Mutation Analysis (MutSig 2CV v3.1)
Lung Adenocarcinoma (Primary solid tumor)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C1222STD
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/C1222STD
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: LUAD-TP

  • Number of patients in set: 533

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:LUAD-TP.final_analysis_set.maf

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

  • Significantly mutated genes (q ≤ 0.1): 182

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: 182. 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 TP53 tumor protein p53 1901 4 0 4 184 51 31 37 303 287 173 7e-15 0.0033 1e-05 1e-16 3.4e-13
2 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 709 7 0 0 164 1 0 0 165 161 11 1e-16 1e-05 1e-05 1e-16 3.4e-13
3 KEAP1 kelch-like ECH-associated protein 1 1895 14 0 2 71 7 4 10 92 91 82 8.1e-16 0.16 1e-05 1e-16 3.4e-13
4 EGFR epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian) 3999 4 0 3 51 1 4 30 86 72 39 1e-16 1e-05 0.00094 1e-16 3.4e-13
5 RBM10 RNA binding motif protein 10 2882 10 0 2 7 12 9 7 35 33 33 1e-16 0.18 0.0054 1e-16 3.4e-13
6 SMARCA4 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 5189 18 0 5 25 11 5 3 44 41 43 1e-16 0.071 0.23 1.1e-16 3.4e-13
7 STK11 serine/threonine kinase 11 1338 3 0 2 26 19 11 27 83 77 68 4e-16 0.4 0.099 2.7e-15 7e-12
8 RB1 retinoblastoma 1 (including osteosarcoma) 3711 3 0 1 5 9 8 11 33 32 32 2.4e-16 0.35 0.86 4e-15 9.2e-12
9 ARID1A AT rich interactive domain 1A (SWI-like) 6934 7 0 3 16 15 2 4 37 33 36 7.5e-15 0.46 0.071 3.4e-14 6.9e-11
10 NF1 neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease) 12126 4 0 7 30 10 10 17 67 60 65 2.2e-14 0.1 0.27 4.8e-14 8.9e-11
11 BRAF v-raf murine sarcoma viral oncogene homolog B1 2371 14 0 1 34 2 6 1 43 39 22 2.5e-08 1e-05 0.0067 7.4e-12 1.2e-08
12 MGA MAX gene associated 9290 2 0 6 20 18 2 7 47 41 47 2.4e-12 1 0.96 6.7e-11 1e-07
13 CHRND cholinergic receptor, nicotinic, delta 1600 46 0 0 18 2 1 0 21 20 19 7.7e-10 0.079 0.21 1e-09 1.4e-06
14 MET met proto-oncogene (hepatocyte growth factor receptor) 4307 60 0 6 12 1 6 3 22 22 19 0.000012 8e-05 0.024 2.8e-09 3.7e-06
15 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) 1002 1 0 2 16 1 2 3 22 21 18 0.000068 0.0031 1e-05 1.5e-08 0.000017
16 U2AF1 U2 small nuclear RNA auxiliary factor 1 824 305 0 1 12 0 0 0 12 12 3 7e-05 3e-05 0.00012 1.5e-08 0.000017
17 SETD2 SET domain containing 2 7777 6 0 2 19 12 2 8 41 34 41 2.2e-08 1 0.0078 1.6e-08 0.000017
18 DNMT3A DNA (cytosine-5-)-methyltransferase 3 alpha 2952 16 0 3 19 3 1 1 24 22 24 2.8e-07 1 0.0045 1.2e-07 0.00012
19 ERBB2 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) 3889 5 0 3 3 0 2 7 12 12 8 0.00013 4e-05 0.39 2.3e-07 0.00022
20 ATM ataxia telangiectasia mutated 9439 0 0 2 34 10 3 8 55 46 53 1.8e-07 0.16 0.048 2.6e-07 0.00024
21 COL5A2 collagen, type V, alpha 2 4712 14 0 11 43 2 11 2 58 54 56 1.1e-07 0.5 0.065 3e-07 0.00026
22 NFE2L2 nuclear factor (erythroid-derived 2)-like 2 1834 19 0 0 14 1 0 2 17 17 17 9.9e-06 0.24 0.0022 4.4e-07 0.00037
23 PPP3CA protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform 1618 0 0 0 10 1 1 2 14 14 11 0.00065 1e-05 0.72 7e-07 0.00056
24 FCRLA Fc receptor-like A 1169 2 0 3 9 0 5 1 15 15 14 4.8e-07 0.14 0.94 1.6e-06 0.0012
25 ARID2 AT rich interactive domain 2 (ARID, RFX-like) 5588 2 0 6 13 9 5 3 30 27 28 6.1e-06 0.07 0.046 1.7e-06 0.0012
26 SLAMF9 SLAM family member 9 883 10 0 1 10 1 2 0 13 12 13 1.2e-07 1 0.43 2e-06 0.0014
27 SLC4A3 solute carrier family 4, anion exchanger, member 3 3872 5 0 1 14 2 5 1 22 21 21 3.2e-07 0.37 0.4 2.3e-06 0.0015
28 SP100 SP100 nuclear antigen 3318 8 0 1 13 1 4 0 18 18 18 9.6e-07 0.17 0.65 3.1e-06 0.002
29 RPL5 ribosomal protein L5 926 4 0 0 3 1 1 3 8 8 8 9.2e-07 1 0.15 3.8e-06 0.0024
30 AACS acetoacetyl-CoA synthetase 2087 3 0 0 17 2 0 0 19 18 19 3e-06 0.063 0.94 4.9e-06 0.003
31 ITGBL1 integrin, beta-like 1 (with EGF-like repeat domains) 1525 11 0 2 11 3 4 3 21 19 20 1.3e-06 0.46 0.2 6.3e-06 0.0037
32 NLRP6 NLR family, pyrin domain containing 6 2706 12 0 2 9 1 1 0 11 11 9 0.00019 0.0053 0.058 6.6e-06 0.0038
33 STIM1 stromal interaction molecule 1 2102 30 0 2 7 2 1 1 11 10 10 0.0033 0.0071 0.0014 9.4e-06 0.0052
34 NCKAP1L NCK-associated protein 1-like 3506 37 0 4 16 2 1 2 21 21 21 9.4e-07 1 0.66 0.000011 0.0058
35 CTNNB1 catenin (cadherin-associated protein), beta 1, 88kDa 2406 1 0 0 19 0 0 1 20 19 13 0.074 1e-05 0.015 0.000011 0.0058
TP53

