Mutation Analysis (MutSig v2.0 and MutSigCV v0.9 merged result)
Acute Myeloid Leukemia (Primary blood derived cancer - Peripheral blood)
23 May 2013  |  analyses__2013_05_23
Maintainer Information
Citation Information
doi:10.7908/C1H9939H
Maintained by Dan DiCara (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2013): Mutation Analysis (MutSig v2.0 and MutSigCV v0.9 merged result). Broad Institute of MIT and Harvard. doi:10.7908/C1H9939H
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 v2.0 and MutSigCV v0.9 merged result was used to generate the results found in this report.

  • Working with individual set: LAML-TB

  • Number of patients in set: 197

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

  • Significantly mutated genes (q ≤ 0.1): 6

  • Mutations seen in COSMIC: 238

  • Significantly mutated genes in COSMIC territory: 19

  • Significantly mutated genesets: 69

Mutation Preprocessing

  • Read 197 MAFs of type "WashU"

  • Total number of mutations in input MAFs: 2585

  • After removing 41 mutations outside chr1-24: 2544

  • After removing 1 blacklisted mutations: 2543

  • After removing 104 noncoding mutations: 2439

Mutation Filtering

  • Number of mutations before filtering: 2439

  • After removing 204 mutations outside gene set: 2235

  • After removing 14 mutations outside category set: 2221

Results
Breakdown of Mutations by Type

Table 1.  Get Full Table Table representing breakdown of mutations by type.

type count
Frame_Shift_Del 51
Frame_Shift_Ins 110
In_Frame_Del 8
In_Frame_Ins 43
Missense_Mutation 1401
Nonsense_Mutation 108
Silent 450
Splice_Site 50
Total 2221
Breakdown of Mutation Rates by Category Type

Table 2.  Get Full Table A breakdown of mutation rates per category discovered for this individual set.

category n N rate rate_per_mb relative_rate
*CpG->T 509 272310736 1.9e-06 1.9 5.8
*Cp(A/C/T)->T 312 2468091057 1.3e-07 0.13 0.39
A->G 182 2745259222 6.6e-08 0.066 0.21
transver 398 5485661015 7.3e-08 0.073 0.22
indel+null 357 5485661212 6.5e-08 0.065 0.2
double_null 13 5485661212 2.4e-09 0.0024 0.0073
Total 1771 5485661212 3.2e-07 0.32 1
Target Coverage for Each Individual

The x axis represents the samples. The y axis represents the exons, one row per exon, and they are sorted by average coverage across samples. For exons with exactly the same average coverage, they are sorted next by the %GC of the exon. (The secondary sort is especially useful for the zero-coverage exons at the bottom).

Figure 1. 

Distribution of Mutation Counts, Coverage, and Mutation Rates Across Samples

Figure 2.  Patients counts and rates file used to generate this plot: LAML-TB.patients.counts_and_rates.txt

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:

  • N = number of sequenced bases in this gene across the individual set

  • n = 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

  • n1 = number of nonsilent mutations of type: *CpG->T

  • n2 = number of nonsilent mutations of type: *Cp(A/C/T)->T

  • n3 = number of nonsilent mutations of type: A->G

  • n4 = number of nonsilent mutations of type: transver

  • n5 = number of nonsilent mutations of type: indel+null

  • n6 = number of nonsilent mutations of type: double_null

  • p_cons = p-value for enrichment of mutations at evolutionarily most-conserved sites in gene

  • p_joint = p-value for clustering + conservation

  • p = p-value (overall)

  • q = q-value, False Discovery Rate (Benjamini-Hochberg procedure)

