Lung Adenocarcinoma: Mutation Analysis (MutSig v2.0)

Maintained by Dan DiCara (Broad Institute)

- Overview

+ Introduction

- Summary

MAF used for this analysis:LUAD.final_analysis_set.maf
Significantly mutated genes (q ≤ 0.1): 124
Mutations seen in COSMIC: 266
Significantly mutated genes in COSMIC territory: 11
Genes with clustered mutations (≤ 3 aa apart): 87
Significantly mutated genesets: 11
Significantly mutated genesets: (excluding sig. mutated genes):0

Mutation Preprocessing

Read 129 MAFs of type "Broad"
Total number of mutations in input MAFs: 132457
After removing 11 mutations outside chr1-24: 132446
After removing 557 blacklisted mutations: 131889
After removing 66504 noncoding mutations: 65385
After collapsing adjacent/redundant mutations: 56034

Mutation Filtering

Number of mutations before filtering: 56034
After removing 675 mutations outside gene set: 55359
After removing 318 mutations outside category set: 55041

- Results

+ Breakdown of Mutations by Type

type	count
Frame_Shift_Del	648
Frame_Shift_Ins	232
In_Frame_Del	93
In_Frame_Ins	10
Missense_Mutation	35707
Nonsense_Mutation	2806
Nonstop_Mutation	30
Silent	14402
Splice_Site	1033
Translation_Start_Site	80
Total	55041

