Mutation Analysis (MutSigCV v0.9)
Brain Lower Grade Glioma (Primary solid tumor)
21 August 2015  |  analyses__2015_08_21
Maintainer Information
Citation Information
doi:10.7908/C13B5ZCV
Maintained by David Heiman (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2015): Mutation Analysis (MutSigCV v0.9). Broad Institute of MIT and Harvard. doi:10.7908/C13B5ZCV
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. MutSigCV v0.9 was used to generate the results found in this report.

  • Working with individual set: LGG-TP

  • Number of patients in set: 513

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:LGG-TP.final_analysis_set.maf

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

  • Significantly mutated genes (q ≤ 0.1): 27

Results
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: LGG-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:

  • 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

  • nflank = number of noncoding mutations from this gene's flanking region, across the individual set

  • 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: 27. 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).

gene Nnon Nsil Nflank nnon npat nsite nsil nflank nnei fMLE p score time q
ATRX 3095955 763857 363321 215 191 185 7 0 1 2.8 0 910 0.48 0
TP53 484785 141588 105266 319 248 145 2 0 4 2.2 0 870 0.44 0
NOTCH1 2048409 592002 194180 55 42 43 3 0 20 0.97 2.1e-15 190 0.42 1.3e-11
IDH1 516591 133380 82782 398 398 2 0 0 13 0.89 3e-15 1400 0.45 1.4e-11
PIK3CA 1333287 341145 202356 50 45 29 0 0 20 1.6 4.3e-15 160 0.44 1.4e-11
IDH2 470934 124146 91469 20 20 3 0 0 20 0.66 5.2e-15 73 0.42 1.4e-11
EGFR 1580040 431946 300468 45 35 28 1 1 20 0.6 5.9e-15 110 0.44 1.4e-11
CIC 1599534 579690 167608 126 108 89 1 0 8 0.91 6.3e-15 450 0.44 1.4e-11
FUBP1 789507 232902 202356 51 48 46 1 0 5 0.83 1e-14 280 0.44 2.1e-11
PIK3R1 956232 245727 176295 24 22 18 2 0 20 1.3 1.4e-14 110 0.43 2.5e-11
PTEN 499662 120042 88914 25 25 23 0 0 20 0.98 1.9e-14 110 0.55 3.2e-11
NF1 4828356 1353294 605024 51 33 47 2 0 0 0.56 6.8e-12 150 0.41 1e-08
TCF12 899289 257526 204911 16 15 15 0 0 7 1.9 8.9e-12 89 0.44 1.3e-08
SMARCA4 1661607 469908 281561 28 26 25 5 1 20 1.5 4.2e-10 88 0.45 5.4e-07
NIPBL 3422736 907497 448147 24 18 24 0 0 20 0.9 1.8e-08 86 0.57 0.000022
BCOR 1828332 546858 104755 16 15 16 6 0 20 1.4 4.1e-08 71 0.55 0.000047
EMG1 348840 106191 62853 6 6 2 0 0 20 1.1 5.6e-08 40 0.46 6e-05
ARID1A 2291571 675108 192136 26 20 26 2 0 2 0.91 1.1e-07 99 0.44 0.00011
CREBZF 385263 130815 7665 7 7 2 0 0 20 1.5 5.5e-07 43 0.51 0.00053
SOX4 195966 61047 2555 7 6 7 0 0 20 0.52 2.4e-06 30 0.68 0.0022
SPANXD 120042 31293 21973 5 5 5 0 0 20 0.91 0.000027 21 0.41 0.024
NKX2-2 279072 87723 17885 6 6 6 0 0 20 1.2 0.000035 28 0.55 0.029
NKD2 274455 82593 39858 4 4 3 0 0 20 0.43 0.000036 24 0.54 0.029
CUL4B 1091664 273942 211554 12 10 12 2 0 13 1.5 0.000061 41 0.43 0.047
TMEM216 109782 33345 19929 3 3 1 0 0 20 1.6 0.000089 21 0.41 0.065
MED9 155952 42066 21462 3 3 1 1 0 20 0.83 0.00012 21 0.39 0.086
NDUFAF2 201609 53352 48034 3 3 1 1 1 20 1 0.00014 21 0.38 0.097
DCDC1 447336 121581 77161 6 5 6 1 0 20 1.3 0.00021 25 0.44 0.14
MYT1 1269675 353970 196735 7 6 7 1 0 20 0.63 0.00024 36 0.43 0.15
ZCCHC12 479142 139536 12264 7 7 5 1 0 20 0.67 0.00036 23 0.49 0.22
PAGE1 153900 41553 41902 3 3 3 0 0 20 1.1 0.00041 18 0.39 0.24
MYH4 2427003 626373 388871 15 15 15 1 0 19 1.3 0.00046 48 0.54 0.26
EIF1AX 181602 42579 61320 4 4 3 1 0 20 0.57 0.00049 16 0.36 0.27
CRIPAK 504792 167751 11753 4 4 4 1 0 20 0.82 0.00052 24 0.68 0.28
CDKN1B 238545 66177 88914 3 3 3 0 0 20 0.51 0.00057 20 0.38 0.3
ATRX

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

TP53

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

NOTCH1

Figure S3.  This figure depicts the distribution of mutations and mutation types across the NOTCH1 significant gene.

IDH1

Figure S4.  This figure depicts the distribution of mutations and mutation types across the IDH1 significant gene.

PIK3CA

Figure S5.  This figure depicts the distribution of mutations and mutation types across the PIK3CA significant gene.

IDH2

Figure S6.  This figure depicts the distribution of mutations and mutation types across the IDH2 significant gene.

EGFR

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

CIC

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

FUBP1

Figure S9.  This figure depicts the distribution of mutations and mutation types across the FUBP1 significant gene.

PIK3R1

Figure S10.  This figure depicts the distribution of mutations and mutation types across the PIK3R1 significant gene.

PTEN

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

NF1

Figure S12.  This figure depicts the distribution of mutations and mutation types across the NF1 significant gene.

TCF12

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

SMARCA4

Figure S14.  This figure depicts the distribution of mutations and mutation types across the SMARCA4 significant gene.

NIPBL

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

BCOR

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

ARID1A

Figure S17.  This figure depicts the distribution of mutations and mutation types across the ARID1A significant gene.

CREBZF

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

SOX4

Figure S19.  This figure depicts the distribution of mutations and mutation types across the SOX4 significant gene.

SPANXD

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

NKX2-2

Figure S21.  This figure depicts the distribution of mutations and mutation types across the NKX2-2 significant gene.

NKD2

Figure S22.  This figure depicts the distribution of mutations and mutation types across the NKD2 significant gene.

CUL4B

Figure S23.  This figure depicts the distribution of mutations and mutation types across the CUL4B significant gene.

TMEM216

Figure S24.  This figure depicts the distribution of mutations and mutation types across the TMEM216 significant gene.

MED9

Figure S25.  This figure depicts the distribution of mutations and mutation types across the MED9 significant gene.

NDUFAF2

Figure S26.  This figure depicts the distribution of mutations and mutation types across the NDUFAF2 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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