Mutation Analysis (MutSig v2.0 and MutSigCV v0.9 merged result)
Glioblastoma Multiforme (Primary solid tumor)
23 September 2013  |  analyses__2013_09_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/C15D8Q5Q
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: GBM-TP

  • Number of patients in set: 283

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:GBM-TP.final_analysis_set.maf

  • Significantly mutated genes (q ≤ 0.1): 12

  • Mutations seen in COSMIC: 470

  • Significantly mutated genes in COSMIC territory: 74

  • Significantly mutated genesets: 118

Mutation Preprocessing
  • Read 283 MAFs of type "Broad"

  • Total number of mutations in input MAFs: 21510

Mutation Filtering
  • Number of mutations before filtering: 21510

  • After removing 589 mutations outside gene set: 20921

  • After removing 12 mutations outside category set: 20909

Results
Breakdown of Mutations by Type

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

type count
Frame_Shift_Del 534
Frame_Shift_Ins 206
In_Frame_Del 205
In_Frame_Ins 27
Missense_Mutation 13483
Nonsense_Mutation 808
Nonstop_Mutation 11
Silent 5240
Splice_Site 342
Translation_Start_Site 53
Total 20909
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 5501 471456280 0.000012 12 6.3 2.1
*Cp(A/C/T)->T 2408 3846173156 6.3e-07 0.63 0.34 1.7
A->G 1689 4141354039 4.1e-07 0.41 0.22 2.3
transver 3937 8458983475 4.7e-07 0.47 0.25 5
indel+null 2122 8458983475 2.5e-07 0.25 0.14 NaN
double_null 12 8458983475 1.4e-09 0.0014 0.00077 NaN
Total 15669 8458983475 1.9e-06 1.9 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: GBM-TP.patients.counts_and_rates.txt

Lego Plots

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.

Figure 3.  Get High-res Image SNV Mutation rate lego plot for entire set. Each bin is normalized by base coverage for that bin. Colors represent the six SNV types on the upper right. The three-base context for each mutation is labeled in the 4x4 legend on the lower right. The fractional breakdown of SNV counts is shown in the pie chart on the upper left. If this figure is blank, not enough information was provided in the MAF to generate it.

Figure 4.  Get High-res Image SNV Mutation rate lego plots for 4 slices of mutation allele fraction (0<=AF<0.1, 0.1<=AF<0.25, 0.25<=AF<0.5, & 0.5<=AF) . The color code and three-base context legends are the same as the previous figure. If this figure is blank, not enough information was provided in the MAF to generate it.

