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

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

- 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

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

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

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

+ CoMut Plot

+ 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

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