Table 3.  Get Full Table A Ranked List of Significantly Mutated Genes. Number of significant genes found: 6. 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 description N n npat nsite nsil n1 n2 n3 n4 n5 n6 p_cons p_joint p_cv p q
1 DNMT3A DNA (cytosine-5-)-methyltransferase 3 alpha 512791 57 51 29 0 34 2 3 4 14 0 0 0 1 0 0
2 U2AF1 U2 small nuclear RNA auxiliary factor 1 153266 8 8 2 0 0 5 0 3 0 0 0.00038 0 1 0 0
3 FLT3 fms-related tyrosine kinase 3 597107 56 56 30 0 0 0 1 16 39 0 4.2e-06 0 1 0 0
4 IDH2 isocitrate dehydrogenase 2 (NADP+), mitochondrial 230293 20 20 2 0 16 3 0 1 0 0 0.74 0 1 0 0
5 IDH1 isocitrate dehydrogenase 1 (NADP+), soluble 251569 19 19 2 0 17 0 0 2 0 0 0.98 0 1 0 0
6 NPM1 nucleophosmin (nucleolar phosphoprotein B23, numatrin) 183407 54 54 7 0 0 0 1 0 52 1 0 0 1 0 0
7 NRAS neuroblastoma RAS viral (v-ras) oncogene homolog 115442 15 15 6 0 0 8 1 6 0 0 0.28 4.2e-06 1 0.000056 0.14
8 WT1 Wilms tumor 1 164692 12 12 10 0 1 1 0 0 9 1 1 0.00022 1 0.002 1
9 RUNX1 runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene) 145189 20 18 16 0 2 3 2 2 10 1 0.016 0.0031 1 0.021 1
10 SMG1 smg-1 homolog, phosphatidylinositol 3-kinase-related kinase (C. elegans) 2065151 3 3 3 0 0 1 1 1 0 0 0.12 0.0082 1 0.048 1
11 KIT v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog 585287 9 8 5 0 1 0 0 6 1 1 0.1 0.017 1 0.086 1
12 EZH2 enhancer of zeste homolog 2 (Drosophila) 459010 3 3 3 0 1 0 0 0 1 1 0.83 0.026 1 0.12 1
13 TRPM3 transient receptor potential cation channel, subfamily M, member 3 1053359 2 2 2 0 1 1 0 0 0 0 0.47 0.028 1 0.13 1
14 GATA2 GATA binding protein 2 159964 2 2 2 0 0 1 0 1 0 0 0.026 0.036 1 0.16 1
15 FCGBP Fc fragment of IgG binding protein 2259984 3 3 3 2 1 1 0 1 0 0 0.086 0.037 1 0.16 1
16 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 139279 8 8 6 0 0 4 1 3 0 0 0.65 0.039 1 0.16 1
17 TP53 tumor protein p53 258267 18 15 18 1 3 2 3 2 8 0 0.32 0.04 1 0.17 1
18 GSTK1 glutathione S-transferase kappa 1 172769 2 2 2 0 1 0 0 1 0 0 0.23 0.046 1 0.19 1
19 DOCK2 dedicator of cytokinesis 2 1113838 2 2 2 0 0 0 1 0 1 0 0.017 0.068 1 0.25 1
20 PKD1L2 polycystic kidney disease 1-like 2 1191259 2 2 2 2 1 1 0 0 0 0 0.074 0.075 1 0.27 1
21 CBL Cas-Br-M (murine) ecotropic retroviral transforming sequence 509442 2 2 2 1 0 0 1 0 1 0 0.41 0.084 1 0.29 1
22 PTPN11 protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1) 359328 9 9 9 0 0 3 2 4 0 0 0.3 0.085 1 0.29 1
23 NR2E1 nuclear receptor subfamily 2, group E, member 1 182225 2 2 2 0 0 1 0 1 0 0 0.092 0.1 1 0.33 1
24 PDCD2L programmed cell death 2-like 161934 2 2 2 0 0 0 2 0 0 0 0.094 0.1 1 0.34 1
25 HNRNPK heterogeneous nuclear ribonucleoprotein K 293530 2 2 2 0 0 0 0 0 1 1 0.8 0.11 1 0.34 1
26 CSMD3 CUB and Sushi multiple domains 3 2259590 2 2 2 0 1 1 0 0 0 0 0.15 0.11 1 0.36 1
27 COL12A1 collagen, type XII, alpha 1 1846875 3 3 3 1 1 1 0 1 0 0 0.013 0.11 1 0.36 1
28 KIAA1683 KIAA1683 543523 2 2 2 1 0 0 1 0 1 0 0.078 0.12 1 0.37 1
29 PHACTR1 phosphatase and actin regulator 1 323868 3 3 2 0 0 0 0 1 2 0 0.72 0.12 1 0.38 1
30 NF1 neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease) 1721977 2 2 2 0 1 0 0 0 1 0 0.55 0.14 1 0.42 1
31 DCHS2 dachsous 2 (Drosophila) 1696761 2 2 2 0 1 0 0 1 0 0 0.12 0.14 1 0.42 1
32 SMC1A structural maintenance of chromosomes 1A 744857 7 7 7 0 3 0 1 2 1 0 0.041 0.14 1 0.42 1
33 PLCE1 phospholipase C, epsilon 1 1441843 4 4 4 0 0 0 1 3 0 0 0.94 0.14 1 0.42 1
34 SI sucrase-isomaltase (alpha-glucosidase) 1117384 2 2 2 0 0 0 1 1 0 0 0.26 0.16 1 0.46 1
35 CSMD1 CUB and Sushi multiple domains 1 1689669 4 4 4 0 0 0 0 3 1 0 0.9 0.16 1 0.46 1
COSMIC analyses

