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.
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Working with individual set: BLCA-TP
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Number of patients in set: 130
The input for this pipeline is a set of individuals with the following files associated for each:
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An annotated .maf file describing the mutations called for the respective individual, and their properties.
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A .wig file that contains information about the coverage of the sample.
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MAF used for this analysis:BLCA-TP.final_analysis_set.maf
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Blacklist used for this analysis: pancan_mutation_blacklist.v14.hg19.txt
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Significantly mutated genes (q ≤ 0.1): 17
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Mutations seen in COSMIC: 216
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Significantly mutated genes in COSMIC territory: 10
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Significantly mutated genesets: 21
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Read 130 MAFs of type "Broad"
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Total number of mutations in input MAFs: 39312
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After removing 613 blacklisted mutations: 38699
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Number of mutations before filtering: 38699
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After removing 1 "impossible" mutations in
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gene-patient-category bins of zero coverage: 38698
type | count |
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Frame_Shift_Del | 512 |
Frame_Shift_Ins | 219 |
In_Frame_Del | 151 |
In_Frame_Ins | 20 |
Missense_Mutation | 24876 |
Nonsense_Mutation | 2214 |
Nonstop_Mutation | 47 |
Silent | 10012 |
Splice_Site | 590 |
Translation_Start_Site | 58 |
Total | 38699 |
category | n | N | rate | rate_per_mb | relative_rate | exp_ns_s_ratio |
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Tp*C->(T/G) | 14949 | 505003340 | 3e-05 | 30 | 3.9 | 3 |
Tp*C->A | 1104 | 505003340 | 2.2e-06 | 2.2 | 0.29 | 4 |
(A/C/G)p*C->mut | 5935 | 1437554646 | 4.1e-06 | 4.1 | 0.55 | 3.2 |
A->mut | 2944 | 1865090498 | 1.6e-06 | 1.6 | 0.21 | 3.9 |
indel+null | 3754 | 3807648484 | 9.9e-07 | 0.99 | 0.13 | NaN |
double_null | 0 | 3807648484 | 0 | 0 | 0 | NaN |
Total | 28686 | 3807648484 | 7.5e-06 | 7.5 | 1 | 3.5 |
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). If the figure is unpopulated, then full coverage is assumed (e.g. MutSig CV doesn't use WIGs and assumes full coverage).
The mutation spectrum is depicted in the lego plots below in which the 96 possible mutation types are subdivided into six large blocks, color-coded to reflect the base substitution type. Each large block is further subdivided into the 16 possible pairs of 5' and 3' neighbors, as listed in the 4x4 trinucleotide context legend. The height of each block corresponds to the mutation frequency for that kind of mutation (counts of mutations normalized by the base coverage in a given bin). The shape of the spectrum is a signature for dominant mutational mechanisms in different tumor types.
