Mutation Analysis (MutSig v2.0 and MutSigCV v0.9 merged result)
Uterine Corpus Endometrioid Carcinoma (Primary solid tumor)
23 May 2013  |  analyses__2013_05_23
Maintainer Information
Citation Information
doi:10.7908/C1GH9G17
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/C1GH9G17
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: UCEC-TP

  • Number of patients in set: 248

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:UCEC-TP.final_analysis_set.maf

  • Significantly mutated genes (q ≤ 0.1): 29

  • Mutations seen in COSMIC: 1001

  • Significantly mutated genes in COSMIC territory: 46

  • Significantly mutated genesets: 68

Mutation Preprocessing

  • Read 248 MAFs of type "WashU"

  • Total number of mutations in input MAFs: 184861

  • After removing 118 mutations outside chr1-24: 184743

  • After removing 211 blacklisted mutations: 184532

  • After removing 1932 noncoding mutations: 182600

  • After collapsing adjacent/redundant mutations: 182598

Mutation Filtering

  • Number of mutations before filtering: 182598

  • After removing 15927 mutations outside gene set: 166671

  • After removing 1023 mutations outside category set: 165648

  • After removing 27 "impossible" mutations in

  • gene-patient-category bins of zero coverage: 148671

Results
Breakdown of Mutations by Type

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

type count
Frame_Shift_Del 1055
Frame_Shift_Ins 452
In_Frame_Del 686
In_Frame_Ins 130
Missense_Mutation 110554
Nonsense_Mutation 11525
Nonstop_Mutation 127
Silent 38550
Splice_Site 2569
Total 165648
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 exp_ns_s_ratio
*CpG->T 37482 363920417 0.0001 100 5.6 2.2
*Cp(A/C/T)->mut 48855 3147487610 0.000016 16 0.85 3.4
A->mut 23150 3458111551 6.7e-06 6.7 0.37 3.8
*CpG->(G/A) 1051 363920417 2.9e-06 2.9 0.16 2.7
indel+null 15675 6969519578 2.2e-06 2.2 0.12 NaN
double_null 868 6969519578 1.2e-07 0.12 0.0068 NaN
Total 127081 6969519578 0.000018 18 1 3.5
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: UCEC-TP.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)->mut

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

  • n4 = number of nonsilent mutations of type: *CpG->(G/A)

