Mutation Analysis (MutSig 2CV v3.1)
Glioma (Primary solid tumor)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C1D799F5
Maintained by David Heiman (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2015): Mutation Analysis (MutSig 2CV v3.1). Broad Institute of MIT and Harvard. doi:10.7908/C1D799F5
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 2CV v3.1 was used to generate the results found in this report.

  • Working with individual set: GBMLGG-TP

  • Number of patients in set: 796

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:GBMLGG-TP.final_analysis_set.maf

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

  • Significantly mutated genes (q ≤ 0.1): 132

Results
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 1.  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 2.  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 3.  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:

  • nnon = 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

  • p = p-value (overall)

  • q = q-value, False Discovery Rate (Benjamini-Hochberg procedure)

Table 1.  Get Full Table A Ranked List of Significantly Mutated Genes. Number of significant genes found: 132. 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 longname codelen nnei nncd nsil nmis nstp nspl nind nnon npat nsite pCV pCL pFN p q
1 IDH1 isocitrate dehydrogenase 1 (NADP+), soluble 1277 8 0 0 412 0 0 0 412 412 2 1e-16 1e-05 1 1e-16 2e-13
2 TP53 tumor protein p53 1900 9 0 3 325 23 19 48 415 327 166 1.5e-15 1e-05 1e-05 1e-16 2e-13
3 ATRX alpha thalassemia/mental retardation syndrome X-linked (RAD54 homolog, S. cerevisiae) 7615 4 0 9 37 50 20 126 233 210 198 1.7e-15 1e-05 0.22 1e-16 2e-13
4 PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1) 1244 226 1 0 63 18 7 26 114 111 89 1e-16 0.0065 0.73 1e-16 2e-13
5 CIC capicua homolog (Drosophila) 4905 6 0 1 66 9 3 49 127 109 90 1e-16 1e-05 0.54 1e-16 2e-13
6 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 3287 2 1 0 64 2 4 12 82 74 48 7.9e-14 1e-05 0.016 1e-16 2e-13
7 NF1 neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease) 12128 12 0 3 15 24 12 35 86 62 79 1e-16 0.0047 0.97 1e-16 2e-13
8 PIK3R1 phosphoinositide-3-kinase, regulatory subunit 1 (alpha) 2361 7 0 2 21 2 3 31 57 54 41 5.8e-16 1e-05 0.22 1e-16 2e-13
9 NOTCH1 Notch homolog 1, translocation-associated (Drosophila) 7800 12 0 3 25 2 4 24 55 42 43 6.2e-16 1e-05 0.19 1e-16 2e-13
10 FUBP1 far upstream element (FUSE) binding protein 1 2013 1 1 1 1 11 9 29 50 47 45 1.5e-16 0.016 0.98 2.2e-16 4.1e-13
11 RB1 retinoblastoma 1 (including osteosarcoma) 3704 5 0 1 2 12 6 11 31 30 27 3.6e-16 0.071 0.019 3.3e-16 5.6e-13
12 IDH2 isocitrate dehydrogenase 2 (NADP+), mitochondrial 1401 8 0 0 20 0 0 0 20 20 3 7.1e-11 1e-05 1 2.6e-14 3.9e-11
13 TCF12 transcription factor 12 (HTF4, helix-loop-helix transcription factors 4) 2278 9 0 0 1 0 2 18 21 19 19 6.7e-14 0.045 0.13 5.4e-14 7.7e-11
14 STK19 serine/threonine kinase 19 4548 12 0 0 3 0 0 9 12 11 4 7.1e-09 1e-05 0.6 2.2e-12 2.9e-09
15 ARID1A AT rich interactive domain 1A (SWI-like) 6934 16 0 4 10 7 1 10 28 22 28 1.7e-13 1 0.91 5.2e-12 6.4e-09
16 NIPBL Nipped-B homolog (Drosophila) 8642 10 0 1 10 5 3 8 26 20 25 1.5e-11 0.16 0.75 7.2e-11 8.3e-08
17 SMARCA4 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 5189 18 0 6 24 0 0 6 30 27 27 1.3e-09 0.0027 0.43 1.5e-10 1.6e-07
18 CREBZF CREB/ATF bZIP transcription factor 1065 59 0 0 2 0 0 7 9 9 3 6e-06 1e-05 0.53 1.5e-09 1.5e-06
19 EMG1 EMG1 nucleolar protein homolog (S. cerevisiae) 1360 28 0 0 0 1 0 6 7 7 3 8.6e-07 4e-05 0.92 1.9e-09 1.8e-06
20 ZNF709 zinc finger protein 709 1939 17 0 0 7 0 0 0 7 7 3 0.000015 1e-05 0.9 3.6e-09 3.3e-06
21 RPL5 ribosomal protein L5 926 14 0 0 5 1 2 2 10 10 10 3.2e-10 1 0.56 7.3e-09 6.4e-06
22 STAG2 stromal antigen 2 3939 14 0 1 4 5 5 3 17 16 17 1.5e-09 1 0.61 3.3e-08 0.000027
23 IRS4 insulin receptor substrate 4 3778 5 0 1 5 1 0 6 12 10 8 0.00024 5e-05 0.0017 5e-08 4e-05
24 REN renin 1259 2 0 0 3 0 0 4 7 7 4 5.7e-07 0.0026 0.92 5.6e-08 0.000043
25 TNRC18 trinucleotide repeat containing 18 9019 9 0 1 5 1 1 6 13 12 12 1.2e-08 0.19 0.98 6.2e-08 0.000045
26 NRAS neuroblastoma RAS viral (v-ras) oncogene homolog 945 49 0 0 5 0 0 0 5 5 3 4.9e-06 0.0004 0.14 6.7e-08 0.000048
27 PLCG1 phospholipase C, gamma 1 4000 46 0 3 10 0 1 1 12 11 10 0.000077 3e-05 0.092 7.9e-08 0.000053
28 SLC26A3 solute carrier family 26, member 3 2375 51 0 1 10 1 0 0 11 11 10 9.7e-08 0.14 0.091 1.3e-07 0.000088
29 ZBTB20 zinc finger and BTB domain containing 20 2238 0 0 3 15 1 0 7 23 22 20 7.1e-06 0.01 0.041 2.1e-07 0.00013
30 TRERF1 transcriptional regulating factor 1 3655 6 0 1 2 0 1 4 7 7 5 0.000044 0.00028 0.58 3.4e-07 0.00021
31 MX2 myxovirus (influenza virus) resistance 2 (mouse) 2200 86 0 1 7 2 0 0 9 9 8 8.4e-07 0.082 0.24 3.6e-07 0.00021
32 ZMIZ1 zinc finger, MIZ-type containing 1 3288 22 0 0 9 0 0 4 13 13 11 0.000024 0.0046 0.06 3.7e-07 0.00021
33 DDX5 DEAD (Asp-Glu-Ala-Asp) box polypeptide 5 2021 36 0 0 4 0 0 5 9 9 6 0.000032 0.001 0.39 3.8e-07 0.00021
34 DNMT3A DNA (cytosine-5-)-methyltransferase 3 alpha 2952 49 0 1 8 3 0 0 11 10 11 9.1e-08 1 0.14 4.6e-07 0.00025
35 PTPN11 protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1) 1842 36 0 2 11 0 0 0 11 11 9 4.6e-06 0.0058 0.57 5.5e-07 0.00029
IDH1

