mutations and mutation types across the KIF3B significant gene.

KRTAP4-1

Figure S27.  This figure depicts the distribution of mutations and mutation types across the KRTAP4-1 significant gene.

LNP1

Figure S28.  This figure depicts the distribution of mutations and mutation types across the LNP1 significant gene.

OR10A7

Figure S29.  This figure depicts the distribution of mutations and mutation types across the OR10A7 significant gene.

OR2T2

Figure S30.  This figure depicts the distribution of mutations and mutation types across the OR2T2 significant gene.

OTOP1

Figure S31.  This figure depicts the distribution of mutations and mutation types across the OTOP1 significant gene.

PTTG1IP

Figure S32.  This figure depicts the distribution of mutations and mutation types across the PTTG1IP significant gene.

TMEM40

Figure S33.  This figure depicts the distribution of mutations and mutation types across the TMEM40 significant gene.

ADAMTSL4

Figure S34.  This figure depicts the distribution of mutations and mutation types across the ADAMTSL4 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: 10. Number of genes displayed: 10

rank gene description n cos n_cos N_cos cos_ev p q
1 ZC3H3 zinc finger CCCH-type containing 3 5 1 5 57 5 2.1e-15 9.5e-12
2 TNFRSF9 tumor necrosis factor receptor superfamily, member 9 7 1 4 57 4 9.2e-15 2.1e-11
3 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 33 52 33 2964 423105 1.1e-13 1.4e-10
4 TTK TTK protein kinase 5 2 4 114 12 1.3e-13 1.4e-10
5 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) 13 332 13 18924 380 5.8e-13 4.6e-10
6 TP53 tumor protein p53 37 356 35 20292 9591 6.2e-13 4.6e-10
7 SMAD4 SMAD family member 4 10 159 6 9063 16 1.7e-09 1.1e-06
8 ADAMTS18 ADAM metallopeptidase with thrombospondin type 1 motif, 18 8 8 3 456 6 2.4e-08 0.000014
9 GNAS GNAS complex locus 6 7 2 399 420 0.000011 0.0054
10 TGFBR2 transforming growth factor, beta receptor II (70/80kDa) 4 12 2 684 2 0.000031 0.014

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)

Clustered Mutations

Table 5.  Get Full Table Genes with Clustered Mutations

num gene desc n mindist nmuts0 nmuts3 nmuts12 npairs0 npairs3 npairs12
4229 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 33 0 412 412 412 412 412 412
8240 TP53 tumor protein p53 37 0 10 25 54 10 25 54
2069 DDX11 DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 11 (CHL1-like helicase homolog, S. cerevisiae) 5 0 10 10 10 10 10 10
2408 EFCAB6 EF-hand calcium binding domain 6 10 0 9 21 21 9 21 21
9248 ZNF844 zinc finger protein 844 8 0 8 8 16 8 8 16
4089 KIAA0907 KIAA0907 14 0 7 15 15 7 15 15
6201 POLR3B polymerase (RNA) III (DNA directed) polypeptide B 7 0 6 6 15 6 6 15
1593 CHRD chordin 6 0 6 6 10 6 6 10
2739 FAM75A6 family with sequence similarity 75, member A6 6 0 6 6 6 6 6 6
4281 KRTAP4-11 keratin associated protein 4-11 7 0 6 6 6 6 6 6

Note:

n - number of mutations in this gene in the individual set.

mindist - distance (in aa) between closest pair of mutations in this gene

npairs3 - how many pairs of mutations are within 3 aa of each other.

npairs12 - how many pairs of mutations are within 12 aa of each other.

Geneset Analyses

Table 6.  Get Full Table A Ranked List of Significantly Mutated Genesets. (Source: MSigDB GSEA Cannonical Pathway Set).Number of significant genesets found: 20. 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 RNAPATHWAY dsRNA-activated protein kinase phosphorylates elF2a, which generally inhibits translation, and activates NF-kB to provoke inflammation. CHUK, DNAJC3, EIF2S1, EIF2S2, MAP3K14, NFKB1, NFKBIA, PRKR, RELA, TP53 9 CHUK(1), DNAJC3(3), NFKBIA(2), RELA(1), TP53(37) 859778 44 39 40 3 9 2 9 9 15 0 0.0062 1.4e-15 3.2e-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(2), DAXX(7), HRAS(1), PML(1), RB1(1), SIRT1(1), SP100(4), TNFRSF1A(2), TNFRSF1B(2), TP53(37) 1656321 58 41 50 5 13 3 12 10 20 0 0.0038 1.8e-15 3.2e-13
3 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(2), MYC(4), SP1(1), TP53(37) 607537 44 41 37 0 9 1 8 7 19 0 0.000057 2.1e-15 3.2e-13
4 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(8), CDKN2A(13), MDM2(1), MYC(4), PIK3CA(1), PIK3R1(1), POLR1A(3), POLR1B(2), RB1(1), TP53(37) 1763289 71 39 61 3 12 5 13 8 33 0 0.00016 2.1e-15 3.2e-13
5 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(6), CCND1(1), CCNE1(1), CDK4(2), MDM2(1), RB1(1), TP53(37) 1563583 52 40 48 3 12 4 11 9 16 0 0.0016 3.8e-15 4.7e-13
6 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 ARF1(1), CCND1(1), CDK4(2), CDKN2A(13), MDM2(1), NXT1(1), TP53(37) 738429 56 38 50 0 12 2 10 7 25 0 6.3e-06 5.3e-15 4.9e-13
7 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(2), AKT1(2), ATM(6), CSNK1D(1), FHL2(1), HIC1(1), HIF1A(1), MAPK8(1), MDM2(1), TP53(37) 1809048 53 40 49 4 10 3 11 11 18 0 0.0034 6e-15 4.9e-13
8 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 ABL1(8), ATM(6), BRCA1(3), CHEK1(3), CHEK2(1), MAPK8(1), MDM2(1), MRE11A(2), NFKBIA(2), RBBP8(2), RELA(1), TP53(37) 2565925 67 43 60 3 13 6 15 9 24 0 0.00032 6.3e-15 4.9e-13
9 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(6), CDC25A(2), CDC25C(2), CDK4(2), CHEK1(3), MYT1(9), RB1(1), TP53(37), YWHAH(1) 1510491 63 42 53 5 12 4 11 10 26 0 0.012 8e-15 5e-13
10 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 IFNGR1(2), IFNGR2(4), IKBKB(2), JAK2(2), LIN7A(1), NFKBIA(2), RB1(1), RELA(1), TNFRSF1A(2), TNFRSF1B(2), TP53(37), USH1C(1) 1594010 57 42 50 6 12 3 13 9 20 0 0.0094 8.4e-15 5e-13

