Mutation Analysis (MutSig v2.0 and MutSigCV v0.9 merged result)

Lung Adenocarcinoma (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/C1M043GP

- Overview

+ Introduction

- Summary

MAF used for this analysis:LUAD-TP.final_analysis_set.maf
Significantly mutated genes (q ≤ 0.1): 96
Mutations seen in COSMIC: 516
Significantly mutated genes in COSMIC territory: 23
Significantly mutated genesets: 16

Mutation Preprocessing

Read 229 MAFs of type "Broad"
Total number of mutations in input MAFs: 251233
After removing 79 mutations outside chr1-24: 251154
After removing 1211 blacklisted mutations: 249943
After removing 144408 noncoding mutations: 105535
After collapsing adjacent/redundant mutations: 94095

Mutation Filtering

Number of mutations before filtering: 94095
After removing 1293 mutations outside gene set: 92802
After removing 182 mutations outside category set: 92620

- Results

+ Breakdown of Mutations by Type

type	count
Frame_Shift_Del	1515
Frame_Shift_Ins	584
In_Frame_Del	183
In_Frame_Ins	22
Missense_Mutation	60561
Nonsense_Mutation	4805
Nonstop_Mutation	58
Silent	22884
Splice_Site	1874
Translation_Start_Site	134
Total	92620