Figure S1.  This figure depicts the distribution of mutations and mutation types across the IDH1 significant gene.

TP53

Figure S2.  This figure depicts the distribution of mutations and mutation types across the TP53 significant gene.

ATRX

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

PTEN

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

CIC

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

PIK3CA

Figure S6.  This figure depicts the distribution of mutations and mutation types across the PIK3CA significant gene.

NF1

Figure S7.  This figure depicts the distribution of mutations and mutation types across the NF1 significant gene.

PIK3R1

Figure S8.  This figure depicts the distribution of mutations and mutation types across the PIK3R1 significant gene.

NOTCH1

Figure S9.  This figure depicts the distribution of mutations and mutation types across the NOTCH1 significant gene.

FUBP1

Figure S10.  This figure depicts the distribution of mutations and mutation types across the FUBP1 significant gene.

RB1

Figure S11.  This figure depicts the distribution of mutations and mutation types across the RB1 significant gene.

IDH2

Figure S12.  This figure depicts the distribution of mutations and mutation types across the IDH2 significant gene.

TCF12

Figure S13.  This figure depicts the distribution of mutations and mutation types across the TCF12 significant gene.

STK19

Figure S14.  This figure depicts the distribution of mutations and mutation types across the STK19 significant gene.

ARID1A

Figure S15.  This figure depicts the distribution of mutations and mutation types across the ARID1A significant gene.

NIPBL

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

SMARCA4

Figure S17.  This figure depicts the distribution of mutations and mutation types across the SMARCA4 significant gene.

CREBZF

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

EMG1

Figure S19.  This figure depicts the distribution of mutations and mutation types across the EMG1 significant gene.

ZNF709

Figure S20.  This figure depicts the distribution of mutations and mutation types across the ZNF709 significant gene.

RPL5

Figure S21.  This figure depicts the distribution of mutations and mutation types across the RPL5 significant gene.

STAG2

Figure S22.  This figure depicts the distribution of mutations and mutation types across the STAG2 significant gene.

IRS4

Figure S23.  This figure depicts the distribution of mutations and mutation types across the IRS4 significant gene.

REN

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

TNRC18

Figure S25.  This figure depicts the distribution of mutations and mutation types across the TNRC18 significant gene.

NRAS

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

PLCG1

Figure S27.  This figure depicts the distribution of mutations and mutation types across the PLCG1 significant gene.

SLC26A3

Figure S28.  This figure depicts the distribution of mutations and mutation types across the SLC26A3 significant gene.

ZBTB20

Figure S29.  This figure depicts the distribution of mutations and mutation types across the ZBTB20 significant gene.

TRERF1

Figure S30.  This figure depicts the distribution of mutations and mutation types across the TRERF1 significant gene.

MX2

Figure S31.  This figure depicts the distribution of mutations and mutation types across the MX2 significant gene.

ZMIZ1

Figure S32.  This figure depicts the distribution of mutations and mutation types across the ZMIZ1 significant gene.

DDX5

Figure S33.  This figure depicts the distribution of mutations and mutation types across the DDX5 significant gene.

DNMT3A

Figure S34.  This figure depicts the distribution of mutations and mutation types across the DNMT3A significant gene.

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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