  • 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: 29. 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 PPP2R1A protein phosphatase 2 (formerly 2A), regulatory subunit A , alpha isoform 434902 30 27 18 3 10 17 1 0 2 0 0.23 0 9.7e-08 0 0
2 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 813637 172 132 76 3 31 61 68 3 9 0 8e-07 0 2.4e-15 0 0
3 CTNNB1 catenin (cadherin-associated protein), beta 1, 88kDa 592248 80 74 25 7 5 61 14 0 0 0 2e-07 0 4.9e-15 0 0
4 PIK3R1 phosphoinositide-3-kinase, regulatory subunit 1 (alpha) 581125 100 83 77 2 4 4 13 1 63 15 0.58 0 2.8e-15 0 0
5 PRKAR1B protein kinase, cAMP-dependent, regulatory, type I, beta 242642 4 4 4 3 2 0 0 1 1 0 0 0 0.56 0 0
6 PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1) 306286 228 161 134 5 20 29 21 33 98 27 0.9 1e-06 0 0 0
7 RPL22 ribosomal protein L22 97813 31 31 7 0 1 0 3 0 26 1 0.012 0 1.3e-15 0 0
8 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 175322 53 53 11 2 1 47 4 1 0 0 0.00019 0 3.1e-12 0 0
9 TP53 tumor protein p53 317550 74 69 50 2 23 18 15 1 17 0 2.6e-06 0 5.3e-15 0 0
10 FBXW7 F-box and WD repeat domain containing 7 638720 46 39 30 1 22 12 2 1 8 1 0.015 0.00081 3.7e-14 1.1e-15 1.9e-12
11 CTCF CCCTC-binding factor (zinc finger protein) 547098 49 45 39 1 8 4 7 0 27 3 0.1 0.021 6.2e-15 5e-15 7.6e-12
12 ARID1A AT rich interactive domain 1A (SWI-like) 1412380 93 83 78 5 2 7 5 1 64 14 0.88 1 1.1e-15 3.9e-14 5.5e-11
13 SPOP speckle-type POZ protein 287083 23 21 18 0 5 8 6 0 4 0 0.05 0.0015 5.2e-09 2.1e-10 2.7e-07
14 ARID5B AT rich interactive domain 5B (MRF1-like) 886908 34 29 34 9 5 5 8 2 13 1 0.98 0.17 1.4e-09 5.2e-09 6.3e-06
15 FGFR2 fibroblast growth factor receptor 2 (bacteria-expressed kinase, keratinocyte growth factor receptor, craniofacial dysostosis 1, Crouzon syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome) 687457 34 31 19 3 3 5 13 9 3 1 0.38 0.059 1.2e-08 1.6e-08 0.000018
16 CCND1 cyclin D1 154874 15 15 13 1 1 7 3 0 4 0 0.28 0.001 1e-06 2.3e-08 0.000024
17 SMTNL2 smoothelin-like 2 189739 9 9 3 2 0 2 0 0 7 0 0.67 0.000094 0.000012 2.4e-08 0.000024
18 NFE2L2 nuclear factor (erythroid-derived 2)-like 2 446498 15 15 12 0 2 3 5 3 2 0 0.039 0.000082 0.000095 1.5e-07 0.00014
19 CHD4 chromodomain helicase DNA binding protein 4 1452335 43 35 38 2 16 16 8 0 2 1 0.7 0.046 1.1e-06 9.2e-07 0.00081
20 RBMX RNA binding motif protein, X-linked 309438 14 13 8 0 1 4 2 0 7 0 0.2 0.014 0.000022 4.8e-06 0.004
21 FAM9A family with sequence similarity 9, member A 249932 20 14 20 1 2 12 1 0 4 1 1 0.26 1.6e-06 6.8e-06 0.0054
22 HPD 4-hydroxyphenylpyruvate dioxygenase 304730 7 7 3 0 0 0 1 0 6 0 0.00056 0.00021 0.0025 8e-06 0.0061
23 MORC4 MORC family CW-type zinc finger 4 675031 28 20 26 2 6 10 1 0 11 0 0.31 0.91 6.2e-07 8.6e-06 0.0063
24 CASP8 caspase 8, apoptosis-related cysteine peptidase 434533 21 17 19 6 2 8 3 0 8 0 0.034 0.1 0.000015 0.000022 0.015
25 ABI1 abl-interactor 1 390369 5 4 2 5 0 5 0 0 0 0 1 2.8e-06 1 0.000039 0.026
26 FOXA2 forkhead box A2 222670 13 12 13 1 1 3 3 0 6 0 0.28 0.21 0.000016 0.000045 0.029
27 BRS3 bombesin-like receptor 3 299754 17 15 17 2 1 11 1 0 4 0 0.21 0.2 0.000051 0.00013 0.079
28 NRAS neuroblastoma RAS viral (v-ras) oncogene homolog 145328 9 9 6 2 1 4 3 0 1 0 0.015 0.014 0.00084 0.00014 0.085
29 DNER delta/notch-like EGF repeat containing 485604 21 18 20 1 4 9 5 0 3 0 0.0045 0.016 0.00075 0.00015 0.085
30 TIAL1 TIA1 cytotoxic granule-associated RNA binding protein-like 1 297036 15 11 15 2 5 4 1 0 5 0 0.42 0.079 0.00019 0.00019 0.1
31 RPL14 ribosomal protein L14 165361 8 7 4 0 0 1 0 2 5 0 0.95 0.016 0.0012 0.00023 0.12
32 SGK1 serum/glucocorticoid regulated kinase 1 469608 16 15 14 3 2 5 1 1 7 0 0.011 0.049 0.00039 0.00023 0.12
33 SLC48A1 solute carrier family 48 (heme transporter), member 1 64852 5 5 5 0 1 2 1 0 1 0 0.88 1 0.000025 0.00029 0.15
34 BCOR BCL6 co-repressor 1283685 43 30 34 19 13 13 14 0 3 0 0.028 0.029 0.00088 0.0003 0.15
35 ZNF263 zinc finger protein 263 495567 13 8 10 0 1 9 1 0 2 0 0.014 0.00012 0.26 0.00035 0.17
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: 46. Number of genes displayed: 10

