Mutation Analysis (MutSig 2CV v3.1)
Acute Myeloid Leukemia (Primary blood derived cancer - Peripheral blood)
28 January 2016 | analyses__2016_01_28
Maintainer Information
Citation Information
doi:10.7908/C1D21X2X
Maintained by David Heiman (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2016): Mutation Analysis (MutSig 2CV v3.1). Broad Institute of MIT and Harvard. doi:10.7908/C1D21X2X
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: LAML-TB

- Number of patients in set: 193

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:LAML-TB.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 | FLT3 | fms-related tyrosine kinase 3 | 3076 | 187 | 0 | 0 | 15 | 0 | 0 | 37 | 52 | 52 | 29 | 1e-16 | 1e-05 | 1e-05 | 1e-16 | 2.3e-13
2 | DNMT3A | DNA (cytosine-5-)-methyltransferase 3 alpha | 2952 | 49 | 0 | 0 | 39 | 5 | 6 | 4 | 54 | 48 | 28 | 1e-16 | 1e-05 | 1e-05 | 1e-16 | 2.3e-13
3 | NPM1 | nucleophosmin (nucleolar phosphoprotein B23, numatrin) | 936 | 266 | 0 | 0 | 1 | 0 | 0 | 33 | 34 | 33 | 8 | 1.1e-16 | 1e-05 | 1e-05 | 1e-16 | 2.3e-13
4 | IDH2 | isocitrate dehydrogenase 2 (NADP+), mitochondrial | 1401 | 685 | 0 | 0 | 20 | 0 | 0 | 0 | 20 | 20 | 2 | 1.4e-15 | 1e-05 | 0.4 | 1e-16 | 2.3e-13
5 | IDH1 | isocitrate dehydrogenase 1 (NADP+), soluble | 1277 | 561 | 0 | 0 | 18 | 0 | 0 | 0 | 18 | 18 | 2 | 1e-16 | 1e-05 | 1 | 1e-16 | 2.3e-13
6 | TET2 | tet oncogene family member 2 | 6134 | 70 | 0 | 0 | 4 | 8 | 0 | 15 | 27 | 17 | 26 | 1e-16 | 0.7 | 1e-05 | 1e-16 | 2.3e-13
7 | NRAS | neuroblastoma RAS viral (v-ras) oncogene homolog | 590 | 34 | 0 | 0 | 15 | 0 | 0 | 0 | 15 | 15 | 6 | 1.3e-16 | 1e-05 | 0.1 | 1e-16 | 2.3e-13
8 | WT1 | Wilms tumor 1 | 1590 | 101 | 0 | 0 | 2 | 0 | 2 | 8 | 12 | 12 | 10 | 1e-16 | 0.0017 | 1 | 1e-16 | 2.3e-13
9 | U2AF1 | U2 small nuclear RNA auxiliary factor 1 | 824 | 130 | 0 | 0 | 8 | 0 | 0 | 0 | 8 | 8 | 2 | 5.3e-13 | 1e-05 | 2e-05 | 2.2e-16 | 4.5e-13
10 | RUNX1 | runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene) | 1520 | 1000 | 0 | 0 | 8 | 5 | 1 | 5 | 19 | 16 | 15 | 1.1e-15 | 0.09 | 0.0082 | 4.4e-16 | 8.1e-13
11 | CEBPA | CCAAT/enhancer binding protein (C/EBP), alpha | 1077 | 7 | 0 | 0 | 2 | 1 | 0 | 16 | 19 | 13 | 16 | 1e-16 | 0.31 | 0.79 | 2.1e-15 | 3.5e-12
12 | TP53 | tumor protein p53 | 1314 | 498 | 0 | 0 | 11 | 1 | 3 | 4 | 19 | 15 | 19 | 4.4e-16 | 1 | 0.14 | 4.6e-15 | 6.9e-12
13 | KRAS | v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog | 709 | 122 | 0 | 0 | 8 | 0 | 0 | 0 | 8 | 8 | 6 | 6.8e-12 | 0.012 | 0.66 | 2.6e-12 | 3.6e-09
14 | PHF6 | PHD finger protein 6 | 1241 | 143 | 0 | 0 | 2 | 1 | 1 | 2 | 6 | 6 | 6 | 6.1e-13 | 1 | 0.17 | 5e-12 | 6.5e-09
15 | STAG2 | stromal antigen 2 | 3939 | 74 | 0 | 0 | 0 | 3 | 3 | 0 | 6 | 6 | 6 | 6.6e-11 | 1 | 0.93 | 1.6e-09 | 2e-06
16 | KIT | v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog | 3013 | 32 | 0 | 0 | 7 | 0 | 0 | 3 | 10 | 8 | 6 | 0.000045 | 1e-05 | 0.23 | 1e-08 | 0.000011
17 | RAD21 | RAD21 homolog (S. pombe) | 1948 | 58 | 0 | 0 | 0 | 2 | 0 | 3 | 5 | 5 | 5 | 4.7e-10 | 1 | 0.6 | 1.1e-08 | 0.000011
18 | EZH2 | enhancer of zeste homolog 2 (Drosophila) | 2332 | 188 | 0 | 0 | 1 | 0 | 1 | 2 | 4 | 3 | 4 | 4.4e-07 | 0.0081 | 0.56 | 7.4e-08 | 0.000075
19 | SMC3 | structural maintenance of chromosomes 3 | 3766 | 54 | 0 | 0 | 5 | 1 | 1 | 0 | 7 | 7 | 7 | 2.1e-08 | 1 | 0.16 | 3.9e-07 | 0.00037
20 | ASXL1 | additional sex combs like 1 (Drosophila) | 4678 | 29 | 0 | 0 | 0 | 2 | 1 | 2 | 5 | 5 | 5 | 1.4e-07 | 1 | 0.88 | 2.3e-06 | 0.0021
21 | SMC1A | structural maintenance of chromosomes 1A | 3800 | 46 | 0 | 0 | 5 | 0 | 1 | 0 | 6 | 6 | 6 | 1.4e-06 | 1 | 0.1 | 3.4e-06 | 0.003
22 | GIGYF2 | GRB10 interacting GYF protein 2 | 4080 | 76 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 2 | 2 | 5e-05 | 0.01 | 0.92 | 7.7e-06 | 0.0064
23 | PTPN11 | protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1) | 1842 | 24 | 0 | 0 | 9 | 0 | 0 | 0 | 9 | 9 | 9 | 1.3e-06 | 1 | 0.3 | 9.7e-06 | 0.0077
24 | SUZ12 | suppressor of zeste 12 homolog (Drosophila) | 2280 | 34 | 0 | 0 | 2 | 0 | 0 | 1 | 3 | 3 | 3 | 0.000019 | 1 | 0.88 | 0.00023 | 0.17
25 | THRAP3 | thyroid hormone receptor associated protein 3 | 2908 | 104 | 0 | 0 | 1 | 1 | 0 | 0 | 2 | 2 | 2 | 0.00016 | 1 | 0.16 | 0.00044 | 0.32
26 | COL12A1 | collagen, type XII, alpha 1 | 9452 | 81 | 0 | 1 | 2 | 0 | 1 | 0 | 3 | 3 | 3 | 0.0015 | 1 | 0.016 | 0.00059 | 0.42
27 | RBBP4 | retinoblastoma binding protein 4 | 1324 | 133 | 0 | 0 | 2 | 0 | 0 | 0 | 2 | 2 | 1 | 0.0064 | 0.01 | 0.66 | 0.00068 | 0.46
28 | HNRNPK | heterogeneous nuclear ribonucleoprotein K | 1488 | 1000 | 0 | 0 | 0 | 0 | 0 | 3 | 3 | 2 | 3 | 0.014 | 0.0067 | 0.48 | 0.00093 | 0.61
29 | KDM6A | lysine (K)-specific demethylase 6A | 4318 | 36 | 0 | 0 | 2 | 0 | 1 | 0 | 3 | 3 | 3 | 0.0001 | 1 | 0.34 | 0.001 | 0.65
30 | CACNA1B | calcium channel, voltage-dependent, N type, alpha 1B subunit | 7200 | 49 | 0 | 0 | 2 | 0 | 1 | 0 | 3 | 3 | 3 | 0.0012 | 1 | 0.092 | 0.0016 | 0.99
31 | GPBP1 | GC-rich promoter binding protein 1 | 1487 | 537 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 0.0018 | NaN | NaN | 0.0018 | 1
32 | C12orf11 | chromosome 12 open reading frame 11 | 2185 | 218 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 0.002 | NaN | NaN | 0.002 | 1
33 | NAA15 | N(alpha)-acetyltransferase 15, NatA auxiliary subunit | 2677 | 227 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 0.002 | NaN | NaN | 0.002 | 1
34 | CTCF | CCCTC-binding factor (zinc finger protein) | 2224 | 126 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 0.002 | NaN | NaN | 0.002 | 1
35 | PARP2 | poly (ADP-ribose) polymerase family, member 2 | 1814 | 342 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 1 | 0.0022 | NaN | NaN | 0.0022 | 1