Column Descriptions:
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N = number of sequenced bases in this gene across the individual set
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n = number of (nonsilent) mutations in this gene across the individual set
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npat = number of patients (individuals) with at least one nonsilent mutation
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nsite = number of unique sites having a non-silent mutation
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nsil = number of silent mutations in this gene across the individual set
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n1 = number of nonsilent mutations of type: Tp*C->(T/G)
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n2 = number of nonsilent mutations of type: Tp*C->A
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n3 = number of nonsilent mutations of type: (A/C/G)p*C->mut
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n4 = number of nonsilent mutations of type: A->mut
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n5 = number of nonsilent mutations of type: indel+null
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n6 = number of nonsilent mutations of type: double_null
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p_cons = p-value for enrichment of mutations at evolutionarily most-conserved sites in gene
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p_joint = p-value for clustering + conservation
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p = p-value (overall)
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q = q-value, False Discovery Rate (Benjamini-Hochberg procedure)
rank | gene | description | N | n | npat | nsite | nsil | n1 | n2 | n3 | n4 | n5 | n6 | p_clust | p_cons | p_joint | p_cv | p | q |
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1 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | 423746 | 26 | 26 | 11 | 1 | 22 | 2 | 0 | 2 | 0 | 0 | 0 | 0.00012 | 0 | 3.4e-07 | 0 | 0 |
2 | TP53 | tumor protein p53 | 158975 | 75 | 64 | 50 | 1 | 19 | 0 | 34 | 4 | 18 | 0 | 0 | 0 | 0 | 5e-15 | 0 | 0 |
3 | CDKN1A | cyclin-dependent kinase inhibitor 1A (p21, Cip1) | 63890 | 18 | 18 | 17 | 0 | 1 | 0 | 2 | 0 | 15 | 0 | 0.11 | 0.46 | 0.18 | 3.7e-15 | 2.4e-14 | 1.5e-10 |
4 | RB1 | retinoblastoma 1 (including osteosarcoma) | 328495 | 19 | 17 | 17 | 0 | 2 | 1 | 0 | 1 | 15 | 0 | 0.36 | 0.72 | 0.51 | 1.9e-14 | 3.2e-13 | 1.4e-09 |
5 | ARID1A | AT rich interactive domain 1A (SWI-like) | 760474 | 38 | 32 | 36 | 2 | 10 | 1 | 0 | 1 | 26 | 0 | 0.81 | 0.72 | 1 | 2.3e-14 | 7.4e-13 | 2.7e-09 |
6 | MLL2 | myeloid/lymphoid or mixed-lineage leukemia 2 | 1849473 | 40 | 36 | 40 | 5 | 10 | 0 | 3 | 2 | 25 | 0 | 0.58 | 0.46 | 0.79 | 9.7e-14 | 2.4e-12 | 7.2e-09 |