+ Breakdown of Mutation Rates by Category Type

category	n	N	rate	rate_per_mb	relative_rate	exp_ns_s_ratio
*CpG->A	8888	379287204	0.000023	23	2.3	2.1
*Cp(A/C/T)->A	22068	3108508517	7.1e-06	7.1	0.7	5
C->(T/G)	18984	3487795721	5.4e-06	5.4	0.53	2.8
A->mut	10752	3354933814	3.2e-06	3.2	0.31	3.9
indel+null	8896	6842729535	1.3e-06	1.3	0.13	NaN
double_null	148	6842729535	2.2e-08	0.022	0.0021	NaN
Total	69736	6842729535	1e-05	10	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->A
n2 = number of nonsilent mutations of type: *Cp(A/C/T)->A
n3 = number of nonsilent mutations of type: C->(T/G)
n4 = number of nonsilent mutations of type: A->mut
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: 96. 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	CDKN2A	cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)	226023	14	14	14	1	0	1	4	4	5	0	4e-07	0	1.3e-11	0	0
2	KRAS	v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog	161903	60	60	6	0	0	47	10	3	0	0	0	0	5.2e-15	0	0
3	TP53	tumor protein p53	288082	128	119	106	2	8	22	31	18	49	0	9.2e-06	0	1.9e-15	0	0
4	EGFR	epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)	918061	33	27	19	7	2	5	4	13	9	0	0.0029	0	1.2e-14	0	0
5	STK11	serine/threonine kinase 11	199230	21	20	20	0	0	4	2	4	11	0	0.037	0.0023	7.7e-15	6.7e-16	2.4e-12
6	KEAP1	kelch-like ECH-associated protein 1	418841	39	39	37	0	4	8	13	10	4	0	0.026	0.021	5.6e-15	4.3e-15	1.3e-11
7	CRIPAK	cysteine-rich PAK1 inhibitor	280983	15	13	8	4	2	1	3	0	9	0	0.13	0.0015	2.3e-13	1.3e-14	3.3e-11
8	RBM10	RNA binding motif protein 10	445634	12	12	12	1	1	0	1	0	10	0	0.29	0.092	4.1e-12	1.1e-11	2.5e-08
9	NF1	neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease)	2003521	30	27	29	4	0	4	6	4	13	3	0.35	0.18	1.5e-11	7.5e-11	1.5e-07
10	FLG	filaggrin	2748000	128	60	126	26	19	65	23	10	10	1	0.67	0.54	8e-12	1.2e-10	2.1e-07
11	GPR112	G protein-coupled receptor 112	2137715	57	47	56	18	2	25	16	10	4	0	0.48	0.14	4.4e-11	1.7e-10	2.8e-07
12	SMARCA4	SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4	1051339	18	17	18	2	0	0	3	4	11	0	0.73	0.55	1.6e-11	2.3e-10	3.5e-07
13	MUC7	mucin 7, secreted	261518	19	17	19	1	0	8	3	5	3	0	0.66	0.11	4.2e-09	1e-08	0.000014
14	COL11A1	collagen, type XI, alpha 1	1338734	68	50	67	14	3	28	13	8	16	0	0.16	0.33	1.5e-09	1.2e-08	0.000015
15	HRNR	hornerin	1502240	50	33	50	11	6	17	14	4	8	1	0.98	0.0079	9.3e-08	1.6e-08	2e-05
16	SPRR3	small proline-rich protein 3	117706	7	7	4	0	0	1	0	1	5	0	0.074	0.0019	1e-06	4.1e-08	0.000046
17	BRAF	v-raf murine sarcoma viral oncogene homolog B1	510899	17	17	12	1	1	7	2	5	2	0	0.43	0.061	1e-07	1.3e-07	0.00013
18	U2AF1	U2 small nuclear RNA auxiliary factor 1	188925	6	6	2	0	0	0	6	0	0	0	0.0055	0.000085	0.00015	2.4e-07	0.00024
19	NRAS	neuroblastoma RAS viral (v-ras) oncogene homolog	134194	4	4	2	1	0	1	0	3	0	0	0.21	1.2e-06	0.029	6.3e-07	0.00059
20	PCK1	phosphoenolpyruvate carboxykinase 1 (soluble)	436245	12	12	12	2	3	2	3	1	3	0	0.052	0.0031	0.000014	8e-07	0.00072
21	CSMD3	CUB and Sushi multiple domains 3	2626630	161	98	159	33	4	76	36	24	20	1	0.9	1	7.4e-08	1.3e-06	0.0011
22	RB1	retinoblastoma 1 (including osteosarcoma)	626086	13	13	13	1	0	2	1	1	9	0	0.66	0.68	1.5e-07	1.8e-06	0.0015
23	RIMS2	regulating synaptic membrane exocytosis 2	994318	45	39	45	4	4	16	10	8	7	0	0.24	0.26	5.3e-07	2.3e-06	0.0018
24	RIT1	Ras-like without CAAX 1	155720	10	9	9	1	2	4	0	2	2	0	0.43	0.18	8.4e-07	2.5e-06	0.0019
25	FTSJD1	FtsJ methyltransferase domain containing 1	530593	11	11	11	0	1	1	2	1	6	0	0.038	0.074	2.3e-06	2.8e-06	0.002
26	LRP1B	low density lipoprotein-related protein 1B (deleted in tumors)	3243556	148	86	146	27	7	57	37	24	22	1	0.094	0.42	9e-07	6e-06	0.0042
27	OR10J3	olfactory receptor, family 10, subfamily J, member 3	227168	11	11	11	3	1	4	4	2	0	0	0.016	0.0092	0.000088	0.000012	0.0081
28	SETD2	SET domain containing 2	1461707	21	18	21	1	1	4	2	4	9	1	0.16	0.071	0.000012	0.000013	0.0084
29	LTBP1	latent transforming growth factor beta binding protein 1	1142710	28	28	28	7	1	11	9	3	4	0	0.29	0.72	1.3e-06	0.000014	0.0088
30	ZCCHC5	zinc finger, CCHC domain containing 5	293120	16	15	15	4	1	10	3	0	2	0	0.9	1	1.2e-06	0.000017	0.01
31	MYL10	myosin, light chain 10, regulatory	120225	7	7	7	1	1	3	0	0	3	0	0.41	0.64	2e-06	0.000019	0.011
32	GBA3	glucosidase, beta, acid 3 (cytosolic)	297929	12	12	12	2	1	4	3	1	3	0	0.26	0.0097	0.00015	0.000021	0.012
33	ADAMTS5	ADAM metallopeptidase with thrombospondin type 1 motif, 5 (aggrecanase-2)	589217	22	21	22	7	1	11	5	2	3	0	0.18	0.082	0.000019	0.000023	0.012
34	ZNF268	zinc finger protein 268	98241	7	7	7	1	0	2	0	1	4	0	0.029	0.1	0.000021	3e-05	0.016
35	OR4Q3	olfactory receptor, family 4, subfamily Q, member 3	216176	14	14	14	5	1	5	4	3	1	0	0.31	0.65	3.8e-06	0.000035	0.018