CoMut Plot

Figure 5.  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)->T

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

  • n4 = number of nonsilent mutations of type: transver

  • 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: 12. 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_clust p_cons p_joint p_cv p q
1 EGFR epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian) 1131442 92 74 44 7 10 44 2 32 4 0 0 0 0 2.9e-15 0 0
2 PIK3R1 phosphoinositide-3-kinase, regulatory subunit 1 (alpha) 668244 33 32 27 0 0 3 4 7 19 0 3.6e-06 0.085 4.8e-06 4.7e-15 0 0
3 BRAF v-raf murine sarcoma viral oncogene homolog B1 631073 6 6 2 1 0 1 0 5 0 0 0 0.08 0 0.043 0 0
4 IDH1 isocitrate dehydrogenase 1 (NADP+), soluble 361231 14 14 2 0 13 0 0 1 0 0 0 0.83 0 1.1e-06 0 0
5 TP53 tumor protein p53 358092 96 79 59 1 29 15 11 23 18 0 0 0 0 0 0 0
6 PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1) 337830 90 87 73 0 5 20 10 13 42 0 0.0045 0.39 0.014 2.2e-15 1.2e-15 3.7e-12
7 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 924699 33 30 28 0 5 8 7 6 7 0 0.012 0.17 0.014 7.7e-15 4.1e-15 1.1e-11
8 RB1 retinoblastoma 1 (including osteosarcoma) 752003 26 25 24 1 1 0 0 2 22 1 0.044 0.023 0.017 6.4e-15 4.1e-15 1.1e-11
9 PRB2 proline-rich protein BstNI subfamily 2 357375 6 6 2 0 0 0 0 0 6 0 0.00042 0.57 0.0015 2.5e-06 7.8e-08 0.00016
10 NF1 neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease) 2457594 30 29 30 1 0 2 1 1 21 5 0.16 0.95 0.26 4.5e-08 2.2e-07 0.0004
11 STAG2 stromal antigen 2 1110411 12 12 12 0 0 0 0 2 10 0 0.29 0.59 0.45 3.8e-07 2.8e-06 0.0046
12 CDC27 cell division cycle 27 homolog (S. cerevisiae) 715613 7 6 3 0 0 0 1 0 6 0 0.00028 0.036 0.00025 0.00073 3.1e-06 0.0046
13 WNT2 wingless-type MMTV integration site family member 2 311956 5 5 5 0 3 0 0 1 1 0 0.003 0.03 0.00066 0.013 0.00011 0.15
14 TPTE2 transmembrane phosphoinositide 3-phosphatase and tensin homolog 2 464692 8 8 6 0 2 1 0 2 3 0 0.028 0.021 0.02 0.00054 0.00013 0.17
15 GABRA6 gamma-aminobutyric acid (GABA) A receptor, alpha 6 395438 11 11 10 1 4 2 1 4 0 0 0.73 0.34 0.76 0.000018 0.00016 0.2
16 CD3EAP CD3e molecule, epsilon associated protein 427771 3 3 1 0 0 0 0 0 3 0 0.000069 0.88 0.0048 0.0074 0.0004 0.45
17 QKI quaking homolog, KH domain RNA binding (mouse) 327911 5 5 5 0 0 0 0 2 3 0 0.4 0.0052 0.028 0.0016 0.00049 0.53
18 PODXL podocalyxin-like 420137 3 3 1 0 0 0 0 0 3 0 0.0001 0.47 0.0021 0.037 0.00083 0.83
19 OGDH oxoglutarate (alpha-ketoglutarate) dehydrogenase (lipoamide) 916526 3 3 1 3 0 0 0 0 3 0 0.000076 0.16 0.00031 0.29 0.00094 0.89
20 RPL5 ribosomal protein L5 261806 7 7 7 0 0 1 1 0 5 0 0.44 0.072 0.19 0.00074 0.0014 1
21 CDKN2C cyclin-dependent kinase inhibitor 2C (p18, inhibits CDK4) 145441 3 3 3 0 0 0 0 0 3 0 0.17 0.94 0.42 0.00037 0.0015 1
22 OR5AR1 olfactory receptor, family 5, subfamily AR, member 1 264117 7 7 7 0 3 0 2 2 0 0 0.38 0.077 0.18 0.00085 0.0015 1
23 CDHR3 cadherin-related family member 3 766365 3 3 3 0 1 1 0 0 1 0 0.002 0.0097 0.00028 0.7 0.0019 1
24 PSPH phosphoserine phosphatase 197527 5 5 3 0 0 3 0 1 1 0 0.083 0.35 0.18 0.0012 0.002 1
25 ZPBP zona pellucida binding protein 282197 5 5 4 0 3 0 1 0 1 0 0.0081 0.37 0.019 0.012 0.002 1
26 TMEM147 transmembrane protein 147 198835 2 2 1 0 0 2 0 0 0 0 0.014 0.013 0.0017 0.15 0.0024 1
27 LZTR1 leucine-zipper-like transcription regulator 1 647961 10 10 10 0 4 0 1 4 1 0 0.29 0.18 0.24 0.0012 0.0027 1
28 LRRC55 leucine rich repeat containing 55 292293 6 6 6 1 4 0 0 1 1 0 0.1 0.61 0.21 0.0015 0.0029 1
29 LCE4A late cornified envelope 4A 86032 2 2 1 0 0 0 0 0 2 0 0.0099 0.74 0.38 0.00085 0.0029 1
30 POTEF POTE ankyrin domain family, member F 720525 5 5 5 1 1 0 0 4 0 0 0.0024 1 0.0033 0.098 0.0029 1
31 ZNF697 zinc finger protein 697 167111 3 3 3 0 2 0 0 0 1 0 0.18 0.04 0.048 0.0077 0.0033 1
32 UGT2A3 UDP glucuronosyltransferase 2 family, polypeptide A3 450901 6 6 6 0 1 0 2 2 1 0 0.22 0.013 0.041 0.0099 0.0036 1
33 RBM47 RNA binding motif protein 47 475159 8 8 8 3 7 0 1 0 0 0 0.0081 0.92 0.018 0.026 0.0041 1
34 OR5P2 olfactory receptor, family 5, subfamily P, member 2 274349 4 4 3 0 3 0 0 0 1 0 0.058 0.61 0.098 0.0059 0.0049 1
35 OTC ornithine carbamoyltransferase 310746 3 3 3 0 0 1 1 1 0 0 0.012 0.25 0.015 0.045 0.0056 1
EGFR

Figure S1.  This figure depicts the distribution of mutations and mutation types across the EGFR significant gene.

PIK3R1

Figure S2.  This figure depicts the distribution of mutations and mutation types across the PIK3R1 significant gene.

BRAF

Figure S3.  This figure depicts the distribution of mutations and mutation types across the BRAF significant gene.

