Mutation Analysis (MutSig 2CV v3.1)
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: PAAD-TP

  • Number of patients in set: 126

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:PAAD-TP.final_analysis_set.maf

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

  • Significantly mutated genes (q ≤ 0.1): 603

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: 603. 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 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 709 10 1 0 103 0 0 0 103 100 4 7.7e-16 1e-05 1e-05 1e-16 1.3e-13
2 TP53 tumor protein p53 1890 3 0 0 51 11 3 17 82 81 61 1.4e-15 0.01 1e-05 1e-16 1.3e-13
3 MAMLD1 mastermind-like domain containing 1 3467 38 0 2 3 0 0 28 31 28 4 1e-16 1e-05 0.059 1e-16 1.3e-13
4 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) 1002 1 0 1 6 8 0 13 27 27 17 1e-16 4e-05 1e-05 1e-16 1.3e-13
5 CD99L2 CD99 molecule-like 2 829 90 0 0 1 0 0 19 20 20 3 1e-16 1e-05 0.55 1e-16 1.3e-13
6 IPP intracisternal A particle-promoted polypeptide 1889 104 0 0 0 1 0 20 21 20 2 1e-16 1e-05 1 1e-16 1.3e-13
7 IRS1 insulin receptor substrate 1 3735 0 0 4 5 0 0 16 21 20 6 2.5e-14 1e-05 1 1e-16 1.3e-13
8 C19orf55 chromosome 19 open reading frame 55 1320 23 0 0 2 0 0 14 16 16 3 2.3e-16 1e-05 0.99 1e-16 1.3e-13
9 C15orf24 chromosome 15 open reading frame 24 2477 21 0 1 0 0 0 15 15 15 1 1e-16 1e-05 1 1e-16 1.3e-13
10 QRICH1 glutamine-rich 1 2416 2 0 2 2 0 0 12 14 14 3 1.1e-14 1e-05 0.0076 1e-16 1.3e-13
11 IFT46 intraflagellar transport 46 homolog (Chlamydomonas) 1112 21 1 0 1 0 2 11 14 13 5 1.2e-14 1e-05 0.88 1e-16 1.3e-13
12 ARHGAP18 Rho GTPase activating protein 18 2050 35 0 1 1 0 0 11 12 12 2 7.3e-14 1e-05 0.0059 1e-16 1.3e-13
13 EME2 essential meiotic endonuclease 1 homolog 2 (S. pombe) 1550 17 1 0 0 0 0 11 11 11 1 6.3e-15 1e-05 0.81 1e-16 1.3e-13
14 SMAD4 SMAD family member 4 1699 35 0 0 12 5 0 10 27 26 25 1e-16 0.11 0.039 1.1e-16 1.3e-13
15 NPNT nephronectin 1891 27 0 1 1 0 0 11 12 12 2 3e-13 1e-05 0.96 1.1e-16 1.3e-13
16 TNFSF9 tumor necrosis factor (ligand) superfamily, member 9 775 7 0 1 0 0 0 12 12 12 1 2e-13 1e-05 0.92 1.1e-16 1.3e-13
17 SRP14 signal recognition particle 14kDa (homologous Alu RNA binding protein) 429 62 0 0 0 0 0 9 9 9 1 4.5e-13 1e-05 1 2.2e-16 2.4e-13
18 SORBS2 sorbin and SH3 domain containing 2 4493 21 0 3 7 1 0 10 18 17 6 7.6e-13 1e-05 0.18 3.3e-16 3.4e-13
19 ERF Ets2 repressor factor 1659 30 0 0 4 0 0 12 16 13 7 1.1e-12 1e-05 0.58 4.4e-16 4.3e-13
20 MED9 mediator complex subunit 9 447 4 0 1 0 0 0 7 7 7 1 3.1e-12 1e-05 0.48 1.2e-15 1.1e-12
21 BHLHB9 basic helix-loop-helix domain containing, class B, 9 1644 146 0 0 1 0 0 11 12 12 2 3.4e-12 1e-05 0.15 1.3e-15 1.2e-12
22 ZNF185 zinc finger protein 185 (LIM domain) 2400 44 0 0 0 0 0 10 10 10 1 1.1e-11 1e-05 0.93 4.3e-15 3.6e-12
23 IRX4 iroquois homeobox 4 1576 38 0 0 1 0 0 9 10 10 2 1.2e-11 1e-05 0.037 4.6e-15 3.6e-12
24 ZMIZ1 zinc finger, MIZ-type containing 1 3288 44 0 1 0 0 0 13 13 13 3 2.1e-11 1e-05 0.98 7.8e-15 5.9e-12
25 EDC4 enhancer of mRNA decapping 4 4328 72 0 3 1 0 0 15 16 16 3 3.6e-11 1e-05 1 1.3e-14 9.7e-12
26 CCDC135 coiled-coil domain containing 135 2693 46 0 0 3 0 0 12 15 13 4 4.3e-11 1e-05 1 1.6e-14 1.1e-11
27 APP amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) 2381 17 0 0 3 0 0 10 13 12 4 5.6e-11 1e-05 0.87 2e-14 1.4e-11
28 TMC4 transmembrane channel-like 4 2252 35 0 1 2 0 0 18 20 20 3 6.3e-11 1e-05 0.011 2.3e-14 1.5e-11
29 PHF13 PHD finger protein 13 915 200 0 0 1 0 0 8 9 9 2 9.4e-11 1e-05 0.99 3.4e-14 2.1e-11
30 B4GALT2 UDP-Gal:betaGlcNAc beta 1,4- galactosyltransferase, polypeptide 2 1561 3 0 0 1 0 0 10 11 10 3 1.2e-10 1e-05 1 4.4e-14 2.6e-11
31 GAGE2A G antigen 2A 1486 13 0 0 0 0 0 6 6 6 1 1.2e-10 1e-05 0.82 4.4e-14 2.6e-11
32 YIPF2 Yip1 domain family, member 2 1258 50 0 0 2 0 0 10 12 11 3 1.5e-10 1e-05 0.97 5.2e-14 3e-11
33 MED15 mediator complex subunit 15 2437 1 0 1 3 0 0 11 14 12 6 1.9e-10 1e-05 0.86 6.8e-14 3.8e-11
34 MBD3 methyl-CpG binding domain protein 3 898 156 0 0 1 0 0 8 9 9 2 3.2e-10 1e-05 1 1.1e-13 6e-11
35 WWTR1 WW domain containing transcription regulator 1 1227 11 0 0 3 0 0 10 13 12 4 5.1e-10 1e-05 0.82 1.7e-13 9e-11
KRAS