In this analysis, COSMIC is used as a filter to increase power by restricting the territory of each gene. Cosmic version: v48.

Table 4.  Get Full Table Significantly mutated genes (COSMIC territory only). To access the database please go to: COSMIC. Number of significant genes found: 19. Number of genes displayed: 10

rank gene description n cos n_cos N_cos cos_ev p q
1 TP53 tumor protein p53 18 824 16 162328 3427 0 0
2 IDH1 isocitrate dehydrogenase 1 (NADP+), soluble 19 5 19 985 28348 5.2e-14 9.1e-11
3 IDH2 isocitrate dehydrogenase 2 (NADP+), mitochondrial 20 6 20 1182 2000 6.3e-14 9.1e-11
4 PTPN11 protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1) 9 32 8 6304 216 3.3e-13 3e-10
5 NRAS neuroblastoma RAS viral (v-ras) oncogene homolog 15 33 15 6501 11840 3.4e-13 3e-10
6 NPM1 nucleophosmin (nucleolar phosphoprotein B23, numatrin) 54 41 53 8077 112668 4.3e-13 3.1e-10
7 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 8 52 7 10244 46308 5.4e-13 3.4e-10
8 FLT3 fms-related tyrosine kinase 3 56 124 52 24428 6301 1.3e-12 7e-10
9 RUNX1 runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene) 20 178 18 35066 93 1.8e-12 8.3e-10
10 WT1 Wilms tumor 1 12 185 9 36445 444 1.9e-12 8.3e-10

Note:

n - number of (nonsilent) mutations in this gene across the individual set.

cos = number of unique mutated sites in this gene in COSMIC

n_cos = overlap between n and cos.

N_cos = number of individuals times cos.

cos_ev = total evidence: number of reports in COSMIC for mutations seen in this gene.

p = p-value for seeing the observed amount of overlap in this gene)

q = q-value, False Discovery Rate (Benjamini-Hochberg procedure)

Geneset Analyses

Table 5.  Get Full Table A Ranked List of Significantly Mutated Genesets. (Source: MSigDB GSEA Cannonical Pathway Set).Number of significant genesets found: 69. Number of genesets displayed: 10