rank gene description n cos n_cos N_cos cos_ev p q
1 PIK3R1 phosphoinositide-3-kinase, regulatory subunit 1 (alpha) 100 33 39 8184 111 0 0
2 KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 53 52 49 12896 556649 0 0
3 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 172 220 150 54560 35669 0 0
4 CTNNB1 catenin (cadherin-associated protein), beta 1, 88kDa 80 138 67 34224 23813 0 0
5 FGFR2 fibroblast growth factor receptor 2 (bacteria-expressed kinase, keratinocyte growth factor receptor, craniofacial dysostosis 1, Crouzon syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome) 34 51 24 12648 113 0 0
6 FBXW7 F-box and WD repeat domain containing 7 46 91 29 22568 852 0 0
7 PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1) 228 767 219 190216 15125 0 0
8 TP53 tumor protein p53 74 356 72 88288 24186 0 0
9 NRAS neuroblastoma RAS viral (v-ras) oncogene homolog 9 33 6 8184 6490 1.3e-08 6.5e-06
10 RB1 retinoblastoma 1 (including osteosarcoma) 26 267 11 66216 30 6.6e-08 0.000029

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: 68. 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_ns_s p q
1 ARFPATHWAY Cyclin-dependent kinase inhibitor 2A is a tumor suppressor that induces G1 arrest and can activate the p53 pathway, leading to G2/M arrest. ABL1, CDKN2A, E2F1, MDM2, MYC, PIK3CA, PIK3R1, POLR1A, POLR1B, POLR1C, POLR1D, RAC1, RB1, TBX2, TP53, TWIST1 16 ABL1(8), CDKN2A(2), E2F1(9), MDM2(4), MYC(8), PIK3CA(172), PIK3R1(100), POLR1A(16), POLR1B(16), POLR1C(2), POLR1D(3), RAC1(1), RB1(26), TBX2(2), TP53(74), TWIST1(1) 7080267 444 223 300 50 87 115 119 6 99 18 4.87e-10 <1.00e-15 <3.80e-14
2 METPATHWAY The hepatocyte growth factor receptor c-Met stimulates proliferation and alters cell motility and adhesion on binding the ligand HGF. ACTA1, CRK, CRKL, DOCK1, ELK1, FOS, GAB1, GRB2, GRF2, HGF, HRAS, ITGA1, ITGB1, JUN, MAP2K1, MAP2K2, MAP4K1, MAPK1, MAPK3, MAPK8, MET, PAK1, PIK3CA, PIK3R1, PTEN, PTK2, PTK2B, PTPN11, PXN, RAF1, RAP1A, RAP1B, RASA1, SOS1, SRC, STAT3 35 ACTA1(5), CRK(2), CRKL(6), DOCK1(24), ELK1(3), FOS(3), GAB1(8), GRB2(3), HGF(14), HRAS(1), ITGA1(17), ITGB1(8), JUN(1), MAP2K1(2), MAP2K2(5), MAP4K1(11), MAPK1(2), MAPK3(3), MAPK8(10), MET(17), PAK1(3), PIK3CA(172), PIK3R1(100), PTEN(228), PTK2(12), PTK2B(16), PTPN11(8), PXN(6), RAF1(8), RAP1A(4), RAP1B(2), RASA1(30), SOS1(13), SRC(3), STAT3(10) 16563754 760 217 538 93 135 188 148 37 208 44 7.33e-15 <1.00e-15 <3.80e-14