+ 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: 23. Number of genes displayed: 10

rank	gene	description	n	cos	n_cos	N_cos	cos_ev	p	q
1	LRP1B	low density lipoprotein-related protein 1B (deleted in tumors)	148	18	8	4122	8	1.8e-13	8e-10
2	KRAS	v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog	60	52	60	11908	797017	4.7e-13	1.1e-09
3	BRAF	v-raf murine sarcoma viral oncogene homolog B1	17	89	12	20381	28944	7.4e-13	1.1e-09
4	STK11	serine/threonine kinase 11	21	130	14	29770	27	9.9e-13	1.1e-09
5	EGFR	epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)	33	293	29	67097	10294	1.5e-12	1.1e-09
6	TP53	tumor protein p53	128	356	122	81524	18207	1.6e-12	1.1e-09
7	CDKN2A	cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)	14	332	14	76028	259	1.7e-12	1.1e-09
8	MET	met proto-oncogene (hepatocyte growth factor receptor)	12	34	6	7786	64	3.2e-10	1.8e-07
9	PIK3CA	phosphoinositide-3-kinase, catalytic, alpha polypeptide	11	220	9	50380	3946	4.3e-09	2.2e-06
10	NF1	neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease)	30	285	9	65265	13	3.9e-08	0.000017

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: 16. Number of genesets displayed: 10