7 | FBXW7 | F-box and WD repeat domain containing 7 | 317856 | 16 | 13 | 12 | 0 | 4 | 0 | 5 | 1 | 6 | 0 | 0.000016 | 0.023 | 3e-05 | 7.4e-09 | 6.6e-12 | 1.7e-08 |
8 | KDM6A | lysine (K)-specific demethylase 6A | 498061 | 32 | 31 | 26 | 2 | 2 | 0 | 2 | 0 | 28 | 0 | 0.22 | 0.098 | 0.2 | 2.1e-12 | 1.2e-11 | 2.8e-08 |
9 | ELF3 | E74-like factor 3 (ets domain transcription factor, epithelial-specific ) | 147808 | 15 | 11 | 14 | 0 | 3 | 0 | 2 | 1 | 9 | 0 | 0.5 | 0.37 | 0.52 | 2.3e-10 | 2.8e-09 | 5.6e-06 |
10 | FGFR3 | fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism) | 249631 | 21 | 16 | 11 | 2 | 12 | 0 | 7 | 1 | 1 | 0 | 1e-06 | 0.12 | 5e-06 | 0.000061 | 7e-09 | 0.000013 |
11 | FOXQ1 | forkhead box Q1 | 48787 | 7 | 7 | 4 | 1 | 3 | 0 | 0 | 0 | 4 | 0 | 0.23 | 0.046 | 0.11 | 1.2e-08 | 2.8e-08 | 0.000046 |
12 | STAG2 | stromal antigen 2 | 504437 | 14 | 14 | 13 | 3 | 2 | 0 | 0 | 0 | 12 | 0 | 0.13 | 0.28 | 0.21 | 4.6e-08 | 1.9e-07 | 0.00029 |
13 | NFE2L2 | nuclear factor (erythroid-derived 2)-like 2 | 231964 | 12 | 11 | 9 | 0 | 7 | 0 | 2 | 3 | 0 | 0 | 0.0023 | 0.0052 | 0.0002 | 0.00051 | 1.7e-06 | 0.0024 |
14 | CDKN2A | cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) | 96310 | 8 | 7 | 8 | 0 | 2 | 0 | 2 | 0 | 4 | 0 | 0.13 | 0.0002 | 0.00067 | 0.0044 | 0.000041 | 0.052 |
15 | KLF5 | Kruppel-like factor 5 (intestinal) | 146260 | 11 | 10 | 10 | 2 | 5 | 1 | 2 | 0 | 3 | 0 | 0.75 | 0.056 | 0.21 | 0.000018 | 5e-05 | 0.06 |
16 | ASXL2 | additional sex combs like 2 (Drosophila) | 550886 | 11 | 9 | 11 | 0 | 6 | 0 | 1 | 0 | 4 | 0 | 0.00072 | 0.0093 | 0.00028 | 0.015 | 0.000057 | 0.064 |
17 | TSC1 | tuberous sclerosis 1 | 463238 | 11 | 11 | 11 | 0 | 2 | 0 | 1 | 0 | 8 | 0 | 0.17 | 0.11 | 0.16 | 0.000034 | 0.000072 | 0.076 |
18 | ERCC2 | excision repair cross-complementing rodent repair deficiency, complementation group 2 (xeroderma pigmentosum D) | 280493 | 16 | 16 | 13 | 2 | 4 | 1 | 4 | 7 | 0 | 0 | 0.42 | 0.019 | 0.073 | 0.00011 | 0.0001 | 0.1 |
19 | TXNIP | thioredoxin interacting protein | 157040 | 12 | 9 | 12 | 2 | 3 | 1 | 2 | 1 | 5 | 0 | 0.23 | 0.034 | 0.11 | 0.000081 | 0.00011 | 0.11 |
20 | EP300 | E1A binding protein p300 | 955361 | 26 | 21 | 26 | 3 | 7 | 2 | 4 | 4 | 9 | 0 | 0.065 | 0.43 | 0.1 | 0.00015 | 0.00019 | 0.17 |
21 | RXRA | retinoid X receptor, alpha | 181152 | 12 | 12 | 6 | 2 | 6 | 2 | 3 | 1 | 0 | 0 | 0.0059 | 0.029 | 0.0027 | 0.0067 | 0.00021 | 0.18 |
22 | FOXA1 | forkhead box A1 | 135106 | 7 | 7 | 7 | 1 | 2 | 0 | 0 | 0 | 5 | 0 | 0.45 | 0.25 | 0.44 | 0.000044 | 0.00023 | 0.19 |
23 | PHLDA3 | pleckstrin homology-like domain, family A, member 3 | 43621 | 4 | 4 | 3 | 1 | 2 | 0 | 1 | 0 | 1 | 0 | 0.014 | 0.18 | 0.014 | 0.0015 | 0.00025 | 0.2 |
24 | ERBB3 | v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) | 545990 | 14 | 14 | 10 | 1 | 5 | 2 | 5 | 2 | 0 | 0 | 0.0006 | 0.64 | 0.0018 | 0.017 | 0.00035 | 0.26 |
25 | SCN10A | sodium channel, voltage-gated, type X, alpha subunit | 772958 | 7 | 4 | 7 | 2 | 3 | 1 | 0 | 1 | 2 | 0 | 0.000017 | 0.065 | 0.000048 | 1 | 0.00052 | 0.38 |
26 | CX3CL1 | chemokine (C-X3-C motif) ligand 1 | 156672 | 5 | 5 | 5 | 1 | 2 | 0 | 2 | 0 | 1 | 0 | 0.02 | 0.029 | 0.0044 | 0.016 | 0.00075 | 0.52 |