3 PTENPATHWAY PTEN suppresses AKT-induced cell proliferation and antagonizes the action of PI3K. AKT1, BCAR1, CDKN1B, FOXO3A, GRB2, ILK, ITGB1, MAPK1, MAPK3, PDK2, PDPK1, PIK3CA, PIK3R1, PTEN, PTK2, SHC1, SOS1, TNFSF6 16 AKT1(4), BCAR1(8), CDKN1B(7), GRB2(3), ILK(5), ITGB1(8), MAPK1(2), MAPK3(3), PDK2(5), PDPK1(3), PIK3CA(172), PIK3R1(100), PTEN(228), PTK2(12), SHC1(7), SOS1(13) 6867110 580 213 364 30 73 121 124 37 183 42 <1.00e-15 <1.00e-15 <3.80e-14
4 GSK3PATHWAY Bacterial lipopolysaccharide activates AKT to promote the survival and activation of macrophages and inhibits Gsk3-beta to promote beta-catenin accumulation in the nucleus. AKT1, APC, AXIN1, CCND1, CD14, CTNNB1, DVL1, FZD1, GJA1, GNAI1, GSK3B, IRAK1, LBP, LEF1, LY96, MYD88, NFKB1, PDPK1, PIK3CA, PIK3R1, PPP2CA, PRKR, RELA, TIRAP, TLR4, TOLLIP, WNT1 26 AKT1(4), APC(56), AXIN1(9), CCND1(15), CD14(2), CTNNB1(80), DVL1(3), FZD1(3), GJA1(5), GNAI1(5), GSK3B(13), IRAK1(4), LBP(3), LEF1(9), LY96(4), MYD88(3), NFKB1(10), PDPK1(3), PIK3CA(172), PIK3R1(100), PPP2CA(6), RELA(6), TIRAP(2), TLR4(17), TOLLIP(1), WNT1(1) 10634125 536 210 356 58 77 201 122 6 110 20 2.06e-13 <1.00e-15 <3.80e-14
5 SA_PTEN_PATHWAY PTEN is a tumor suppressor that dephosphorylates the lipid messenger phosphatidylinositol triphosphate. AKT1, AKT2, AKT3, BPNT1, GRB2, ILK, MAPK1, MAPK3, PDK1, PIK3CA, PIK3CD, PIP3-E, PTEN, PTK2B, RBL2, SHC1, SOS1 16 AKT1(4), AKT2(6), AKT3(11), BPNT1(3), GRB2(3), ILK(5), MAPK1(2), MAPK3(3), PDK1(2), PIK3CA(172), PIK3CD(12), PTEN(228), PTK2B(16), RBL2(19), SHC1(7), SOS1(13) 7243620 506 208 307 39 92 126 107 36 117 28 <1.00e-15 <1.00e-15 <3.80e-14
6 EDG1PATHWAY The lipid S1P is an EDG1 ligand promoting chemotaxis via Rac1 and cell survival and proliferation via ERK activation. ADCY1, AKT1, ARHA, ASAH1, EDG1, GNAI1, GNB1, GNGT1, ITGAV, ITGB3, MAPK1, MAPK3, PDGFA, PDGFRA, PIK3CA, PIK3R1, PLCB1, PRKCA, PRKCB1, PTK2, RAC1, SKIP, SMPD1, SMPD2, SPHK1, SRC 22 ADCY1(21), AKT1(4), ASAH1(7), GNAI1(5), GNB1(2), GNGT1(1), ITGAV(10), ITGB3(11), MAPK1(2), MAPK3(3), PDGFA(3), PDGFRA(24), PIK3CA(172), PIK3R1(100), PLCB1(5), PRKCA(10), PTK2(12), RAC1(1), SMPD1(11), SMPD2(7), SPHK1(2), SRC(3) 9845923 416 201 295 65 72 117 114 6 90 17 1.52e-05 <1.00e-15 <3.80e-14