rank geneset description genes N_genes mut_tally N n npat nsite nsil n1 n2 n3 n4 n5 n6 p q
1 HSA00480_GLUTATHIONE_METABOLISM Genes involved in glutathione metabolism ANPEP, G6PD, GCLC, GCLM, GGT1, GGTL3, GGTL4, GPX1, GPX2, GPX3, GPX4, GPX5, GPX6, GPX7, GSR, GSS, GSTA1, GSTA2, GSTA3, GSTA4, GSTA5, GSTK1, GSTM1, GSTM2, GSTM3, GSTM4, GSTM5, GSTO2, GSTP1, GSTT1, GSTT2, GSTZ1, IDH1, IDH2, MGST1, MGST2, MGST3, OPLAH, TXNDC12 34 GCLM(1), GPX2(1), GSTK1(2), GSTM3(1), IDH1(19), IDH2(20) 5770918 44 42 9 0 34 4 0 6 0 0 <1.00e-15 <2.05e-13
2 GLUTATHIONE_METABOLISM ANPEP, G6PD, GCLC, GCLM, GGT1, GPX1, GPX2, GPX3, GPX4, GPX5, GSS, GSTA1, GSTA2, GSTA3, GSTA4, GSTM1, GSTM2, GSTM3, GSTM4, GSTM5, GSTO2, GSTP1, GSTT1, GSTT2, GSTZ1, IDH1, IDH2, MGST1, MGST2, MGST3, PGD 29 GCLM(1), GPX2(1), GSTM3(1), IDH1(19), IDH2(20) 5170462 42 40 7 0 33 4 0 5 0 0 <1.00e-15 <2.05e-13
3 HSA04060_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION Genes involved in cytokine-cytokine receptor interaction ACVR1, ACVR1B, ACVR2A, ACVR2B, AMH, AMHR2, BMP2, BMP7, BMPR1A, BMPR1B, BMPR2, CCL1, CCL11, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3, CCL4, CCL5, CCL7, CCL8, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CD27, CD40, CD40LG, CD70, CLCF1, CNTF, CNTFR, CRLF2, CSF1, CSF1R, CSF2, CSF2RA, CSF2RB, CSF3, CSF3R, CTF1, CX3CL1, CX3CR1, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL16, CXCL2, CXCL3, CXCL5, CXCL6, CXCL9, CXCR3, CXCR4, CXCR6, EDA, EDA2R, EDAR, EGF, EGFR, EPO, EPOR, FAS, FASLG, FLJ78302, FLT1, FLT3, FLT3LG, FLT4, GDF5, GH1, GH2, GHR, HGF, IFNA1, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA2, IFNA21, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNAR1, IFNAR2, IFNB1, IFNE1, IFNG, IFNGR1, IFNGR2, IFNK, IFNW1, IL10, IL10RA, IL10RB, IL11, IL11RA, IL12A, IL12B, IL12RB1, IL12RB2, IL13, IL13RA1, IL15, IL15RA, IL17A, IL17B, IL17RA, IL17RB, IL18, IL18R1, IL18RAP, IL19, IL1A, IL1B, IL1R1, IL1R2, IL1RAP, IL2, IL20, IL20RA, IL21, IL21R, IL22, IL22RA1, IL22RA2, IL23A, IL23R, IL24, IL25, IL26, IL28A, IL28B, IL28RA, IL29, IL2RA, IL2RB, IL2RG, IL3, IL3RA, IL4, IL4R, IL5, IL5RA, IL6, IL6R, IL6ST, IL7, IL7R, IL8, IL8RA, IL8RB, IL9, IL9R, INHBA, INHBB, INHBC, INHBE, KDR, KIT, KITLG, LEP, LEPR, LIF, LIFR, LOC728045, LTA, LTB, LTBR, MET, MPL, NGFR, OSM, OSMR, PDGFB, PDGFC, PDGFRA, PDGFRB, PF4, PF4V1, PLEKHO2, PPBP, PRL, PRLR, RELT, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, TNF, TNFRSF10A, TNFRSF10B, TNFRSF10C, TNFRSF10D, TNFRSF11A, TNFRSF11B, TNFRSF12A, TNFRSF13B, TNFRSF13C, TNFRSF14, TNFRSF17, TNFRSF18, TNFRSF19, TNFRSF1A, TNFRSF1B, TNFRSF21, TNFRSF25, TNFRSF4, TNFRSF6B, TNFRSF8, TNFRSF9, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF13B, TNFSF14, TNFSF15, TNFSF18, TNFSF4, TNFSF8, TNFSF9, TPO, TSLP, VEGFA, VEGFB, VEGFC, XCL1, XCL2, XCR1 242 ACVR2B(1), CCL11(1), CCL16(1), CCL20(1), CCL21(1), CD70(1), CSF3R(1), EGFR(2), FLT1(1), FLT3(56), IL1R1(1), KDR(2), KIT(9), MPL(1), PDGFRA(1), PDGFRB(1), TPO(1) 49587855 82 78 52 4 7 5 2 27 40 1 1.22e-15 2.05e-13