rank	geneset	description	genes	N_genes	mut_tally	N	n	npat	nsite	nsil	n1	n2	n3	n4	n5	p_ns_s	p	q
1	P53PATHWAY	p53 induces cell cycle arrest or apoptosis under conditions of DNA damage.	APAF1, ATM, BAX, BCL2, CCND1, CCNE1, CDK2, CDK4, CDKN1A, E2F1, GADD45A, MDM2, PCNA, RB1, TIMP3, TP53	16	APAF1(8), ATM(22), BAX(1), BCL2(1), CCND1(2), CCNE1(3), CDK2(4), CDK4(2), CDKN1A(1), E2F1(3), GADD45A(1), MDM2(2), PCNA(1), RB1(13), TP53(128)	6266585	192	143	169	16	16	37	42	29	68	1.9e-06	<1.00e-15	<1.54e-13
2	P53HYPOXIAPATHWAY	Hypoxia induces p53 accumulation and consequent apoptosis with p53-mediated cell cycle arrest, which is present under conditions of DNA damage.	ABCB1, AKT1, ATM, BAX, CDKN1A, CPB2, CSNK1A1, CSNK1D, FHL2, GADD45A, HIC1, HIF1A, HSPA1A, HSPCA, IGFBP3, MAPK8, MDM2, NFKBIB, NQO1, TP53	19	ABCB1(20), ATM(22), BAX(1), CDKN1A(1), CPB2(4), CSNK1A1(1), CSNK1D(2), GADD45A(1), HIF1A(1), IGFBP3(2), MAPK8(3), MDM2(2), NQO1(3), TP53(128)	7172280	191	138	167	18	17	40	45	27	62	0.000012	<1.00e-15	<1.54e-13
3	PLK3PATHWAY	Active Plk3 phosphorylates CDC25c, blocking the G2/M transition, and phosphorylates p53 to induce apoptosis.	ATM, ATR, CDC25C, CHEK1, CHEK2, CNK, TP53, YWHAH	7	ATM(22), ATR(17), CDC25C(3), CHEK1(6), CHEK2(2), TP53(128)	5517526	178	136	155	7	10	35	48	28	57	1e-08	<1.00e-15	<1.54e-13
4	TERTPATHWAY	hTERC, the RNA subunit of telomerase, and hTERT, the catalytic protein subunit, are required for telomerase activity and are overexpressed in many cancers.	HDAC1, MAX, MYC, SP1, SP3, TP53, WT1, ZNF42	7	HDAC1(3), MAX(3), SP1(1), SP3(4), TP53(128), WT1(8)	2427858	147	122	125	10	9	29	35	21	53	1.2e-06	<1.00e-15	<1.54e-13
5	SA_G1_AND_S_PHASES	Cdk2, 4, and 6 bind cyclin D in G1, while cdk2/cyclin E promotes the G1/S transition.	ARF1, ARF3, CCND1, CDK2, CDK4, CDKN1A, CDKN1B, CDKN2A, CFL1, E2F1, E2F2, MDM2, NXT1, PRB1, TP53	15	ARF3(1), CCND1(2), CDK2(4), CDK4(2), CDKN1A(1), CDKN1B(3), CDKN2A(14), E2F1(3), MDM2(2), NXT1(1), PRB1(3), TP53(128)	2958909	164	125	142	8	15	29	38	24	58	1.1e-09	1.44e-15	1.78e-13
6	RNAPATHWAY	dsRNA-activated protein kinase phosphorylates elF2a, which generally inhibits translation, and activates NF-kB to provoke inflammation.	CHUK, DNAJC3, EIF2S1, EIF2S2, MAP3K14, NFKB1, NFKBIA, PRKR, RELA, TP53	9	CHUK(3), DNAJC3(3), MAP3K14(1), NFKB1(3), NFKBIA(1), TP53(128)	3372941	139	121	117	9	9	23	36	18	53	2.2e-06	2.44e-15	2.51e-13
7	ATMPATHWAY	The tumor-suppressing protein kinase ATM responds to radiation-induced DNA damage by blocking cell-cycle progression and activating DNA repair.	ABL1, ATM, BRCA1, CDKN1A, CHEK1, CHEK2, GADD45A, JUN, MAPK8, MDM2, MRE11A, NBS1, NFKB1, NFKBIA, RAD50, RAD51, RBBP8, RELA, TP53, TP73	19	ABL1(2), ATM(22), BRCA1(9), CDKN1A(1), CHEK1(6), CHEK2(2), GADD45A(1), JUN(1), MAPK8(3), MDM2(2), MRE11A(6), NFKB1(3), NFKBIA(1), RAD50(3), RAD51(1), RBBP8(3), TP53(128), TP73(4)	10278207	198	140	175	16	15	41	53	28	61	1.7e-06	3.11e-15	2.61e-13
8	RBPATHWAY	The ATM protein kinase recognizes DNA damage and blocks cell cycle progression by phosphorylating chk1 and p53, which normally inhibits Rb to allow G1/S transitions.	ATM, CDC2, CDC25A, CDC25B, CDC25C, CDK2, CDK4, CHEK1, MYT1, RB1, TP53, WEE1, YWHAH	12	ATM(22), CDC25A(4), CDC25B(1), CDC25C(3), CDK2(4), CDK4(2), CHEK1(6), MYT1(6), RB1(13), TP53(128), WEE1(3)	6070332	192	140	169	13	15	37	43	29	68	1.6e-07	3.66e-15	2.61e-13
9	TIDPATHWAY	On ligand binding, interferon gamma receptors stimulate JAK2 kinase to phosphorylate STAT transcription factors, which promote expression of interferon responsive genes.	DNAJA3, HSPA1A, IFNG, IFNGR1, IFNGR2, IKBKB, JAK2, LIN7A, NFKB1, NFKBIA, RB1, RELA, TIP-1, TNF, TNFRSF1A, TNFRSF1B, TP53, USH1C, WT1	18	IFNG(4), IFNGR1(3), IFNGR2(3), IKBKB(3), JAK2(4), LIN7A(2), NFKB1(3), NFKBIA(1), RB1(13), TNFRSF1B(1), TP53(128), USH1C(4), WT1(8)	6332308	177	133	155	16	15	35	41	21	65	1.8e-06	3.89e-15	2.61e-13
10	PMLPATHWAY	Ring-shaped PML nuclear bodies regulate transcription and are required co-activators in p53- and DAXX-mediated apoptosis.	CREBBP, DAXX, HRAS, PAX3, PML, PRAM-1, RARA, RB1, SIRT1, SP100, TNF, TNFRSF1A, TNFRSF1B, TNFRSF6, TNFSF6, TP53, UBL1	13	CREBBP(4), DAXX(6), HRAS(1), PAX3(6), PML(7), RARA(3), RB1(13), SIRT1(1), SP100(9), TNFRSF1B(1), TP53(128)	6622222	179	131	157	15	14	30	47	25	63	3.8e-07	4.33e-15	2.61e-13

+ Methods & Data

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