27 | MIPOL1 | mirror-image polydactyly 1 | 169688 | 7 | 7 | 6 | 1 | 5 | 0 | 0 | 0 | 2 | 0 | 0.035 | 0.23 | 0.048 | 0.0016 | 0.0008 | 0.53 |
28 | ZFP36L1 | zinc finger protein 36, C3H type-like 1 | 132732 | 6 | 6 | 6 | 0 | 0 | 0 | 1 | 2 | 3 | 0 | 0.18 | 0.81 | 0.3 | 0.0003 | 0.00093 | 0.6 |
29 | MLL3 | myeloid/lymphoid or mixed-lineage leukemia 3 | 1920318 | 30 | 27 | 30 | 3 | 13 | 1 | 4 | 2 | 10 | 0 | 0.42 | 0.2 | 0.34 | 0.00031 | 0.0011 | 0.68 |
30 | KCNK2 | potassium channel, subfamily K, member 2 | 174364 | 5 | 5 | 3 | 0 | 4 | 0 | 1 | 0 | 0 | 0 | 0.0027 | 1 | 0.0039 | 0.033 | 0.0013 | 0.77 |
31 | E2F8 | E2F transcription factor 8 | 343445 | 5 | 5 | 5 | 1 | 2 | 0 | 0 | 2 | 1 | 0 | 0.053 | 0.00024 | 0.001 | 0.15 | 0.0014 | 0.84 |
32 | RARG | retinoic acid receptor, gamma | 177817 | 11 | 10 | 11 | 3 | 4 | 0 | 3 | 2 | 2 | 0 | 0.013 | 0.42 | 0.026 | 0.0057 | 0.0015 | 0.84 |
33 | HORMAD1 | HORMA domain containing 1 | 152773 | 7 | 7 | 7 | 1 | 3 | 1 | 0 | 0 | 3 | 0 | 0.43 | 0.82 | 0.58 | 0.00026 | 0.0015 | 0.84 |
34 | MBD1 | methyl-CpG binding domain protein 1 | 262475 | 6 | 6 | 6 | 0 | 1 | 0 | 0 | 1 | 4 | 0 | 0.048 | 0.067 | 0.032 | 0.0053 | 0.0016 | 0.87 |
35 | SPTAN1 | spectrin, alpha, non-erythrocytic 1 (alpha-fodrin) | 966972 | 34 | 15 | 34 | 9 | 20 | 1 | 4 | 0 | 9 | 0 | 0.0001 | 0.26 | 0.00022 | 0.98 | 0.0021 | 1 |
In this analysis, COSMIC is used as a filter to increase power by restricting the territory of each gene. Cosmic version: v48.
rank | gene | description | n | cos | n_cos | N_cos | cos_ev | p | q |
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1 | FGFR3 | fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism) | 21 | 62 | 15 | 8060 | 10223 | 0 | 0 |
2 | TP53 | tumor protein p53 | 75 | 356 | 72 | 46280 | 19158 | 0 | 0 |
3 | PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | 26 | 220 | 21 | 28600 | 10307 | 0 | 0 |
4 | FBXW7 | F-box and WD repeat domain containing 7 | 16 | 91 | 8 | 11830 | 176 | 0 | 0 |
5 | RB1 | retinoblastoma 1 (including osteosarcoma) | 19 | 267 | 10 | 34710 | 38 | 1.9e-14 | 1.7e-11 |
6 | ERBB2 | v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) | 11 | 42 | 5 | 5460 | 16 | 9.5e-10 | 7.1e-07 |
7 | CDKN2A | cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) | 8 | 332 | 8 | 43160 | 214 | 2.3e-09 | 1.5e-06 |
8 | HRAS | v-Ha-ras Harvey rat sarcoma viral oncogene homolog | 6 | 19 | 4 | 2470 | 1325 | 4.9e-09 | 2.8e-06 |
9 | ATM | ataxia telangiectasia mutated | 19 | 245 | 7 | 31850 | 11 | 7.4e-09 | 3.7e-06 |
10 | ERBB3 | v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) | 14 | 6 | 3 | 780 | 3 | 3.4e-08 | 0.000015 |
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)
rank | geneset | description | genes | N_genes | mut_tally | N | n | npat | nsite | nsil | n1 | n2 | n3 | n4 | n5 | n6 | p_ns_s | p | q |
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1 | 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(18), DAXX(1), HRAS(6), PAX3(4), PML(3), RARA(3), RB1(19), SIRT1(1), SP100(6), TNFRSF1B(3), TP53(75) | 3649856 | 139 | 81 | 109 | 8 | 41 | 1 | 51 | 7 | 39 | 0 | 2.1e-08 | <1.00e-15 | <3.08e-13 |