4 HSA00271_METHIONINE_METABOLISM Genes involved in methionine metabolism AHCY, AMD1, BHMT, CBS, CTH, DNMT1, DNMT3A, DNMT3B, KIAA0828, MARS, MARS2, MAT1A, MAT2B, MTAP, MTFMT, MTR, SRM, TAT 17 DNMT1(1), DNMT3A(57), DNMT3B(1), MAT1A(1) 5703150 60 53 32 0 36 2 3 5 14 0 1.33e-15 2.05e-13
5 NUCLEAR_RECEPTORS ALK, AR, ESR1, ESR2, ESRRA, HNF4A, NPM1, NR0B1, NR1D2, NR1H2, NR1H3, NR1I2, NR1I3, NR2C2, NR2E1, NR2F1, NR2F2, NR2F6, NR3C1, NR4A1, NR4A2, NR5A1, NR5A2, PGR, PPARA, PPARD, PPARG, RARA, RARB, RARG, ROR1, RORA, RORC, RXRA, RXRB, RXRG, THRA, THRA, NR1D1, THRB, VDR 38 NPM1(54), NR2E1(2), THRB(1) 11589707 57 56 10 0 1 1 1 1 52 1 2.11e-15 2.25e-13
6 HSA04640_HEMATOPOIETIC_CELL_LINEAGE Genes involved in hematopoietic cell lineage ANPEP, CD14, CD19, CD1A, CD1B, CD1C, CD1D, CD1E, CD2, CD22, CD24, CD33, CD34, CD36, CD37, CD38, CD3D, CD3E, CD3G, CD4, CD44, CD5, CD55, CD59, CD7, CD8A, CD8B, CD9, CR1, CR2, CSF1, CSF1R, CSF2, CSF2RA, CSF3, CSF3R, DNTT, EPO, EPOR, FCER2, FCGR1A, FLT3, FLT3LG, GP1BA, GP1BB, GP5, GP9, GYPA, HLA-DRA, HLA-DRB1, HLA-DRB3, HLA-DRB4, HLA-DRB5, IL11, IL11RA, IL1A, IL1B, IL1R1, IL1R2, IL2RA, IL3, IL3RA, IL4, IL4R, IL5, IL5RA, IL6, IL6R, IL7, IL7R, IL9R, ITGA1, ITGA2, ITGA2B, ITGA3, ITGA4, ITGA5, ITGA6, ITGAM, ITGB3, KIT, KITLG, MME, MS4A1, TFRC, THPO, TNF, TPO 83 CR1(1), CSF3R(1), FLT3(56), HLA-DRB1(1), IL1R1(1), KIT(9), TPO(1) 23989281 70 68 40 1 2 2 1 24 40 1 2.44e-15 2.25e-13
7 HSA00720_REDUCTIVE_CARBOXYLATE_CYCLE Genes involved in reductive carboxylate cycle (CO2 fixation) ACLY, ACO1, ACO2, ACSS1, ACSS2, FH, IDH1, IDH2, LOC441996, MDH1, MDH2, SUCLA2 11 IDH1(19), IDH2(20) 3866716 39 38 4 0 33 3 0 3 0 0 2.55e-15 2.25e-13
8 METHIONINE_METABOLISM AHCY, BHMT, CBS, CTH, DNMT1, DNMT2, DNMT3A, DNMT3B, MARS, MARS2, MAT1A, MAT2B, MTR 12 DNMT1(1), DNMT3A(57), DNMT3B(1), MAT1A(1) 4841078 60 53 32 0 36 2 3 5 14 0 3.11e-15 2.39e-13
9 REDUCTIVE_CARBOXYLATE_CYCLE_CO2_FIXATION ACO1, ACO2, FH, IDH1, IDH2, MDH1, MDH2, SDHB, SUCLA2 9 IDH1(19), IDH2(20) 2582079 39 38 4 0 33 3 0 3 0 0 3.55e-15 2.43e-13
10 KREBPATHWAY The Krebs (citric acid) cycle takes place in mitochondria, where it extracts energy in the form of electron carriers NADH and FADH2, which drive the electron transport chain. ACO2, CS, FH, IDH2, MDH1, OGDH, SDHA, SUCLA2 8 IDH2(20) 2741649 20 20 2 0 16 3 0 1 0 0 4.66e-15 2.47e-13
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

This is an experimental feature. The full results of the analysis summarized in this report can be downloaded from the TCGA Data Coordination Center.

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