+ Breakdown of Mutation Rates by Category Type

category	n	N	rate	rate_per_mb	relative_rate	exp_ns_s_ratio
*CpG->A	6856	213659604	0.000032	32	3	2.1
*Cp(A/C/T)->A	13232	1751081217	7.6e-06	7.6	0.72	5
C->(T/G)	10225	1964740821	5.2e-06	5.2	0.49	2.8
A->mut	5448	1889897214	2.9e-06	2.9	0.27	3.9
indel+null	4773	3854638035	1.2e-06	1.2	0.12	NaN
double_null	105	3854638035	2.7e-08	0.027	0.0026	NaN
Total	40639	3854638035	0.000011	11	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_classic = p-value for the observed amount of nonsilent mutations being elevated in this gene
p_ns_s = p-value for the observed nonsilent/silent ratio being elevated in this gene
p_ks = p-value for clustering of mutations (Kolmogorov-Smirnoff test)
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: 124. 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_classic	p_ns_s	p_ks	p_cons	p_joint	p	q
1	STK11	serine/threonine kinase 11	112230	18	17	17	0	0	4	1	4	9	0	3.2e-15	0.018	0.00013	0.0027	0.000052	0.000	0.000
2	TP53	tumor protein p53	162282	65	58	55	2	4	12	16	10	23	0	4.3e-15	0.000023	2e-07	2e-07	0	<1.00e-15	<3.62e-12
3	KRAS	v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog	91203	35	35	3	0	0	31	3	1	0	0	2.3e-15	0.042	2e-07	2e-07	0	<1.00e-15	<3.62e-12
4	EGFR	epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)	517161	24	19	14	5	2	4	3	9	6	0	0.00014	0.57	2e-07	0.0013	0	<1.00e-15	<3.62e-12
5	OR6C4	olfactory receptor, family 6, subfamily C, member 4	120228	2	2	2	0	0	0	1	0	1	0	0.13	0.4	0.06	0.0076	0	<1.00e-15	<3.62e-12
6	KEAP1	kelch-like ECH-associated protein 1	235941	24	24	23	0	2	3	11	6	2	0	7.7e-15	0.00076	0.081	0.15	0.082	2.28e-14	6.86e-11
7	BRAF	v-raf murine sarcoma viral oncogene homolog B1	287799	13	13	9	1	1	4	2	4	2	0	9.6e-08	0.17	0.0036	0.097	0.0054	1.16e-08	3.00e-05
8	NAV3	neuron navigator 3	934992	36	27	36	2	3	22	5	5	0	1	1.3e-09	0.022	0.39	0.52	0.48	1.35e-08	3.06e-05
9	CD5L	CD5 molecule-like	137772	11	11	11	1	3	2	0	3	3	0	4.1e-08	0.2	0.17	0.01	0.018	1.57e-08	3.15e-05
10	CDKN2A	cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)	127323	7	7	7	1	0	1	1	2	3	0	8.7e-06	0.64	0.013	0.00038	0.00027	4.89e-08	8.84e-05
11	REG3A	regenerating islet-derived 3 alpha	70692	11	10	11	1	0	3	5	1	2	0	8.4e-09	0.24	0.23	0.66	0.47	8.04e-08	0.000132
12	RIMS2	regulating synaptic membrane exocytosis 2	560118	27	22	27	2	2	10	6	4	5	0	3e-08	0.12	0.23	0.095	0.17	1.04e-07	0.000157
13	U2AF1	U2 small nuclear RNA auxiliary factor 1	106425	4	4	1	0	0	0	4	0	0	0	0.0071	0.32	4e-07	1e-05	1.2e-06	1.67e-07	0.000233
14	DCAF4L2	DDB1 and CUL4 associated factor 4-like 2	153768	11	10	11	1	1	4	2	2	2	0	1.2e-07	0.2	0.07	0.86	0.18	3.99e-07	0.000515
15	MAGEC1	melanoma antigen family C, 1	436020	21	19	21	2	1	10	5	4	1	0	4.7e-08	0.14	0.32	0.67	0.56	4.84e-07	0.000584
16	IL1RAPL1	interleukin 1 receptor accessory protein-like 1	273222	11	11	10	0	1	3	4	2	1	0	2.1e-06	0.083	0.054	0.024	0.017	6.31e-07	0.000713
17	CDH8	cadherin 8, type 2	315276	13	13	12	0	1	5	3	1	3	0	1.4e-06	0.062	0.041	0.12	0.044	1.11e-06	0.00118
18	OR2T33	olfactory receptor, family 2, subfamily T, member 33	124614	10	9	10	1	3	3	1	2	1	0	2.3e-07	0.18	0.18	0.6	0.3	1.21e-06	0.00122
19	TMTC1	transmembrane and tetratricopeptide repeat containing 1	306117	17	13	16	2	2	9	3	1	2	0	9.2e-07	0.24	0.57	0.038	0.12	1.95e-06	0.00186
20	HGF	hepatocyte growth factor (hepapoietin A; scatter factor)	285993	18	14	18	1	0	10	3	4	1	0	2.2e-07	0.21	0.77	0.31	0.63	2.35e-06	0.00212
21	SNTG1	syntrophin, gamma 1	209238	15	14	15	2	2	4	3	4	2	0	2.9e-07	0.26	0.52	0.24	0.54	2.60e-06	0.00224
22	MUC7	mucin 7, secreted	147318	12	10	12	0	0	5	2	3	2	0	7.3e-07	0.078	0.14	0.55	0.27	3.26e-06	0.00268
23	OR2T4	olfactory receptor, family 2, subfamily T, member 4	135579	11	10	11	1	0	4	5	2	0	0	9.7e-07	0.14	0.12	0.81	0.25	3.95e-06	0.00311
24	OR2W3	olfactory receptor, family 2, subfamily W, member 3	122163	11	10	11	1	2	4	2	2	1	0	4.1e-07	0.11	0.39	0.89	0.64	4.23e-06	0.00319
25	EPHA6	EPH receptor A6	425442	18	15	18	3	1	10	4	2	1	0	0.000069	0.45	0.03	0.011	0.0045	4.93e-06	0.00357
26	CARM1	coactivator-associated arginine methyltransferase 1	203949	3	3	2	0	0	0	3	0	0	0	0.17	0.3	1.8e-06	0.26	2.2e-06	6.05e-06	0.00405
27	RBM10	RNA binding motif protein 10	251034	10	10	10	1	1	0	1	0	8	0	9.8e-06	0.085	0.091	0.1	0.041	6.26e-06	0.00405
28	CDH10	cadherin 10, type 2 (T2-cadherin)	311019	30	24	30	6	3	15	8	1	3	0	4.9e-07	0.49	0.67	0.46	0.81	6.26e-06	0.00405
29	OR2L3	olfactory receptor, family 2, subfamily L, member 3	121647	10	9	10	1	0	5	2	3	0	0	8.6e-07	0.26	0.36	0.6	0.51	6.85e-06	0.00428
30	REG1B	regenerating islet-derived 1 beta (pancreatic stone protein, pancreatic thread protein)	67209	6	6	6	0	0	3	1	2	0	0	0.000013	0.28	0.045	0.14	0.049	9.98e-06	0.00602
31	PDE10A	phosphodiesterase 10A	313212	9	9	9	1	2	2	3	2	0	0	0.0014	0.3	0.00031	0.54	0.0005	1.10e-05	0.00641
32	SEC14L1	SEC14-like 1 (S. cerevisiae)	287412	4	4	4	2	2	0	1	1	0	0	0.55	0.84	0.073	2e-07	1.4e-06	1.15e-05	0.00651
33	CDH18	cadherin 18, type 2	311793	14	13	14	1	0	9	2	3	0	0	5.3e-06	0.25	0.3	0.088	0.16	1.27e-05	0.00668
34	SETD2	SET domain containing 2	823407	16	13	16	0	0	3	1	2	9	1	0.00052	0.055	0.00085	0.25	0.0016	1.29e-05	0.00668
35	OR4C46	olfactory receptor, family 4, subfamily C, member 46	120228	9	9	8	1	0	4	1	3	1	0	1e-06	0.3	0.64	0.56	0.87	1.32e-05	0.00668

