Mutation Analysis (MutSig 2CV v3.1)
Skin Cutaneous Melanoma (Metastatic)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C1H70DX6
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/C1H70DX6
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: 290

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): 107

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: 107. 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 945 2 0 1 88 1 1 0 90 87 10 4.7e-16 1e-05 1e-05 1e-16 6.8e-13
2 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) 1002 1 1 2 19 15 5 6 45 41 24 1e-16 1e-05 1e-05 1e-16 6.8e-13
3 TP53 tumor protein p53 1901 0 0 2 33 10 6 5 54 48 43 2.9e-13 0.00072 1e-05 1.1e-16 6.8e-13
4 PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1) 1244 3 0 0 10 6 2 7 25 25 23 1e-16 0.38 0.46 2e-15 9.2e-12
5 NF1 neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease) 12125 2 0 10 19 22 8 4 53 38 48 1.1e-12 0.0032 0.95 3e-13 1.1e-09
6 RAC1 ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) 660 17 0 1 20 0 0 0 20 20 9 4.7e-11 0.0014 0.84 3.7e-12 1.1e-08
7 ARID2 AT rich interactive domain 2 (ARID, RFX-like) 5588 2 0 7 21 22 3 5 51 37 40 3.4e-08 3e-05 0.2 4.8e-11 1.3e-07
8 PPP6C protein phosphatase 6, catalytic subunit 1057 8 0 3 16 2 2 1 21 20 15 3.7e-09 0.022 0.76 4.9e-09 0.000011
9 MAP2K1 mitogen-activated protein kinase kinase 1 1224 7 0 3 16 2 0 0 18 16 9 0.000069 1e-05 0.76 1.5e-08 0.000031
10 COL3A1 collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant) 4601 13 0 14 71 6 11 0 88 59 80 1.4e-07 0.02 1 1.2e-07 0.00021
11 ZFX zinc finger protein, X-linked 2505 5 0 1 8 5 0 3 16 15 15 1.2e-06 0.2 0.014 2.1e-07 0.00034
12 HSD11B1 hydroxysteroid (11-beta) dehydrogenase 1 905 7 0 0 14 0 0 0 14 14 13 2.2e-08 0.64 0.62 4e-07 0.00062
13 IL5RA interleukin 5 receptor, alpha 1327 15 0 1 12 3 2 0 17 17 15 4.5e-08 0.38 0.72 4.6e-07 0.00065
14 FAM58A family with sequence similarity 58, member A 762 3 0 0 1 1 2 2 6 6 5 1.1e-06 0.16 0.046 1.2e-06 0.0015
15 IDH1 isocitrate dehydrogenase 1 (NADP+), soluble 1277 5 0 3 14 0 1 0 15 15 5 0.0069 1e-05 0.98 1.2e-06 0.0015
16 DMC1 DMC1 dosage suppressor of mck1 homolog, meiosis-specific homologous recombination (yeast) 1075 12 0 2 7 2 3 0 12 11 9 0.000011 0.0051 1 2.2e-06 0.0025
17 CYP3A5 cytochrome P450, family 3, subfamily A, polypeptide 5 1560 14 0 2 10 1 4 0 15 13 15 4.4e-07 0.28 0.82 2.8e-06 0.0028
18 SLC38A4 solute carrier family 38, member 4 1703 8 0 4 35 0 2 0 37 33 31 2e-06 0.024 0.9 2.8e-06 0.0028
19 DDX3X DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked 2053 18 0 2 12 4 0 5 21 20 19 1.5e-06 0.07 0.55 3.1e-06 0.0028
20 DSG3 desmoglein 3 (pemphigus vulgaris antigen) 3061 1 0 12 65 0 3 0 68 48 56 0.019 1e-05 0.74 3.2e-06 0.0028
21 S100A8 S100 calcium binding protein A8 292 7 0 2 7 0 2 0 9 8 7 0.000017 0.005 0.61 3.2e-06 0.0028
22 RPGRIP1 retinitis pigmentosa GTPase regulator interacting protein 1 3955 36 0 8 31 4 0 0 35 27 32 5.4e-06 0.078 0.13 4.3e-06 0.0036
23 OXA1L oxidase (cytochrome c) assembly 1-like 1524 9 0 2 8 0 0 0 8 8 3 0.028 1e-05 1 4.6e-06 0.0036
24 NBPF1 neuroblastoma breakpoint family, member 1 3522 0 0 7 27 3 1 0 31 27 27 0.031 1e-05 0.84 4.9e-06 0.0038
25 PDE1A phosphodiesterase 1A, calmodulin-dependent 1744 1 0 12 40 0 4 0 44 40 33 0.00044 0.00085 0.033 5.3e-06 0.0039
26 GML glycosylphosphatidylinositol anchored molecule like protein 489 24 0 1 11 0 1 0 12 11 11 2.6e-06 0.24 0.19 5.8e-06 0.0041
27 RQCD1 RCD1 required for cell differentiation1 homolog (S. pombe) 927 14 0 1 9 0 0 0 9 9 4 0.00093 0.00098 0.13 7.9e-06 0.0054
28 TRERF1 transcriptional regulating factor 1 3655 0 0 14 33 2 1 3 39 26 33 0.067 1e-05 0.36 1e-05 0.0067
29 C1QTNF9 C1q and tumor necrosis factor related protein 9 1014 9 0 3 14 1 1 0 16 16 13 7.5e-06 0.088 0.95 0.000012 0.0075
30 KRTAP5-10 keratin associated protein 5-10 611 16 0 2 11 0 0 0 11 10 7 0.0092 5e-05 0.77 0.000015 0.0091
31 KEL Kell blood group, metallo-endopeptidase 2271 2 0 22 35 3 5 1 44 36 35 0.023 1e-05 0.81 2e-05 0.012
32 GAGE2D G antigen 2D 1115 4 0 0 0 0 0 4 4 4 1 0.0018 0.0005 0.75 0.000028 0.016
33 BRAF v-raf murine sarcoma viral oncogene homolog B1 2371 1 0 5 165 1 2 1 169 145 19 0.21 1e-05 1e-05 3e-05 0.017
34 PARM1 prostate androgen-regulated mucin-like protein 1 945 13 0 2 18 1 0 0 19 19 16 0.000014 0.096 0.57 0.000032 0.017
35 KYNU kynureninase (L-kynurenine hydrolase) 1478 7 0 3 13 1 2 0 16 16 13 0.000048 0.024 0.6 0.000033 0.017
NRAS

