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: KIRP-TP

  • Number of patients in set: 282

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:KIRP-TP.final_analysis_set.maf

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

  • Significantly mutated genes (q ≤ 0.1): 23

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: 23. 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 SETD2 SET domain containing 2 7777 11 0 1 5 2 1 10 18 16 18 7.7e-10 0.076 0.2 6.1e-10 9e-06
2 NF2 neurofibromin 2 (merlin) 1894 131 0 0 1 2 3 4 10 10 10 1.2e-10 1 0.31 1.2e-09 9e-06
3 ZNF814 zinc finger protein 814 2576 78 0 0 10 1 0 2 13 9 5 6e-06 1e-05 0.66 1.5e-09 9e-06
4 MET met proto-oncogene (hepatocyte growth factor receptor) 4307 15 0 0 21 0 0 1 22 21 14 0.000011 1e-05 2e-05 2.6e-09 0.000012
5 NEFH neurofilament, heavy polypeptide 200kDa 3077 3 0 0 1 0 0 6 7 6 6 3.4e-08 0.052 0.8 4.8e-08 0.00018
6 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 709 445 0 0 5 0 0 0 5 5 1 0.00033 1e-05 0.21 6.8e-08 0.00021
7 CUL3 cullin 3 2367 3 0 0 4 4 1 3 12 10 11 5.3e-07 0.16 1 1.7e-06 0.0046
8 PCF11 PCF11, cleavage and polyadenylation factor subunit, homolog (S. cerevisiae) 4728 21 0 2 12 0 0 0 12 11 9 0.0017 4e-05 0.97 2e-06 0.0046
9 BCLAF1 BCL2-associated transcription factor 1 2807 15 0 1 3 0 2 1 6 6 4 0.0013 0.00013 0.66 4.5e-06 0.0091
10 PAM peptidylglycine alpha-amidating monooxygenase 3021 7 0 0 3 0 0 2 5 3 5 0.056 1e-05 0.47 8.6e-06 0.016
11 SMARCB1 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1 1190 0 0 0 2 0 0 4 6 6 5 0.000018 0.049 0.9 0.000016 0.024
12 KDM6A lysine (K)-specific demethylase 6A 4318 16 0 0 1 3 1 6 11 10 11 1.1e-06 1 0.78 0.000016 0.024
13 AR androgen receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease) 2813 3 0 1 16 0 0 0 16 13 9 0.12 1e-05 1 0.000017 0.024
14 TP53 tumor protein p53 1889 219 0 0 5 1 0 1 7 7 7 3e-05 1 0.078 0.000061 0.064
15 KRTAP4-5 keratin associated protein 4-5 548 774 0 0 4 0 0 1 5 5 4 0.0029 0.0012 0.9 0.000063 0.064
16 BRAF v-raf murine sarcoma viral oncogene homolog B1 2371 60 0 1 2 0 1 1 4 4 3 0.015 0.0068 0.017 0.000063 0.064
17 KIAA0922 KIAA0922 4971 17 0 0 2 2 1 0 5 5 5 0.000024 1 0.16 0.000064 0.064
18 KRT2 keratin 2 (epidermal ichthyosis bullosa of Siemens) 1954 146 0 0 2 0 0 3 5 5 4 0.0031 0.018 0.02 0.000065 0.064
19 ALMS1 Alstrom syndrome 1 12592 21 0 4 8 1 0 1 10 8 6 0.5 1e-05 0.0081 0.000066 0.064
20 GXYLT1 glucoside xylosyltransferase 1 1351 46 0 0 3 0 0 1 4 4 3 0.00043 0.015 0.77 0.000084 0.076
21 ATP1B1 ATPase, Na+/K+ transporting, beta 1 polypeptide 932 79 0 0 4 0 0 3 7 7 7 0.000021 1 0.32 0.00011 0.095
22 PBRM1 polybromo 1 5418 26 0 0 3 2 2 5 12 11 12 9.2e-06 1 0.81 0.00012 0.095
23 CCBL2 cysteine conjugate-beta lyase 2 2586 67 0 0 1 1 0 2 4 2 4 0.095 0.0001 0.93 0.00012 0.095
24 PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1) 1244 322 0 0 2 1 1 4 8 7 8 0.000015 1 0.96 0.00018 0.13
25 SAV1 salvador homolog 1 (Drosophila) 1168 87 0 0 2 1 0 4 7 6 7 0.000016 1 1 0.00019 0.13
26 CALCR calcitonin receptor 1583 27 0 0 2 0 0 2 4 3 3 0.16 0.0001 0.073 0.00019 0.13
27 IGSF3 immunoglobulin superfamily, member 3 3685 11 0 0 2 0 2 0 4 4 4 0.000027 1 0.97 0.00032 0.21
28 NFE2L2 nuclear factor (erythroid-derived 2)-like 2 1834 72 0 0 6 0 0 0 6 6 6 0.0071 0.028 0.048 0.00033 0.21
29 PARD6B par-6 partitioning defective 6 homolog beta (C. elegans) 1127 453 0 0 5 1 0 1 7 7 7 0.000033 1 0.34 0.00037 0.23
30 FNIP2 folliculin interacting protein 2 3409 57 0 1 3 0 1 2 6 6 6 0.00044 1 0.058 0.00045 0.27
31 ZNF628 zinc finger protein 628 3172 110 0 0 2 0 0 2 4 2 4 0.046 0.02 0.016 0.00053 0.3
32 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 3287 2 0 0 6 0 0 0 6 5 4 0.37 0.00013 0.51 0.00053 0.3
33 KIAA0664 KIAA0664 4030 16 0 0 4 0 1 1 6 6 6 0.00029 1 0.13 0.00056 0.31
34 MUC2 mucin 2, oligomeric mucus/gel-forming 8640 102 0 3 10 0 0 1 11 11 9 0.023 0.002 0.68 0.00081 0.43
35 STAG2 stromal antigen 2 3939 96 0 1 1 4 0 2 7 7 7 0.00011 1 0.73 0.0011 0.57
SETD2