FLT3

Figure S1. This figure depicts the distribution of mutations and mutation types across the FLT3 significant gene.

DNMT3A

Figure S2. This figure depicts the distribution of mutations and mutation types across the DNMT3A significant gene.

NPM1

Figure S3. This figure depicts the distribution of mutations and mutation types across the NPM1 significant gene.

IDH2

Figure S4. This figure depicts the distribution of mutations and mutation types across the IDH2 significant gene.

IDH1

Figure S5. This figure depicts the distribution of mutations and mutation types across the IDH1 significant gene.

TET2

Figure S6. This figure depicts the distribution of mutations and mutation types across the TET2 significant gene.

NRAS

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

WT1

Figure S8. This figure depicts the distribution of mutations and mutation types across the WT1 significant gene.

U2AF1

Figure S9. This figure depicts the distribution of mutations and mutation types across the U2AF1 significant gene.

RUNX1

Figure S10. This figure depicts the distribution of mutations and mutation types across the RUNX1 significant gene.

CEBPA

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

TP53

Figure S12. This figure depicts the distribution of mutations and mutation types across the TP53 significant gene.

KRAS

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

PHF6

Figure S14. This figure depicts the distribution of mutations and mutation types across the PHF6 significant gene.

STAG2

Figure S15. This figure depicts the distribution of mutations and mutation types across the STAG2 significant gene.

KIT

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

RAD21

Figure S17. This figure depicts the distribution of mutations and mutation types across the RAD21 significant gene.

EZH2

Figure S18. This figure depicts the distribution of mutations and mutation types across the EZH2 significant gene.

SMC3

Figure S19. This figure depicts the distribution of mutations and mutation types across the SMC3 significant gene.

ASXL1

Figure S20. This figure depicts the distribution of mutations and mutation types across the ASXL1 significant gene.

SMC1A

Figure S21. This figure depicts the distribution of mutations and mutation types across the SMC1A significant gene.

GIGYF2

Figure S22. This figure depicts the distribution of mutations and mutation types across the GIGYF2 significant gene.

PTPN11

Figure S23. This figure depicts the distribution of mutations and mutation types across the PTPN11 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.

- Analysis Results (MD5 checksum)

- Auxiliary Data (MD5 checksum)

- MAGE-TAB File (MD5 checksum)

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