2 | 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(1), CDK2(1), CDK4(2), CDKN1A(18), CDKN1B(5), CDKN2A(8), E2F1(1), E2F2(1), PRB1(1), TP53(75) | 1619397 | 114 | 76 | 88 | 5 | 28 | 0 | 39 | 5 | 42 | 0 | 2.5e-07 | <1.00e-15 | <3.08e-13 |
3 | 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), MYC(1), SP1(3), SP3(2), TP53(75), WT1(2) | 1363520 | 84 | 68 | 59 | 4 | 23 | 1 | 34 | 5 | 21 | 0 | 8.7e-06 | 3.77e-15 | 7.75e-13 |
4 | 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 | DNAJA3(1), HSPA1A(2), IFNG(1), IFNGR2(2), IKBKB(4), JAK2(2), NFKB1(1), NFKBIA(2), RB1(19), RELA(2), TNFRSF1B(3), TP53(75), USH1C(1), WT1(2) | 3492287 | 117 | 73 | 90 | 6 | 33 | 2 | 40 | 5 | 37 | 0 | 1.3e-07 | 5.11e-15 | 7.86e-13 |
5 | 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(6), DNAJC3(2), MAP3K14(2), NFKB1(1), NFKBIA(2), RELA(2), TP53(75) | 1894134 | 90 | 67 | 65 | 4 | 27 | 0 | 36 | 4 | 23 | 0 | 5e-06 | 8.44e-15 | 1.04e-12 |
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 | CDK2(1), CUL1(8), E2F1(1), FBXW7(16), RB1(19) | 1585537 | 45 | 36 | 38 | 1 | 14 | 1 | 6 | 2 | 22 | 0 | 0.0004 | 1.35e-13 | 1.38e-11 |
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(1), ATM(19), BAX(1), CCND1(1), CDK2(1), CDK4(2), CDKN1A(18), E2F1(1), GADD45A(1), PCNA(1), RB1(19), TP53(75) | 3493410 | 140 | 87 | 112 | 12 | 36 | 2 | 41 | 8 | 53 | 0 | 0.00029 | 1.65e-12 | 1.45e-10 |
8 | CELLCYCLEPATHWAY | Cyclins interact with cyclin-dependent kinases to form active kinase complexes that regulate progression through the cell cycle. | CCNA1, CCNB1, CCND1, CCND2, CCND3, CCNE1, CCNH, CDC2, CDC25A, CDK2, CDK4, CDK6, CDK7, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CDKN2D, E2F1, RB1, RBL1, TFDP1 | 22 | CCNA1(1), CCNB1(1), CCND1(1), CCND3(5), CCNH(3), CDC25A(1), CDK2(1), CDK4(2), CDK6(1), CDK7(3), CDKN1A(18), CDKN1B(5), CDKN2A(8), CDKN2B(2), CDKN2D(1), E2F1(1), RB1(19), RBL1(1) | 3072916 | 74 | 51 | 71 | 5 | 19 | 2 | 10 | 3 | 40 | 0 | 0.0021 | 5.47e-12 | 4.21e-10 |
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(4), CDKN2A(8), E2F1(1), MYC(1), PIK3CA(26), PIK3R1(2), POLR1A(5), POLR1B(1), POLR1C(1), POLR1D(2), RAC1(1), RB1(19), TBX2(3), TP53(75) | 3902579 | 149 | 79 | 107 | 12 | 57 | 4 | 40 | 9 | 39 | 0 | 8e-07 | 8.37e-12 | 5.73e-10 |
10 | RACCYCDPATHWAY | Ras, Rac, and Rho coordinate to induce cyclin D1 expression and activate cdk2 to promote the G1/S transition. | AKT1, ARHA, CCND1, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, E2F1, HRAS, MAPK1, MAPK3, NFKB1, NFKBIA, PAK1, PIK3CA, PIK3R1, RAC1, RAF1, RB1, RELA, TFDP1 | 22 | CCND1(1), CDK2(1), CDK4(2), CDK6(1), CDKN1A(18), CDKN1B(5), E2F1(1), HRAS(6), MAPK3(3), NFKB1(1), NFKBIA(2), PIK3CA(26), PIK3R1(2), RAC1(1), RAF1(1), RB1(19), RELA(2) | 3908128 | 92 | 64 | 73 | 8 | 40 | 3 | 9 | 5 | 35 | 0 | 0.001 | 1.05e-09 | 6.45e-08 |
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]
In addition to the links below, the full results of the analysis summarized in this report can also be downloaded programmatically using firehose_get, or interactively from either the Broad GDAC website or TCGA Data Coordination Center Portal.