IDH1

Figure S4.  This figure depicts the distribution of mutations and mutation types across the IDH1 significant gene.

TP53

Figure S5.  This figure depicts the distribution of mutations and mutation types across the TP53 significant gene.

PTEN

Figure S6.  This figure depicts the distribution of mutations and mutation types across the PTEN significant gene.

PIK3CA

Figure S7.  This figure depicts the distribution of mutations and mutation types across the PIK3CA significant gene.

RB1

Figure S8.  This figure depicts the distribution of mutations and mutation types across the RB1 significant gene.

NF1

Figure S9.  This figure depicts the distribution of mutations and mutation types across the NF1 significant gene.

STAG2

Figure S10.  This figure depicts the distribution of mutations and mutation types across the STAG2 significant gene.

CDC27

Figure S11.  This figure depicts the distribution of mutations and mutation types across the CDC27 significant gene.

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: 74. Number of genes displayed: 10

rank gene description n cos n_cos N_cos cos_ev p q
1 TP53 tumor protein p53 96 356 92 100748 26305 0 0
2 PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1) 90 767 88 217061 3057 0 0
3 IDH1 isocitrate dehydrogenase 1 (NADP+), soluble 14 5 14 1415 20888 5.8e-14 8.7e-11
4 PIK3R1 phosphoinositide-3-kinase, regulatory subunit 1 (alpha) 33 33 13 9339 25 3.7e-13 4.2e-10
5 PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 33 220 25 62260 5654 2.3e-12 1.6e-09
6 RB1 retinoblastoma 1 (including osteosarcoma) 26 267 17 75561 60 2.7e-12 1.6e-09
7 NF1 neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease) 30 285 11 80655 23 2.8e-12 1.6e-09
8 EGFR epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian) 92 293 70 82919 1144 2.9e-12 1.6e-09
9 BRAF v-raf murine sarcoma viral oncogene homolog B1 6 89 6 25187 71896 1.5e-11 7.4e-09
10 CHEK2 CHK2 checkpoint homolog (S. pombe) 4 2 3 566 3 1.9e-10 8.6e-08

