• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Nature. Author manuscript; available in PMC Nov 2, 2013.
Published in final edited form as:
PMCID: PMC3704730
NIHMSID: NIHMS458933

Integrated Genomic Characterization of Endometrial Carcinoma

The Cancer Genome Atlas Research Network

Summary

We performed an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumors and ~25% of high-grade endometrioid tumors have extensive copy number alterations, few DNA methylation changes, low ER/PR levels, and frequent TP53 mutations. Most endometrioid tumors have few copy number alterations or TP53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, KRAS and novel mutations in the SWI/SNF gene ARID5B. A subset of endometrioid tumors we identified had a dramatically increased transversion mutation frequency, and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy number low, and copy number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may impact post-surgical adjuvant treatment for women with aggressive tumors.

Endometrial cancer arises from the lining of the uterus. It is the fourth most common malignancy among women in the United States, with an estimated 47,000 new cases and 8,000 deaths in 2012.1 Most patients present with low-grade, early-stage disease. The majority of patients with more aggressive, high-grade tumors who have disease spread beyond the uterus will progress within 1 year.2,3 Endometrial cancers have been broadly classified into two groups.4 Type I endometrioid tumors are linked to estrogen excess, obesity, hormone-receptor positivity, and favorable prognosis compared with type II, primarily serous, tumors that are more common in older, non-obese women and have worse outcome. Early-stage endometrioid cancers are often treated with adjuvant radiotherapy, whereas serous tumors are treated with chemotherapy, similar to advanced-stage cancers of either histologic subtype. Therefore, proper subtype classification is critical for selecting appropriate adjuvant therapy.

Several prior reports suggest that PTEN mutations occur early in the neoplastic process of Type I tumors and co-exist frequently with other mutations in the PI3K/AKT pathway.5,6 Other commonly mutated genes in Type I tumors include FGFR2, ARID1A, CTNNB1, PIK3CA, PIK3R1, and KRAS.79 Microsatellite instability (MSI) is found in approximately one-third of Type I tumors but is infrequent in Type II tumors.10 TP53, PIK3CA, and PPP2R1A mutations are frequent in Type II tumors.11,12 Most of these studies have been limited to DNA sequencing only with samples of heterogeneous histologic subtypes and tumor grades. We present a comprehensive, multiplatform analysis of 373 endometrial carcinomas including low-grade endometrioid, high-grade endometrioid, and serous carcinomas. This integrated analysis provides key molecular insights into tumor classification, which may have direct impact on treatment recommendations for patients, and provides opportunities for genome-guided clinical trials and drug development.

Results

Tumor samples and corresponding germline DNA were collected from 373 patients, including 307 endometrioid and 66 serous (53) or mixed histology (13) cases. Local institutional review boards approved all tissue acquisition. The clinical and pathologic characteristics of the samples generally reflect a cross-section of individuals with recurrent endometrial cancer (Supplementary Table 1.1).2,3 The median follow-up of the cohort was 32 months (range, 1–195 months); 21% of the patients have recurred, and 11% have died. Comprehensive molecular analyses were performed at independent centers using six genomic or proteomic platforms (Supplementary Table 1.2). MSI testing performed on all samples using seven repeat loci (Supplementary Table 1.3) found MSI in 40% of endometrioid tumors and 2% of serous tumors.

Somatic copy number alterations

Somatic copy number alterations (SCNAs) were assessed in 363 endometrial carcinomas. Unsupervised hierarchical clustering grouped the tumors into four clusters (Fig. 1a). The first three copy number clusters were composed almost exclusively (97%) of endometrioid tumors without significant differences in tumor grades. Cluster 1 tumors were nearly devoid of broad SCNAs, averaging less than 0.5% genome alteration, with no significant recurrent events. Cluster 1 tumors also had significantly elevated non-synonymous mutation rates compared to all others (median 7.2 × 10−6 vs. 1.7 × 10−6 mutations per megabase (Mb), P<0.001). Copy number clusters 2 and 3 consisted mainly of endometrioid tumors, distinguished by more frequent 1q amplification in cluster 3 than cluster 2 (100% of cluster 3 tumors vs. 33% of cluster 2 tumors) and worse progression-free survival (PFS, P=0.003, log-rank vs. clusters 1 and 2; Fig. 1b).

Figure 1
Somatic copy number alterations in endometrial carcinomas

Most of the serous (50 of 53 [94%]) and mixed histology tumors (8 of 13 [62%]) clustered with 36 (12%) of the 289 endometrioid tumors, including 24% of grade 3 and 5% of grade 1 or 2, into copy number cluster 4; a single group characterized by a very high degree of copy-number alterations (Supplementary Fig. 2.1; focal SCNAs with FDR < 0.15, and Supplementary Data File 2.1). Cluster 4 tumors were characterized by significantly recurrent previously reported focal amplifications of the oncogenes MYC (8q24.12), ERBB2 (17q12), and CCNE1 (19q12),13 and by SCNAs previously unreported in endometrial cancers including those containing FGFR3 (4p16.3) and SOX17 (8q11.23). Cluster 4 tumors also had frequent TP53 mutations (90%), little MSI (6%), and fewer PTEN mutations (11%) than other endometrioid tumors (84%). Overall, these findings suggest that a subset of endometrial tumors contain distinct patterns of SCNAs and mutations that do not correlate with traditional tumor histology or grade.