Figure S1.  This figure depicts the distribution of mutations and mutation types across the TP53 significant gene.

KRAS

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

KEAP1

Figure S3.  This figure depicts the distribution of mutations and mutation types across the KEAP1 significant gene.

EGFR

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

RBM10

Figure S5.  This figure depicts the distribution of mutations and mutation types across the RBM10 significant gene.

SMARCA4

Figure S6.  This figure depicts the distribution of mutations and mutation types across the SMARCA4 significant gene.

STK11

Figure S7.  This figure depicts the distribution of mutations and mutation types across the STK11 significant gene.

RB1

Figure S8.  This figure depicts the distribution of mutations and mutation types across the RB1 significant gene.

ARID1A

Figure S9.  This figure depicts the distribution of mutations and mutation types across the ARID1A significant gene.

NF1

Figure S10.  This figure depicts the distribution of mutations and mutation types across the NF1 significant gene.

BRAF

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

MGA

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

CHRND

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

MET

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

CDKN2A

Figure S15.  This figure depicts the distribution of mutations and mutation types across the CDKN2A significant gene.

U2AF1

Figure S16.  This figure depicts the distribution of mutations and mutation types across the U2AF1 significant gene.

SETD2

Figure S17.  This figure depicts the distribution of mutations and mutation types across the SETD2 significant gene.

DNMT3A

Figure S18.  This figure depicts the distribution of mutations and mutation types across the DNMT3A significant gene.

ERBB2

Figure S19.  This figure depicts the distribution of mutations and mutation types across the ERBB2 significant gene.

ATM

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

COL5A2

Figure S21.  This figure depicts the distribution of mutations and mutation types across the COL5A2 significant gene.

NFE2L2

Figure S22.  This figure depicts the distribution of mutations and mutation types across the NFE2L2 significant gene.

PPP3CA

Figure S23.  This figure depicts the distribution of mutations and mutation types across the PPP3CA significant gene.

FCRLA

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

ARID2

Figure S25.  This figure depicts the distribution of mutations and mutation types across the ARID2 significant gene.

SLAMF9

Figure S26.  This figure depicts the distribution of mutations and mutation types across the SLAMF9 significant gene.

SLC4A3

Figure S27.  This figure depicts the distribution of mutations and mutation types across the SLC4A3 significant gene.

SP100

Figure S28.  This figure depicts the distribution of mutations and mutation types across the SP100 significant gene.

RPL5

Figure S29.  This figure depicts the distribution of mutations and mutation types across the RPL5 significant gene.

AACS

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

ITGBL1

Figure S31.  This figure depicts the distribution of mutations and mutation types across the ITGBL1 significant gene.

NLRP6

Figure S32.  This figure depicts the distribution of mutations and mutation types across the NLRP6 significant gene.

STIM1

Figure S33.  This figure depicts the distribution of mutations and mutation types across the STIM1 significant gene.

NCKAP1L

Figure S34.  This figure depicts the distribution of mutations and mutation types across the NCKAP1L 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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