Table 7.  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 CDC42RACPATHWAY PI3 kinase stimulates cell migration by activating cdc42, which activates ARP2/3, which in turn promotes formation of new actin fibers. ACTR2, ACTR3, ARHA, ARPC1A, ARPC1B, ARPC2, ARPC3, ARPC4, CDC42, PAK1, PDGFRA, PIK3CA, PIK3R1, RAC1, WASL 13 ARPC2(1), CDC42(1), PAK1(2), PDGFRA(8), PIK3CA(1), PIK3R1(1) 1058136 14 9 10 2 2 1 1 3 7 0 0.54 0.0086 1
2 BLYMPHOCYTEPATHWAY B cells express the major histocompatibility complex (class II MHC), immunoglobulins, adhesion proteins, and other factors on their cell surface. CD80, CR1, CR2, FCGR2B, HLA-DRA, HLA-DRB1, ICAM1, ITGAL, ITGB2, PTPRC, TNFRSF5 10 CD80(1), CR1(3), CR2(4), FCGR2B(1), ICAM1(1), ITGAL(2), ITGB2(1), PTPRC(2) 1305486 15 9 14 1 2 3 1 3 5 1 0.074 0.0092 1
3 HSA00785_LIPOIC_ACID_METABOLISM Genes involved in lipoic acid metabolism LIAS, LIPT1, LOC387787 1 LIPT1(2) 64145 2 2 1 0 0 0 0 0 2 0 1 0.02 1
4 ERYTHPATHWAY Erythropoietin selectively stimulates erythrocyte differentiation from CFU-GEMM cells in bone marrow. CCL3, CSF2, CSF3, EPO, FLT3, IGF1, IL11, IL1A, IL3, IL6, IL9, KITLG, TGFB1, TGFB2, TGFB3 15 CCL3(1), FLT3(3), IL6(2), TGFB1(1), TGFB2(2) 724148 9 5 8 1 1 2 4 0 2 0 0.28 0.076 1
5 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), RANBP2(9) 623372 10 5 9 1 0 2 1 2 4 1 0.47 0.086 1
6 CDC25PATHWAY The protein phosphatase Cdc25 is phosphorylated by Chk1 and activates Cdc2 to stimulate eukaryotic cells into M phase. ATM, CDC2, CDC25A, CDC25B, CDC25C, CHEK1, MYT1, WEE1, YWHAH 7 ATM(6), CDC25A(2), CDC25C(2), MYT1(9), YWHAH(1) 1098181 20 9 16 5 2 3 2 3 10 0 0.72 0.096 1
7 CTLPATHWAY Cytotoxic T lymphocytes induce apoptosis in infected cells presenting antigen-MHC-I complexes via the perforin and Fas/Fas ligand pathways. B2M, CD3D, CD3E, CD3G, CD3Z, GZMB, HLA-A, ICAM1, ITGAL, ITGB2, PRF1, TNFRSF6, TNFSF6, TRA@, TRB@ 9 HLA-A(3), ICAM1(1), ITGAL(2), ITGB2(1), PRF1(3) 721204 10 6 8 1 1 1 1 2 5 0 0.39 0.099 1
8 NUCLEOTIDE_GPCRS ADORA1, ADORA2A, ADORA2B, ADORA3, GPR23, LTB4R, P2RY1, P2RY2, P2RY5, P2RY6 8 ADORA2A(1), ADORA3(1), LTB4R(3), P2RY1(2), P2RY2(1), P2RY6(1) 514396 9 5 8 1 4 1 2 0 2 0 0.19 0.14 1
9 ACE2PATHWAY Angiotensin-converting enzyme 2 (ACE2) digests the blood-pressure regulator angiotensin II (AGT) ultimately to the vasodilator AGT1-7. ACE2, AGT, AGTR1, AGTR2, CMA1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6, REN 12 ACE2(1), AGT(2), AGTR2(1), CMA1(1), COL4A1(3), COL4A2(5), COL4A3(1), COL4A4(4), COL4A5(3), COL4A6(3), REN(4) 2187412 28 12 25 1 4 4 9 1 9 1 0.03 0.14 1
10 CREMPATHWAY The transcription factor CREM activates a post-meiotic transcriptional cascade culminating in spermatogenesis. ADCY1, CREM, FHL5, FSHB, FSHR, GNAS, XPO1 7 ADCY1(3), FSHB(1), FSHR(1), GNAS(6), XPO1(1) 837792 12 4 11 1 6 2 3 1 0 0 0.14 0.16 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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