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: 118. 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 MTORPATHWAY Mammalian target of rapamycin (mTOR) senses mitogenic factors and nutrients, including ATP, and induces cell proliferation. AKT1, EIF3S10, EIF4A1, EIF4A2, EIF4B, EIF4E, EIF4EBP1, EIF4G1, EIF4G2, EIF4G3, FKBP1A, FRAP1, MKNK1, PDK2, PDPK1, PIK3CA, PIK3R1, PPP2CA, PTEN, RPS6, RPS6KB1, TSC1, TSC2 21 AKT1(1), EIF4A1(1), EIF4B(1), EIF4G1(1), EIF4G3(1), PIK3CA(33), PIK3R1(33), PTEN(90), TSC2(3) 11773777 164 138 136 2 12 33 21 30 68 0 3.77e-15 <1.00e-15 <5.47e-14
2 G1PATHWAY CDK4/6-cyclin D and CDK2-cyclin E phosphorylate Rb, which allows the transcription of genes needed for the G1/S cell cycle transition. ABL1, ATM, ATR, CCNA1, CCND1, CCNE1, CDC2, CDC25A, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, DHFR, E2F1, GSK3B, HDAC1, MADH3, MADH4, RB1, SKP2, TFDP1, TGFB1, TGFB2, TGFB3, TP53 25 ABL1(2), ATM(4), ATR(4), CCNA1(1), CCNE1(1), CDKN1A(1), CDKN1B(1), CDKN2A(2), CDKN2B(2), GSK3B(1), RB1(26), SKP2(1), TFDP1(1), TP53(96) 12757976 143 103 104 4 31 18 15 34 44 1 3.44e-13 <1.00e-15 <5.47e-14
3 APOPTOSIS_GENMAPP APAF1, BAK1, BCL2L7P1, BAX, BCL2, BCL2L1, BID, BIRC2, BIRC3, BIRC4, CASP2, CASP3, CASP6, CASP7, CASP8, CASP9, CYCS, FADD, FAS, FASLG, GZMB, IKBKG, JUN, MAP2K4, MAP3K1, MAP3K14, MAPK10, MCL1, MDM2, MYC, NFKB1, NFKBIA, PARP1, PRF1, RELA, RIPK1, TNF, TNFRSF1A, TNFRSF1B, TNFSF10, TP53, TRADD, TRAF1, TRAF2 41 BCL2(2), BIRC2(1), BIRC3(1), CASP9(1), GZMB(2), MAP3K1(6), MCL1(1), MDM2(2), MYC(1), NFKB1(1), NFKBIA(1), PARP1(2), RIPK1(1), TNFRSF1A(1), TNFRSF1B(1), TNFSF10(2), TP53(96), TRAF1(1) 15966939 123 95 84 9 35 20 15 29 24 0 2.31e-09 <1.00e-15 <5.47e-14
4 PDGFPATHWAY Platelet-derived growth factor (PDGF) receptor is phosphorylated on ligand binding and promotes cell proliferation. CSNK2A1, ELK1, FOS, GRB2, HRAS, JAK1, JUN, MAP2K1, MAP2K4, MAP3K1, MAPK3, MAPK8, PDGFA, PDGFRA, PIK3CA, PIK3R1, PLCG1, PRKCA, PRKCB1, RAF1, RASA1, SHC1, SOS1, SRF, STAT1, STAT3, STAT5A 26 ELK1(2), FOS(1), JAK1(2), MAP2K1(1), MAP3K1(6), MAPK3(1), PDGFRA(13), PIK3CA(33), PIK3R1(33), PLCG1(6), PRKCA(1), RAF1(1), SOS1(3), SRF(1), STAT1(2), STAT3(1) 14833818 107 91 93 6 10 24 17 24 32 0 3.22e-07 <1.00e-15 <5.47e-14
5 CHEMICALPATHWAY DNA damage promotes Bid cleavage, which stimulates mitochondrial cytochrome c release and consequent caspase activation, resulting in apoptosis. ADPRT, AKT1, APAF1, ATM, BAD, BAX, BCL2, BCL2L1, BID, CASP3, CASP6, CASP7, CASP9, CYCS, EIF2S1, PRKCA, PRKCB1, PTK2, PXN, STAT1, TLN1, TP53 20 AKT1(1), ATM(4), BCL2(2), CASP9(1), PRKCA(1), PXN(1), STAT1(2), TP53(96) 11683717 108 89 71 2 30 16 13 26 23 0 1.18e-11 <1.00e-15 <5.47e-14
6 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 MAX(2), MYC(1), SP1(1), SP3(1), TP53(96), WT1(2) 2998025 103 84 66 3 30 17 11 25 20 0 1.64e-11 <1.00e-15 <5.47e-14
7 CREBPATHWAY CREB is a transcription factor that binds to cAMP-responsive elements (CREs) to activate transcription in response to extracellular signaling. ADCY1, AKT1, CAMK2A, CAMK2B, CAMK2D, CAMK2G, CREB1, GNAS, GRB2, HRAS, MAPK1, MAPK14, MAPK3, PIK3CA, PIK3R1, PRKACB, PRKACG, PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B, PRKCA, PRKCB1, RAC1, RPS6KA1, RPS6KA5, SOS1 26 ADCY1(3), AKT1(1), CAMK2A(1), CREB1(1), MAPK1(2), MAPK3(1), PIK3CA(33), PIK3R1(33), PRKAR1B(1), PRKAR2B(1), PRKCA(1), RPS6KA1(1), RPS6KA5(1), SOS1(3) 12403154 83 74 72 1 13 14 13 16 27 0 4.08e-08 <1.00e-15 <5.47e-14
8 NGFPATHWAY Nerve growth factor (NGF) stimulates neural survival and proliferation via the TrkA and p75 receptors, which induce DAG and IP3 production and activate Ras. CSNK2A1, DPM2, ELK1, FOS, GRB2, HRAS, JUN, KLK2, MAP2K1, MAPK3, MAPK8, NGFB, NGFR, PIK3CA, PIK3R1, PLCG1, RAF1, SHC1, SOS1 18 ELK1(2), FOS(1), MAP2K1(1), MAPK3(1), PIK3CA(33), PIK3R1(33), PLCG1(6), RAF1(1), SOS1(3) 8135723 81 72 70 1 8 13 14 18 28 0 6.60e-08 <1.00e-15 <5.47e-14
9 PLCPATHWAY Phospholipase C hydrolyzes the membrane lipid PIP2 to DAG, which activates protein kinase C, and IP3, which causes calcium influx. AKT1, PIK3CA, PIK3R1, PLCB1, PLCG1, PRKCA, PRKCB1, VAV1 7 AKT1(1), PIK3CA(33), PIK3R1(33), PLCB1(1), PLCG1(6), PRKCA(1), VAV1(4) 5434302 79 70 68 3 8 13 13 16 29 0 8.88e-06 <1.00e-15 <5.47e-14
10 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(4), CHEK1(3), RB1(26), TP53(96), WEE1(1), YWHAH(1) 7486740 131 95 92 2 31 15 14 28 42 1 6.87e-13 1.11e-15 5.47e-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

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.

References
[1] TCGA, Integrated genomic analyses of ovarian carcinoma, Nature 474:609 - 615 (2011)