+ COSMIC analyses

rank	gene	description	n	cos	n_cos	N_cos	cos_ev	p	q
1	KRAS	v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog	35	51	35	6579	491694	0	0
2	TP53	tumor protein p53	65	308	61	39732	8260	0	0
3	BRAF	v-raf murine sarcoma viral oncogene homolog B1	13	88	10	11352	21196	0	0
4	EGFR	epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)	24	218	21	28122	8076	0	0
5	STK11	serine/threonine kinase 11	18	130	12	16770	26	0	0
6	MET	met proto-oncogene (hepatocyte growth factor receptor)	10	33	5	4257	60	1.5e-09	1.1e-06
7	CDKN2A	cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)	7	315	7	40635	126	3.6e-07	0.00023
8	CTNNB1	catenin (cadherin-associated protein), beta 1, 88kDa	9	101	4	13029	1911	0.000013	0.0074
9	SMC2	structural maintenance of chromosomes 2	4	4	2	516	2	0.000015	0.0074
10	SMAD4	SMAD family member 4	6	159	4	20511	17	0.000077	0.035

+ Clustered Mutations

num	gene	desc	n	nmuts0	nmuts3	nmuts12	npairs0	npairs3	npairs12
5758	KRAS	v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog	35	528	528	528	528	528	528
3336	EGFR	epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)	24	22	31	31	22	31	31
11252	TP53	tumor protein p53	65	16	74	202	16	74	202
1083	BRAF	v-raf murine sarcoma viral oncogene homolog B1	13	4	6	10	4	6	10
10430	SPTA1	spectrin, alpha, erythrocytic 1 (elliptocytosis 2)	49	3	5	13	3	5	13
12412	ZNF536	zinc finger protein 536	30	3	4	8	3	4	8
5525	KEAP1	kelch-like ECH-associated protein 1	24	2	6	18	2	6	18
2045	CDH10	cadherin 10, type 2 (T2-cadherin)	30	2	6	12	2	6	12
10549	STK11	serine/threonine kinase 11	18	2	5	19	2	5	19
11427	TSHZ3	teashirt zinc finger homeobox 3	20	2	2	5	2	2	5

+ Geneset Analyses

Table 6. Get Full Table A Ranked List of Significantly Mutated Genesets. (Source: MSigDB GSEA Cannonical Pathway Set).Number of significant genesets found: 11. 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	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(1), MAX(1), SP3(1), TP53(65), WT1(7)	1367658	75	60	65	8	5	18	17	10	25	0.0048	<1.00e-15	<4.10e-13
2	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(1), DNAJC3(2), MAP3K14(1), NFKB1(2), TP53(65)	1900041	71	59	61	7	5	13	19	10	24	0.0043	1.33e-15	4.10e-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(14), ATR(9), CHEK1(6), CHEK2(2), TP53(65)	3108126	96	68	85	7	5	21	24	15	31	0.0011	2.55e-15	5.24e-13
4	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), CDKN1B(2), CDKN2A(7), MDM2(1), PRB1(3), TP53(65)	1666809	87	62	77	7	11	17	18	13	28	0.00011	4.22e-15	6.50e-13
5	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(3), IFNGR1(3), IFNGR2(2), IKBKB(2), JAK2(2), LIN7A(1), NFKB1(2), RB1(5), TNFRSF1B(1), TP53(65), USH1C(3), WT1(7)	3567108	96	68	86	9	9	22	23	12	30	0.00022	8.88e-15	1.09e-12
6	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(2), DAXX(2), HRAS(1), PAX3(3), PML(4), RARA(2), RB1(5), SIRT1(1), SP100(4), TNFRSF1B(1), TP53(65)	3730422	90	64	80	7	7	17	23	14	29	0.000091	4.23e-14	4.34e-12
7	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(4), ATM(14), BAX(1), BCL2(1), CCND1(2), CCNE1(3), CDK2(4), CDK4(2), GADD45A(1), MDM2(1), RB1(5), TP53(65)	3530085	103	73	92	12	11	22	22	16	32	0.0032	1.11e-12	9.79e-11
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(14), CDC25A(2), CDC25B(1), CDK2(4), CDK4(2), CHEK1(6), MYT1(5), RB1(5), TP53(65), WEE1(1)	3419532	105	72	94	12	9	24	22	16	34	0.0042	1.73e-11	1.33e-09
9	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(1), CDKN2A(7), MDM2(1), PIK3CA(5), PIK3R1(1), POLR1A(5), POLR1B(8), POLR1D(1), RB1(5), TP53(65), TWIST1(1)	3965073	100	66	88	11	11	18	24	16	31	0.00078	2.33e-08	1.60e-06
10	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(10), ATM(14), BAX(1), CSNK1A1(1), CSNK1D(1), GADD45A(1), HIF1A(1), IGFBP3(2), MAPK8(3), MDM2(1), NQO1(3), TP53(65)	4040280	103	69	92	13	11	24	22	13	33	0.0072	1.62e-06	0.000100

