Mutation Analysis (MutSig 2CV v3.1)
Colon Adenocarcinoma (Primary solid tumor)
17 October 2014  |  analyses__2014_10_17
Maintainer Information
Citation Information
doi:10.7908/C1BR8R0W
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/C1BR8R0W
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: COAD-TP

  • Number of patients in set: 154

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:COAD-TP.final_analysis_set.maf

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

  • Significantly mutated genes (q ≤ 0.1): 20

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: 20. 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 1 0 4 23 102 0 38 163 107 108 1.6e-15 0.00019 0.97 1e-16 6.1e-13
2 TP53 tumor protein p53 1889 54 0 1 49 13 0 13 75 73 49 1e-16 0.0012 1e-05 1e-16 6.1e-13
3 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 709 17 0 0 59 0 0 0 59 59 9 1e-16 1e-05 0.0042 1e-16 6.1e-13
4 NRAS neuroblastoma RAS viral (v-ras) oncogene homolog 941 34 0 0 15 0 0 0 15 15 7 5.3e-13 1e-05 0.019 2.2e-16 1e-12
5 SMAD4 SMAD family member 4 1699 74 0 0 17 3 0 2 22 18 18 1.8e-12 0.11 0.0063 5.4e-13 2e-09
6 FBXW7 F-box and WD repeat domain containing 7 2580 4 0 2 26 6 0 1 33 29 21 1.5e-11 0.001 0.51 1.1e-12 3.3e-09
7 SMAD2 SMAD family member 2 1444 57 0 1 7 4 0 0 11 10 8 8.9e-08 0.0014 0.073 1.7e-09 4.5e-06
8 BRAF v-raf murine sarcoma viral oncogene homolog B1 2371 12 0 0 21 0 0 0 21 20 3 0.00015 1e-05 0.0048 3.1e-08 0.000071
9 FAM123B family with sequence similarity 123B 3412 27 0 1 5 11 0 3 19 19 17 4.9e-09 0.5 0.51 9.9e-08 0.0002
10 MGC42105 1319 47 0 1 8 2 0 0 10 10 10 5.9e-09 1 0.98 1.2e-07 0.00022
11 ACVR1B activin A receptor, type IB 1679 9 0 0 12 0 0 1 13 13 13 2.9e-06 0.26 0.023 2e-06 0.0033
12 DNMT1 DNA (cytosine-5-)-methyltransferase 1 5059 20 0 3 11 0 0 1 12 12 9 0.18 0.00018 0.11 0.000026 0.038
13 PCBP1 poly(rC) binding protein 1 1071 67 0 0 4 0 0 0 4 4 2 0.02 0.0001 0.021 0.000028 0.038
14 CDC27 cell division cycle 27 homolog (S. cerevisiae) 2565 12 0 2 9 2 0 0 11 10 6 0.0076 0.00011 1 0.000029 0.038
15 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 3287 3 0 1 33 0 0 0 33 26 18 0.24 1e-05 0.00026 0.000033 0.04
16 BCOR BCL6 co-repressor 5324 0 0 2 3 3 0 1 7 6 7 0.0015 1 0.00038 0.000039 0.044
17 ZHX2 zinc fingers and homeoboxes 2 2518 6 0 0 5 1 0 2 8 8 7 0.000027 0.13 0.5 0.000056 0.06
18 KLHL5 kelch-like 5 (Drosophila) 2308 5 0 0 4 1 0 2 7 5 5 0.0021 0.0034 0.048 0.000082 0.078
19 CASP8 caspase 8, apoptosis-related cysteine peptidase 1749 9 0 0 7 2 0 2 11 10 10 0.000026 0.36 0.36 0.000083 0.078
20 PCDHGB1 protocadherin gamma subfamily B, 1 45770 13 0 0 7 1 0 0 8 7 8 6.6e-06 1 0.9 0.000085 0.078
21 UBXN11 UBX domain protein 11 1713 70 0 1 1 0 0 4 5 3 3 0.091 6e-05 0.78 0.00013 0.11
22 MIER3 mesoderm induction early response 1, family member 3 1700 9 0 0 6 2 0 2 10 10 10 0.000014 1 0.64 0.00017 0.15
23 TBC1D10C TBC1 domain family, member 10C 1379 43 0 0 0 0 0 3 3 3 1 0.017 0.001 0.99 0.0002 0.16
24 TCF7L2 transcription factor 7-like 2 (T-cell specific, HMG-box) 2138 14 0 3 8 4 0 1 13 11 13 0.000076 0.2 0.48 0.0002 0.16
25 PCDHGA9 protocadherin gamma subfamily A, 9 22888 12 0 0 4 1 0 0 5 5 5 0.000031 1 0.57 0.00024 0.17
26 PCDHGA7 protocadherin gamma subfamily A, 7 31478 14 0 1 4 1 0 0 5 5 4 0.00044 0.084 0.37 0.00026 0.18
27 KLK2 kallikrein-related peptidase 2 841 67 0 0 3 0 0 0 3 3 1 0.026 0.001 0.53 0.0003 0.2
28 ESR1 estrogen receptor 1 1820 14 0 0 10 2 0 0 12 11 12 3e-05 1 0.74 0.00035 0.22
29 PCDHA3 protocadherin alpha 3 30618 13 0 0 13 0 0 0 13 10 12 0.00027 0.24 0.4 0.00035 0.22
30 HCLS1 hematopoietic cell-specific Lyn substrate 1 1511 28 0 2 4 2 0 1 7 7 6 0.00044 0.28 0.16 0.00051 0.31
31 GGA2 golgi associated, gamma adaptin ear containing, ARF binding protein 2 1908 21 0 1 4 3 0 1 8 8 8 0.00033 1 0.086 0.00066 0.38
32 MYH11 myosin, heavy chain 11, smooth muscle 6141 88 0 4 18 2 0 1 21 16 21 0.00014 1 0.26 0.00069 0.38
33 RNF43 ring finger protein 43 2384 92 0 1 9 0 0 2 11 10 10 0.00042 0.19 0.6 0.00073 0.38
34 CREBBP CREB binding protein (Rubinstein-Taybi syndrome) 7449 98 0 6 16 4 0 1 21 17 21 7e-05 1 0.89 0.00074 0.38
35 PCDHGB5 protocadherin gamma subfamily B, 5 24615 13 0 0 7 0 0 0 7 6 7 0.000072 1 0.47 0.00076 0.38
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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