7 HCMVPATHWAY Cytomegalovirus activates MAP kinase pathways in the host cell, inducing transcription of viral genes. AKT1, CREB1, MAP2K1, MAP2K2, MAP2K3, MAP2K6, MAP3K1, MAPK1, MAPK14, MAPK3, NFKB1, PIK3CA, PIK3R1, RB1, RELA, SP1 16 AKT1(4), CREB1(6), MAP2K1(2), MAP2K2(5), MAP2K3(7), MAP2K6(10), MAP3K1(30), MAPK1(2), MAPK14(4), MAPK3(3), NFKB1(10), PIK3CA(172), PIK3R1(100), RB1(26), RELA(6), SP1(7) 7166136 394 200 272 31 63 112 107 4 89 19 2.19e-12 <1.00e-15 <3.80e-14
8 IL7PATHWAY IL-7 is required for B and T cell development and proliferation and may contribute to activation of VDJ recombination. BCL2, CREBBP, EP300, FYN, IL2RG, IL7, IL7R, JAK1, JAK3, LCK, NMI, PIK3CA, PIK3R1, PTK2B, STAT5A, STAT5B 16 CREBBP(32), EP300(32), FYN(7), IL2RG(13), IL7(1), IL7R(12), JAK1(20), JAK3(10), LCK(5), NMI(3), PIK3CA(172), PIK3R1(100), PTK2B(16), STAT5A(5), STAT5B(7) 10213532 435 200 312 56 77 121 115 6 100 16 3.60e-08 <1.00e-15 <3.80e-14
9 RAC1PATHWAY Rac-1 is a Rho family G protein that stimulates formation of actin-dependent structures such as filopodia and lamellopodia. ARFIP2, CDK5, CDK5R1, CFL1, CHN1, LIMK1, MAP3K1, MYL2, MYLK, NCF2, PAK1, PDGFRA, PIK3CA, PIK3R1, PLD1, PPP1R12B, RAC1, RALBP1, RPS6KB1, TRIO, VAV1, WASF1 22 ARFIP2(1), CDK5(2), CDK5R1(3), CFL1(1), CHN1(3), LIMK1(8), MAP3K1(30), MYL2(2), MYLK(14), NCF2(8), PAK1(3), PDGFRA(24), PIK3CA(172), PIK3R1(100), PLD1(14), PPP1R12B(20), RAC1(1), RALBP1(6), RPS6KB1(5), TRIO(34), VAV1(12), WASF1(3) 12890193 466 200 341 66 88 134 115 6 104 19 1.52e-07 <1.00e-15 <3.80e-14
10 ECMPATHWAY Extracellular matrix induces integrin-mediated FAK phosphorylation in epithelial cells, leading to PI3 and MAP kinase activation and actin reorganization. ARHA, ARHGAP5, DIAPH1, FYN, GSN, HRAS, ITGA1, ITGB1, MAP2K1, MAPK1, MAPK3, MYL2, MYLK, PFN1, PIK3CA, PIK3R1, PTK2, PXN, RAF1, ROCK1, SHC1, SRC, TLN1 22 ARHGAP5(21), DIAPH1(13), FYN(7), GSN(5), HRAS(1), ITGA1(17), ITGB1(8), MAP2K1(2), MAPK1(2), MAPK3(3), MYL2(2), MYLK(14), PFN1(1), PIK3CA(172), PIK3R1(100), PTK2(12), PXN(6), RAF1(8), ROCK1(22), SHC1(7), SRC(3), TLN1(23) 13836087 449 199 329 53 93 128 116 4 91 17 7.62e-10 <1.00e-15 <3.80e-14
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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