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

PTEN

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

NF1

Figure S5.  This figure depicts the distribution of mutations and mutation types across the NF1 significant gene.

RAC1

Figure S6.  This figure depicts the distribution of mutations and mutation types across the RAC1 significant gene.

ARID2

Figure S7.  This figure depicts the distribution of mutations and mutation types across the ARID2 significant gene.

PPP6C

Figure S8.  This figure depicts the distribution of mutations and mutation types across the PPP6C significant gene.

MAP2K1

Figure S9.  This figure depicts the distribution of mutations and mutation types across the MAP2K1 significant gene.

COL3A1

Figure S10.  This figure depicts the distribution of mutations and mutation types across the COL3A1 significant gene.

ZFX

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

HSD11B1

Figure S12.  This figure depicts the distribution of mutations and mutation types across the HSD11B1 significant gene.

IL5RA

Figure S13.  This figure depicts the distribution of mutations and mutation types across the IL5RA significant gene.

FAM58A

Figure S14.  This figure depicts the distribution of mutations and mutation types across the FAM58A significant gene.

IDH1

Figure S15.  This figure depicts the distribution of mutations and mutation types across the IDH1 significant gene.

DMC1

Figure S16.  This figure depicts the distribution of mutations and mutation types across the DMC1 significant gene.

SLC38A4

Figure S17.  This figure depicts the distribution of mutations and mutation types across the SLC38A4 significant gene.

DDX3X

Figure S18.  This figure depicts the distribution of mutations and mutation types across the DDX3X significant gene.

DSG3

Figure S19.  This figure depicts the distribution of mutations and mutation types across the DSG3 significant gene.

S100A8

Figure S20.  This figure depicts the distribution of mutations and mutation types across the S100A8 significant gene.

RPGRIP1

Figure S21.  This figure depicts the distribution of mutations and mutation types across the RPGRIP1 significant gene.

OXA1L

Figure S22.  This figure depicts the distribution of mutations and mutation types across the OXA1L significant gene.

NBPF1

Figure S23.  This figure depicts the distribution of mutations and mutation types across the NBPF1 significant gene.

PDE1A

Figure S24.  This figure depicts the distribution of mutations and mutation types across the PDE1A significant gene.

GML

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

RQCD1

Figure S26.  This figure depicts the distribution of mutations and mutation types across the RQCD1 significant gene.

TRERF1

Figure S27.  This figure depicts the distribution of mutations and mutation types across the TRERF1 significant gene.

C1QTNF9

Figure S28.  This figure depicts the distribution of mutations and mutation types across the C1QTNF9 significant gene.

KRTAP5-10

Figure S29.  This figure depicts the distribution of mutations and mutation types across the KRTAP5-10 significant gene.

KEL

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

BRAF

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

PARM1

Figure S32.  This figure depicts the distribution of mutations and mutation types across the PARM1 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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