Mutation Analysis (MutSigCV v0.9)
Brain Lower Grade Glioma (Primary solid tumor)
28 January 2016  |  analyses__2016_01_28
Maintainer Information
Citation Information
doi:10.7908/C1GM86P3
Maintained by David Heiman (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2016): Mutation Analysis (MutSigCV v0.9). Broad Institute of MIT and Harvard. doi:10.7908/C1GM86P3
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: 516

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): 28

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: 28. 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
NOTCH1 2060388 595464 195320 55 42 43 3 0 20 0.95 0 190 0.53 0
PIK3R1 961824 247164 177330 24 22 18 2 0 20 1.4 1.7e-15 110 0.52 1.5e-11
CIC 1608888 583080 168592 126 108 89 1 0 8 0.89 2.8e-15 450 0.62 1.6e-11
PIK3CA 1341084 343140 203544 50 45 29 0 0 20 1.5 4.9e-15 160 0.61 1.6e-11
IDH2 473688 124872 92006 20 20 3 0 0 20 0.74 5.4e-15 73 0.48 1.6e-11
TP53 487620 142416 105884 323 251 145 2 0 4 2.2 5.8e-15 880 0.6 1.6e-11
ATRX 3114060 768324 365454 219 194 188 7 0 1 2.8 6e-15 930 0.67 1.6e-11
FUBP1 794124 234264 203544 51 48 46 1 0 5 0.81 8.9e-15 280 0.56 1.8e-11
PTEN 502584 120744 89436 25 25 23 0 0 20 0.96 9.1e-15 110 0.51 1.8e-11
IDH1 519612 134160 83268 401 401 2 0 0 13 0.87 1.1e-14 1400 0.54 1.9e-11
EGFR 1589280 434472 302232 45 35 28 1 1 20 0.59 1.2e-14 110 0.51 2e-11
TCF12 904548 259032 206114 16 15 15 0 0 7 1.8 8.9e-12 89 0.54 1.4e-08
NF1 4856592 1361208 608576 51 33 47 3 0 0 0.82 4.4e-11 150 0.49 6.2e-08
SMARCA4 1671324 472656 283214 28 26 25 5 1 20 1.6 7.3e-10 88 0.52 9.6e-07
NIPBL 3442752 912804 450778 24 18 24 0 0 20 0.88 1.8e-08 86 0.51 0.000022
BCOR 1839024 550056 105370 17 15 17 6 0 20 1.4 4e-08 71 0.61 0.000046
ARID1A 2304972 679056 193264 26 20 26 2 0 2 0.89 1.1e-07 99 1.2 0.00011
CREBZF 387516 131580 7710 7 7 2 0 0 20 1.5 7.4e-07 42 0.61 0.00075
EMG1 350880 106812 63222 5 5 2 0 0 20 1.1 2e-06 34 0.62 0.0019
SOX4 197112 61404 2570 7 6 7 1 0 20 0.64 3.5e-06 30 0.61 0.0032
SPANXD 120744 31476 22102 5 5 5 0 0 20 0.89 0.000027 21 0.64 0.023
NKX2-2 280704 88236 17990 6 6 6 0 0 20 1.2 0.000034 28 0.5 0.028
DLX6 166668 47988 12336 4 4 2 0 0 20 1.6 0.000039 25 0.5 0.031
NKD2 276060 83076 40092 4 4 3 0 0 20 0.5 0.000046 24 0.51 0.035
CUL4B 1098048 275544 212796 12 10 12 2 0 13 1.5 0.000059 41 0.56 0.043
TMEM216 110424 33540 20046 3 3 1 0 0 20 1.7 0.0001 21 0.41 0.074
MED9 156864 42312 21588 3 3 1 1 0 20 0.81 0.00012 21 0.52 0.082
NDUFAF2 202788 53664 48316 3 3 1 1 1 20 0.99 0.00014 21 0.59 0.092
DCDC1 449952 122292 77614 6 5 6 1 0 20 1.3 0.00021 25 0.72 0.13
MYH4 2441196 630036 391154 16 16 16 1 0 19 1.3 0.00021 50 0.53 0.13
MYT1 1277100 356040 197890 7 6 7 1 0 20 0.62 0.00024 36 0.63 0.14
ZCCHC12 481944 140352 12336 7 7 5 1 0 20 0.65 0.00036 23 0.44 0.2
PAGE1 154800 41796 42148 3 3 3 0 0 20 1.1 0.0004 18 0.4 0.22
EIF1AX 182664 42828 61680 4 4 3 1 0 20 0.55 0.00049 16 0.46 0.26
CRIPAK 507744 168732 11822 4 4 4 1 0 20 0.8 0.00052 24 0.65 0.27
NOTCH1

Figure S1.  This figure depicts the distribution of mutations and mutation types across the NOTCH1 significant gene.

PIK3R1

Figure S2.  This figure depicts the distribution of mutations and mutation types across the PIK3R1 significant gene.

CIC

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

PIK3CA

Figure S4.  This figure depicts the distribution of mutations and mutation types across the PIK3CA significant gene.

IDH2

Figure S5.  This figure depicts the distribution of mutations and mutation types across the IDH2 significant gene.

TP53

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

ATRX

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

FUBP1

Figure S8.  This figure depicts the distribution of mutations and mutation types across the FUBP1 significant gene.

PTEN

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

IDH1

Figure S10.  This figure depicts the distribution of mutations and mutation types across the IDH1 significant gene.

EGFR

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

TCF12

Figure S12.  This figure depicts the distribution of mutations and mutation types across the TCF12 significant gene.

NF1

Figure S13.  This figure depicts the distribution of mutations and mutation types across the NF1 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.

DLX6

Figure S22.  This figure depicts the distribution of mutations and mutation types across the DLX6 significant gene.

NKD2

Figure S23.  This figure depicts the distribution of mutations and mutation types across the NKD2 significant gene.

CUL4B

Figure S24.  This figure depicts the distribution of mutations and mutation types across the CUL4B significant gene.

TMEM216

Figure S25.  This figure depicts the distribution of mutations and mutation types across the TMEM216 significant gene.

MED9

Figure S26.  This figure depicts the distribution of mutations and mutation types across the MED9 significant gene.

NDUFAF2

Figure S27.  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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