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

TP53

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

MAMLD1

Figure S3.  This figure depicts the distribution of mutations and mutation types across the MAMLD1 significant gene.

CDKN2A

Figure S4.  This figure depicts the distribution of mutations and mutation types across the CDKN2A significant gene.

CD99L2

Figure S5.  This figure depicts the distribution of mutations and mutation types across the CD99L2 significant gene.

IPP

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

IRS1

Figure S7.  This figure depicts the distribution of mutations and mutation types across the IRS1 significant gene.

QRICH1

Figure S8.  This figure depicts the distribution of mutations and mutation types across the QRICH1 significant gene.

IFT46

Figure S9.  This figure depicts the distribution of mutations and mutation types across the IFT46 significant gene.

EME2

Figure S10.  This figure depicts the distribution of mutations and mutation types across the EME2 significant gene.

SMAD4

Figure S11.  This figure depicts the distribution of mutations and mutation types across the SMAD4 significant gene.

NPNT

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

TNFSF9

Figure S13.  This figure depicts the distribution of mutations and mutation types across the TNFSF9 significant gene.

SRP14

Figure S14.  This figure depicts the distribution of mutations and mutation types across the SRP14 significant gene.

SORBS2

Figure S15.  This figure depicts the distribution of mutations and mutation types across the SORBS2 significant gene.

ERF

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

MED9

Figure S17.  This figure depicts the distribution of mutations and mutation types across the MED9 significant gene.

BHLHB9

Figure S18.  This figure depicts the distribution of mutations and mutation types across the BHLHB9 significant gene.

ZNF185

Figure S19.  This figure depicts the distribution of mutations and mutation types across the ZNF185 significant gene.

IRX4

Figure S20.  This figure depicts the distribution of mutations and mutation types across the IRX4 significant gene.

ZMIZ1

Figure S21.  This figure depicts the distribution of mutations and mutation types across the ZMIZ1 significant gene.

EDC4

Figure S22.  This figure depicts the distribution of mutations and mutation types across the EDC4 significant gene.

CCDC135

Figure S23.  This figure depicts the distribution of mutations and mutation types across the CCDC135 significant gene.

APP

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

TMC4

Figure S25.  This figure depicts the distribution of mutations and mutation types across the TMC4 significant gene.

PHF13

Figure S26.  This figure depicts the distribution of mutations and mutation types across the PHF13 significant gene.

B4GALT2

Figure S27.  This figure depicts the distribution of mutations and mutation types across the B4GALT2 significant gene.

YIPF2

Figure S28.  This figure depicts the distribution of mutations and mutation types across the YIPF2 significant gene.

MED15

Figure S29.  This figure depicts the distribution of mutations and mutation types across the MED15 significant gene.

MBD3

Figure S30.  This figure depicts the distribution of mutations and mutation types across the MBD3 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]

References
[1] TCGA, Integrated genomic analyses of ovarian carcinoma, Nature 474:609 - 615 (2011)
Made with Nozzle