Mutation Analysis (MutSig 2CV v3.1)
Skin Cutaneous Melanoma (Metastatic)
15 July 2014  |  analyses__2014_07_15
Maintainer Information
Citation Information
doi:10.7908/C1ZC81PZ
Maintained by David Heiman (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2014): Mutation Analysis (MutSig 2CV v3.1). Broad Institute of MIT and Harvard. doi:10.7908/C1ZC81PZ
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: SKCM-TM

  • Number of patients in set: 278

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:SKCM-TM.final_analysis_set.maf

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

  • Significantly mutated genes (q ≤ 0.1): 83

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: 83. 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 NRAS neuroblastoma RAS viral (v-ras) oncogene homolog 941 2 0 0 85 0 1 0 86 86 11 6.8e-15 1e-05 1e-05 1e-16 4.6e-13
2 TP53 tumor protein p53 1890 0 0 0 30 11 6 5 52 47 42 7e-15 0.0086 1e-05 1e-16 4.6e-13
3 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) 1002 1 0 1 14 17 5 6 42 41 19 2.2e-16 1e-05 1e-05 1e-16 4.6e-13
4 RPS27 ribosomal protein S27 (metallopanstimulin 1) 271 46 0 0 1 0 24 0 25 24 3 1e-16 NaN NaN 1e-16 4.6e-13
5 MRPS31 mitochondrial ribosomal protein S31 1216 11 0 0 2 0 17 1 20 19 5 1e-16 1 0.4 2.1e-15 7.7e-12
6 NF1 neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease) 12120 1 0 8 19 21 6 4 50 38 46 3.1e-14 0.029 0.97 8.3e-14 2.5e-10
7 RAC1 ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) 660 30 0 1 20 0 0 0 20 20 9 1.1e-11 0.0019 0.84 9.3e-13 2.4e-09
8 ARID2 AT rich interactive domain 2 (ARID, RFX-like) 5588 2 0 5 20 22 3 3 48 35 37 1.4e-08 2e-05 0.23 5.4e-11 1.2e-07
9 C15orf23 chromosome 15 open reading frame 23 1024 3 0 3 20 0 0 0 20 19 8 1.1e-06 1e-05 1 2.8e-10 5.8e-07
10 PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1) 1244 6 0 0 10 4 2 7 23 23 21 4.6e-11 0.17 0.55 3.4e-10 6.2e-07
11 NOTCH2NL Notch homolog 2 (Drosophila) N-terminal like 727 26 0 1 13 1 0 1 15 15 14 3.8e-08 0.075 0.7 8.8e-08 0.00015
12 MAP2K1 mitogen-activated protein kinase kinase 1 1224 7 0 2 12 2 0 0 14 14 7 0.000092 3e-05 0.86 1.3e-07 0.00019
13 PPP6C protein phosphatase 6, catalytic subunit 1057 8 0 3 16 2 2 1 21 20 15 4e-07 0.017 0.8 2.9e-07 0.00039
14 IDH1 isocitrate dehydrogenase 1 (NADP+), soluble 1277 11 0 2 15 0 1 0 16 16 6 0.000094 3e-05 0.98 3e-07 0.00039
15 PDE1A phosphodiesterase 1A, calmodulin-dependent 1744 2 0 9 39 0 4 0 43 39 33 0.000038 0.00058 0.054 3.3e-07 0.0004
16 HMGCR 3-hydroxy-3-methylglutaryl-Coenzyme A reductase 2743 1 0 1 6 0 6 0 12 11 8 0.00025 0.00013 0.28 7.6e-07 0.00086
17 PHGDH phosphoglycerate dehydrogenase 1646 1 0 0 10 2 0 0 12 12 9 0.0052 1e-05 0.1 9.2e-07 0.00099
18 SLC38A4 solute carrier family 38, member 4 1700 13 0 4 35 0 3 0 38 34 32 1.6e-06 0.03 0.85 1.9e-06 0.0019
19 CDK4 cyclin-dependent kinase 4 940 3 0 0 7 0 0 0 7 7 4 0.012 1e-05 0.076 2.1e-06 0.002
20 FAM58A family with sequence similarity 58, member A 762 3 0 0 0 1 2 2 5 5 4 2.9e-06 0.16 0.078 2.5e-06 0.0023
21 EMG1 EMG1 nucleolar protein homolog (S. cerevisiae) 1360 29 0 0 3 0 0 6 9 9 5 0.00021 0.00085 0.83 3.9e-06 0.0034
22 RQCD1 RCD1 required for cell differentiation1 homolog (S. pombe) 927 12 0 1 9 0 0 0 9 9 4 0.00063 0.00053 0.13 5.6e-06 0.0047
23 HSD11B1 hydroxysteroid (11-beta) dehydrogenase 1 905 7 0 0 14 0 0 0 14 14 13 3.9e-07 0.63 0.62 6.2e-06 0.0048
24 DMC1 DMC1 dosage suppressor of mck1 homolog, meiosis-specific homologous recombination (yeast) 1075 6 0 1 8 2 2 0 12 12 9 3.9e-06 0.072 1 6.2e-06 0.0048
25 NRK Nik related kinase 4861 6 0 6 41 3 2 2 48 44 45 0.000012 0.27 0.015 7.6e-06 0.0055
26 TAF1A TATA box binding protein (TBP)-associated factor, RNA polymerase I, A, 48kDa 1393 15 0 1 14 0 0 0 14 13 7 0.05 1e-05 0.36 7.8e-06 0.0055
27 OXA1L oxidase (cytochrome c) assembly 1-like 1524 9 0 2 8 0 0 0 8 8 3 0.08 1e-05 1 0.000012 0.0081
28 COL3A1 collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant) 4601 8 0 13 66 6 10 0 82 57 75 0.000022 0.019 1 0.000014 0.0088
29 TCHHL1 trichohyalin-like 1 2723 3 0 12 50 4 0 0 54 39 50 0.000034 0.026 0.55 0.000017 0.011
30 IL5RA interleukin 5 receptor, alpha 1327 13 0 1 12 3 2 0 17 17 15 3.1e-06 0.29 0.69 2e-05 0.012
31 NBPF7 neuroblastoma breakpoint family, member 7 1293 8 0 1 13 0 1 2 16 13 13 0.00035 0.0037 0.84 0.000026 0.015
32 KEL Kell blood group, metallo-endopeptidase 2271 3 0 21 35 3 5 1 44 37 35 0.023 3e-05 0.85 0.000032 0.018
33 C7orf58 chromosome 7 open reading frame 58 3209 1 0 10 34 3 6 0 43 35 36 0.0048 0.0065 0.012 0.000033 0.018
34 NBPF1 neuroblastoma breakpoint family, member 1 3519 0 0 11 42 2 3 0 47 39 36 0.24 1e-05 0.67 0.000034 0.018
35 TMEM216 transmembrane protein 216 467 292 0 0 0 0 8 0 8 8 1 0.0039 0.0004 1 0.000034 0.018
NRAS

