Mutation Analysis (MutSig 2CV v3.1)
Colorectal Adenocarcinoma (Primary solid tumor)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C1X0661N
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/C1X0661N
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: COADREAD-TP

  • Number of patients in set: 489

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:COADREAD-TP.final_analysis_set.maf

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

  • Significantly mutated genes (q ≤ 0.1): 1511

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: 1511. 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 APC adenomatous polyposis coli 8592 0 0 194 324 393 9 131 857 401 435 1e-16 1e-05 1 1e-16 3.7e-13
2 TP53 tumor protein p53 1314 0 0 76 342 47 16 33 438 320 224 1e-16 1e-05 1e-05 1e-16 3.7e-13
3 ARID1A AT rich interactive domain 1A (SWI-like) 6934 2 0 19 52 23 0 21 96 83 73 2.3e-16 1e-05 0.039 1e-16 3.7e-13
4 RNF43 ring finger protein 43 2384 6 0 2 17 2 0 37 56 47 28 1.6e-16 1e-05 0.26 1e-16 3.7e-13
5 CRIPAK cysteine-rich PAK1 inhibitor 1341 19 0 3 13 1 0 17 31 29 17 1e-15 1e-05 0.018 1e-16 3.7e-13
6 SOX9 SRY (sex determining region Y)-box 9 (campomelic dysplasia, autosomal sex-reversal) 1538 1 0 0 8 7 1 29 45 41 42 1e-16 0.15 0.58 8.9e-16 2.7e-12
7 MUC4 mucin 4, cell surface associated 3623 0 0 27 37 0 0 132 169 118 68 1e-16 1 0.31 3.8e-15 9.8e-12
8 B2M beta-2-microglobulin 374 4 0 1 9 2 5 8 24 18 18 3.8e-15 0.074 0.15 1.3e-14 2.6e-11
9 ZFP36L2 zinc finger protein 36, C3H type-like 2 1489 23 0 1 1 1 0 15 17 17 14 1.1e-13 0.0076 0.07 1.3e-14 2.6e-11
10 RBM38 RNA binding motif protein 38 493 0 0 2 5 1 0 37 43 43 5 4e-16 1 0.91 1.4e-14 2.6e-11
11 ACVR1B activin A receptor, type IB 1679 9 0 0 23 7 0 3 33 28 27 1.4e-12 0.00032 0.076 1.8e-14 2.9e-11
12 RBMX RNA binding motif protein, X-linked 1265 39 0 1 11 0 0 15 26 23 10 1.1e-10 1e-05 0.96 3.8e-14 5.8e-11
13 FAM123B family with sequence similarity 123B 3412 19 0 7 23 29 0 11 63 58 46 1.1e-13 0.013 0.76 1.1e-13 1.5e-10
14 TXNDC2 thioredoxin domain-containing 2 (spermatozoa) 1672 46 0 2 6 1 0 20 27 24 10 4.9e-10 1e-05 0.97 1.6e-13 2.1e-10
15 SMAD2 SMAD family member 2 1444 40 0 1 15 9 1 0 25 23 19 2.9e-11 0.0058 0.011 5.7e-13 7e-10
16 SELPLG selectin P ligand 1217 33 0 2 6 0 0 14 20 19 11 6.3e-10 0.00028 0.59 9.7e-12 1.1e-08
17 CDH1 cadherin 1, type 1, E-cadherin (epithelial) 2709 0 0 20 76 10 10 4 100 86 72 6e-08 1e-05 0.21 1.7e-11 1.9e-08
18 WNT1 wingless-type MMTV integration site family, member 1 1125 1 0 0 0 0 0 7 7 7 1 6.9e-08 1e-05 1e-05 2e-11 2e-08
19 BCOR BCL6 co-repressor 5324 0 0 5 12 10 0 9 31 30 28 2.3e-10 0.085 0.0071 2.4e-11 2.3e-08
20 GGT1 gamma-glutamyltransferase 1 1761 0 0 1 0 0 1 9 10 10 3 1.7e-07 1e-05 0.032 4.8e-11 4.4e-08
21 TCF7L2 transcription factor 7-like 2 (T-cell specific, HMG-box) 2138 3 0 6 30 9 1 7 47 44 40 6.7e-11 0.04 0.079 6.2e-11 5.4e-08
22 NTAN1 N-terminal asparagine amidase 971 2 0 1 2 0 0 8 10 10 5 3.5e-07 1e-05 0.99 9.6e-11 7.9e-08
23 KIAA1804 3147 14 0 3 28 2 0 3 33 26 30 5.3e-07 1e-05 0.022 1.4e-10 1.1e-07
24 FMN2 formin 2 5237 1 0 15 33 1 0 39 73 63 41 1.2e-06 1e-05 1 3e-10 2.3e-07
25 STARD3NL STARD3 N-terminal like 737 10 0 2 16 0 0 0 16 15 5 1.2e-06 3e-05 0.00037 3.2e-10 2.4e-07
26 NF2 neurofibromin 2 (merlin) 1894 0 0 27 54 15 12 1 82 67 62 2.8e-06 1e-05 0.41 7.1e-10 5e-07
27 RHOA ras homolog gene family, member A 598 5 0 0 7 3 1 2 13 13 9 1e-08 0.0038 0.48 1.6e-09 1.1e-06
28 BMPR2 bone morphogenetic protein receptor, type II (serine/threonine kinase) 3165 8 0 5 22 12 1 7 42 36 39 6.8e-10 0.08 0.7 2e-09 1.3e-06
29 RPTN repetin 2363 7 0 2 2 1 1 15 19 18 6 1e-05 1e-05 0.28 2.4e-09 1.5e-06
30 C14orf184 447 142 0 0 0 0 0 7 7 7 1 0.000012 1e-05 0.94 2.9e-09 1.7e-06
31 OR4D10 olfactory receptor, family 4, subfamily D, member 10 936 91 0 2 16 0 0 0 16 15 9 0.000014 1e-05 0.015 3.4e-09 2e-06
32 MVK mevalonate kinase 1235 18 0 2 5 0 1 10 16 15 7 0.000017 3e-05 0.0007 4e-09 2.3e-06
33 ATXN3L ataxin 3-like 1068 19 0 2 18 1 0 1 20 19 15 2e-05 1e-05 0.41 4.6e-09 2.5e-06
34 DIP2B DIP2 disco-interacting protein 2 homolog B (Drosophila) 4879 52 0 11 18 2 11 0 31 30 23 1.7e-06 0.00021 0.15 6.2e-09 3.3e-06
35 P2RY13 purinergic receptor P2Y, G-protein coupled, 13 1071 6 0 2 14 1 0 0 15 15 11 0.000033 6e-05 0.052 7.6e-09 4e-06
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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