Figure S1.  This figure depicts the distribution of mutations and mutation types across the SETD2 significant gene.

NF2

Figure S2.  This figure depicts the distribution of mutations and mutation types across the NF2 significant gene.

ZNF814

Figure S3.  This figure depicts the distribution of mutations and mutation types across the ZNF814 significant gene.

MET

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

NEFH

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

KRAS

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

CUL3

Figure S7.  This figure depicts the distribution of mutations and mutation types across the CUL3 significant gene.

PCF11

Figure S8.  This figure depicts the distribution of mutations and mutation types across the PCF11 significant gene.

BCLAF1

Figure S9.  This figure depicts the distribution of mutations and mutation types across the BCLAF1 significant gene.

PAM

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

SMARCB1

Figure S11.  This figure depicts the distribution of mutations and mutation types across the SMARCB1 significant gene.

KDM6A

Figure S12.  This figure depicts the distribution of mutations and mutation types across the KDM6A significant gene.

AR

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

TP53

Figure S14.  This figure depicts the distribution of mutations and mutation types across the TP53 significant gene.

KRTAP4-5

Figure S15.  This figure depicts the distribution of mutations and mutation types across the KRTAP4-5 significant gene.

BRAF

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

KIAA0922

Figure S17.  This figure depicts the distribution of mutations and mutation types across the KIAA0922 significant gene.

KRT2

Figure S18.  This figure depicts the distribution of mutations and mutation types across the KRT2 significant gene.

ALMS1

Figure S19.  This figure depicts the distribution of mutations and mutation types across the ALMS1 significant gene.

GXYLT1

Figure S20.  This figure depicts the distribution of mutations and mutation types across the GXYLT1 significant gene.

ATP1B1

Figure S21.  This figure depicts the distribution of mutations and mutation types across the ATP1B1 significant gene.

PBRM1

Figure S22.  This figure depicts the distribution of mutations and mutation types across the PBRM1 significant gene.

CCBL2

Figure S23.  This figure depicts the distribution of mutations and mutation types across the CCBL2 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)
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