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

TP53

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

CDKN2A

Figure S3.  This figure depicts the distribution of mutations and mutation types across the CDKN2A significant gene.

RPS27

Figure S4.  This figure depicts the distribution of mutations and mutation types across the RPS27 significant gene.

MRPS31

Figure S5.  This figure depicts the distribution of mutations and mutation types across the MRPS31 significant gene.

NF1

Figure S6.  This figure depicts the distribution of mutations and mutation types across the NF1 significant gene.

RAC1

Figure S7.  This figure depicts the distribution of mutations and mutation types across the RAC1 significant gene.

ARID2

Figure S8.  This figure depicts the distribution of mutations and mutation types across the ARID2 significant gene.

C15orf23

Figure S9.  This figure depicts the distribution of mutations and mutation types across the C15orf23 significant gene.

PTEN

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

NOTCH2NL

Figure S11.  This figure depicts the distribution of mutations and mutation types across the NOTCH2NL significant gene.

MAP2K1

Figure S12.  This figure depicts the distribution of mutations and mutation types across the MAP2K1 significant gene.

PPP6C

Figure S13.  This figure depicts the distribution of mutations and mutation types across the PPP6C significant gene.

IDH1

Figure S14.  This figure depicts the distribution of mutations and mutation types across the IDH1 significant gene.

PDE1A

Figure S15.  This figure depicts the distribution of mutations and mutation types across the PDE1A significant gene.

HMGCR

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

PHGDH

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

SLC38A4

Figure S18.  This figure depicts the distribution of mutations and mutation types across the SLC38A4 significant gene.

CDK4

Figure S19.  This figure depicts the distribution of mutations and mutation types across the CDK4 significant gene.

FAM58A

Figure S20.  This figure depicts the distribution of mutations and mutation types across the FAM58A significant gene.

EMG1

Figure S21.  This figure depicts the distribution of mutations and mutation types across the EMG1 significant gene.

RQCD1

Figure S22.  This figure depicts the distribution of mutations and mutation types across the RQCD1 significant gene.

HSD11B1

Figure S23.  This figure depicts the distribution of mutations and mutation types across the HSD11B1 significant gene.

DMC1

Figure S24.  This figure depicts the distribution of mutations and mutation types across the DMC1 significant gene.

NRK

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

TAF1A

Figure S26.  This figure depicts the distribution of mutations and mutation types across the TAF1A significant gene.

OXA1L

Figure S27.  This figure depicts the distribution of mutations and mutation types across the OXA1L significant gene.

COL3A1

Figure S28.  This figure depicts the distribution of mutations and mutation types across the COL3A1 significant gene.

TCHHL1

Figure S29.  This figure depicts the distribution of mutations and mutation types across the TCHHL1 significant gene.

IL5RA

Figure S30.  This figure depicts the distribution of mutations and mutation types across the IL5RA significant gene.

NBPF7

Figure S31.  This figure depicts the distribution of mutations and mutation types across the NBPF7 significant gene.

KEL

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

C7orf58

Figure S33.  This figure depicts the distribution of mutations and mutation types across the C7orf58 significant gene.

NBPF1

Figure S34.  This figure depicts the distribution of mutations and mutation types across the NBPF1 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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