Table 7. Get Full Table A Ranked List of Significantly Mutated Genesets (Excluding Significantly Mutated Genes). Number of significant genesets found: 0. 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	P27PATHWAY	p27 blocks the G1/S transition by inhibiting the checkpoint kinase cdk2/cyclin E and is inhibited by cdk2-mediated ubiquitination.	CCNE1, CDK2, CDKN1B, CKS1B, CUL1, E2F1, NEDD8, RB1, RBX1, SKP1A, SKP2, TFDP1, UBE2M	12	CCNE1(3), CDK2(4), CDKN1B(2), CUL1(3), NEDD8(2), RB1(5), SKP2(3), TFDP1(2), UBE2M(1)	1678032	25	19	25	3	5	4	8	4	4	0.084	0.018	1
2	SKP2E2FPATHWAY	E2F-1, a transcription factor that promotes the G1/S transition, is repressed by Rb and activated by cdk2/cyclin E.	CCNA1, CCNE1, CDC34, CDK2, CUL1, E2F1, RB1, SKP1A, SKP2, TFDP1	9	CCNA1(2), CCNE1(3), CDC34(1), CDK2(4), CUL1(3), RB1(5), SKP2(3), TFDP1(2)	1675581	23	18	23	2	6	5	6	3	3	0.056	0.048	1
3	ST_INTERFERON_GAMMA_PATHWAY	The interferon gamma pathway resembles the JAK-STAT pathway and activates STAT transcription factors.	CISH, IFNG, IFNGR1, JAK1, JAK2, PLA2G2A, PTPRU, REG1A, STAT1, STATIP1	9	IFNG(3), IFNGR1(3), JAK1(5), JAK2(2), PLA2G2A(3), PTPRU(6), REG1A(5), STAT1(2)	2243697	29	22	29	3	5	6	6	5	7	0.043	0.1	1
4	IL18PATHWAY	Pro-inflammatory IL-18 is activated in macrophages by caspase-1 cleavage and, in conjunction with IL-12, stimulates Th1 cell differentiation.	CASP1, IFNG, IL12A, IL12B, IL18, IL2	6	CASP1(2), IFNG(3), IL12A(2), IL2(3)	581919	10	8	10	1	2	5	2	0	1	0.26	0.14	1
5	IFNGPATHWAY	IFN gamma signaling pathway	IFNG, IFNGR1, IFNGR2, JAK1, JAK2, STAT1	6	IFNG(3), IFNGR1(3), IFNGR2(2), JAK1(5), JAK2(2), STAT1(2)	1595988	17	14	17	2	3	1	6	3	4	0.12	0.17	1
6	FBW7PATHWAY	Cyclin E interacts with cell cycle checkpoint kinase cdk2 to allow transcription of genes required for S phase, including transcription of additional cyclin E.	CCNE1, CDC34, CDK2, CUL1, E2F1, FBXW7, RB1, SKP1A, TFDP1	8	CCNE1(3), CDC34(1), CDK2(4), CUL1(3), FBXW7(2), RB1(5), TFDP1(2)	1630818	20	15	20	2	5	4	5	3	3	0.11	0.17	1
7	RECKPATHWAY	RECK is a membrane-anchored inhibitor of matrix metalloproteinases, which are expressed by tumor cells and promote metastasis.	HRAS, MMP14, MMP2, MMP9, RECK, TIMP1, TIMP2, TIMP3, TIMP4	9	HRAS(1), MMP14(2), MMP2(6), MMP9(8), RECK(5), TIMP4(1)	1454862	23	16	23	4	3	4	7	4	5	0.24	0.21	1
8	NUCLEOTIDE_SUGARS_METABOLISM		GALE, GALT, TGDS, UGDH, UXS1	5	GALT(1), TGDS(2), UGDH(3), UXS1(4)	755037	10	9	10	2	1	2	4	0	3	0.56	0.22	1
9	SLRPPATHWAY	Small leucine-rich proteoglycans (SLRPs) interact with and reorganize collagen fibers in the extracellular matrix.	BGN, DCN, DSPG3, FMOD, KERA, LUM	5	BGN(4), DCN(1), FMOD(2), KERA(3), LUM(3)	700083	13	11	13	3	2	4	3	3	1	0.46	0.23	1
10	HSA00902_MONOTERPENOID_BIOSYNTHESIS	Genes involved in monoterpenoid biosynthesis	CYP2C19, CYP2C9	2	CYP2C19(5), CYP2C9(2)	389193	7	6	7	2	2	2	0	1	2	0.68	0.24	1

+ Methods & Data

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