As expected, tumors in the ‘serous-like’ cluster (cluster 4) had significantly worse PFS than tumors in the endometrioid cluster groups (P=0.003, log-rank, Fig. 1b). Potential therapeutically relevant SCNAs included the cluster 2 15q26.2 focal amplification, which contained IGF1R; and cluster 4 amplifications of ERBB2, FGFR1, FGFR3, and LRP1B deletion, which was recently associated with resistance to liposomal doxorubicin in serous ovarian cancer.14

Exome sequence analysis

We sequenced the exomes of 248 tumor/normal pairs. Based on a combination of somatic nucleotide substitutions, MSI, and SCNA, the endometrial tumors were classified into four groups (Fig. 2a and b): 1) an ultra-mutated group with unusually high mutation rates (232×10−6 mutations/Mb) and a unique nucleotide change spectrum; 2) a hypermutated group (18×10−6 mutations/Mb) of MSI tumors, most with MLH1 promoter methylation; 3) a group with lower mutation frequency (2.9×10−6 mutations/Mb) and most of the microsatellite stable (MSS) endometrioid cancers; and 4) a group that consists primarily of serous-like cancers with extensive SCNA (copy-number cluster 4) and a low mutation rate (2.3×10−6 mutations/Mb). The ultra-mutated group consisted of 17 (7%) tumors exemplified by an increased C→A transversion frequency, all with mutations in the exonuclease domain of POLE, and an improved progression-free survival (Fig. 2a and 2c). POLE is a catalytic subunit of DNA polymerase epsilon involved in nuclear DNA replication and repair. We identified hotspot mutations in POLE at P286R and V411L present in 13 (76%) of the 17 ultramutated samples. Significantly mutated genes (SMGs) identified at low False Discovery Rates (Q) in this subset included PTEN (at 94% with Q=0), PIK3R1 (65%, Q=8.3×10−7), PIK3CA (71%, Q=9.1×10−5), FBXW7 (82%, Q=1.4×10−4), KRAS (53%, Q=9.2×10−4), and POLE (100%, Q=4.2×10−3). Mutation rates in POLE mutant endometrial and previously reported ultramutated colorectal tumors exceed that found in any other lineage including lung cancer and melanoma.1517 Germline susceptibility variants have been reported in POLE (L424V) and POLD1 (S478N), but were not found in our endometrial normal exome-seq reads.18

Figure 2
Mutation spectra across endometrial carcinomas

The MSI endometrioid tumors had a mutation frequency approximately 10-fold greater than MSS endometrioid tumors, few SCNAs, frame-shift deletions in RPL22, frequent non-synonymous KRAS mutations, and few mutations in FBXW7, CTNNB1, PPP2R1A, and TP53. The MSS, copy number low, endometrioid tumors had an unusually high frequency of CTNNB1 mutations (52%); the only gene with a higher mutation frequency than the MSI samples. The copy number high group contained all of the remaining serous cases and one-quarter of the grade 3 endometrioid cases. Most of these tumors had TP53 mutations and a high frequency of FBXW7 (22%, Q=0) and PPP2R1A (22%, Q=1.7×10−16) mutations, previously reported as common in uterine serous but not endometrioid carcinomas. Thus, a subset of high-grade endometrioid tumors had similar SCNAs and mutation spectra as uterine serous carcinomas, suggesting these patients might benefit from treatment approaches that parallel those for serous tumors.

There were 48 genes with differential mutation frequencies across the four groups (Fig. 2d, Supplementary Data File S3.1). ARID5B, a member of the same AT-rich interaction domain (ARID) family as ARID1A, was more frequently mutated in MSI (23.1%), than in either MSS endometrioid (5.6%) or high SCNA serous tumors (0%), a novel finding for endometrial cancer. Frame-shifting RPL22 indels near a homopolymer at Lys15 were almost exclusively found in the MSI group (36.9%). The TP53 mutation frequency (>90%) in serous tumors differentiates them from the endometrioid subtypes (11.4%). However, many (10 of 20; 50%) endometrioid tumors with a non-silent TP53 mutation also had non-silent mutations in PTEN, compared to only 1 of 39 (2.6%) serous tumors with TP53 non-silent mutations. Though TP53 mutations are not restricted to serous tumors, the co-existing PTEN mutations in the endometrioid cases suggest a distinct tumorigenic mechanism.

Comparisons of 66 SMGs between traditional histologic subtypes are provided (Supplementary Methods S3) and SMGs across other subcohorts can be found in Supplementary Data File S3.2. The spectrum of PIK3CA and PTEN mutations in endometrial cancer also differs from other solid tumors (Supplementary Methods S3). Integrated analysis may be useful for identifying histologically misclassified cases. For example, a single serous case was identified without a TP53 mutation or extensive SCNA and with a KRAS mutation and high mutation rate. Upon re-review of the histologic section, the case was deemed consistent with a grade 3 endometrioid tumor demonstrating how molecular analysis could reclassify tumor histology and potentially impact treatment decisions.

Multiplatform subtype classifications

All of the endometrial tumors were examined for mRNA expression (n=333), protein expression (n=293), miRNA expression (n=367), and DNA methylation (n=373) (Supplementary Methods S4–S7). Unsupervised k-means clustering of mRNA expression from RNA sequencing identified three robust clusters termed ‘mitotic’, ‘hormonal’, and ‘immunoreactive’ (Supplementary Fig. 4.1) that were significantly correlated with the four integrated clusters; POLE, MSI, CN low and CN high (P<0.0001). Supervised analysis identified signature genes of the POLE cluster (n = 17) mostly involved in cellular metabolism (Fig. 3a). Among the few signature genes in the MSI cluster was decreased MLH1 mRNA expression likely due to its promoter methylation. Elevated progesterone receptor (PGR) expression was noted in the CN low cluster, suggesting responsiveness to hormonal therapy. The CN high cluster, which included most serous and serous-like endometrioid tumors, exhibited the greatest transcriptional activity exemplified by increased cell cycle deregulation (e.g. CCNE1, PIK3CA, MYC, and CDKN2A) and TP53 mutation (Supplementary Figs. 4.2 and 4.3). This is consistent with reports that elevated CDKN2A can distinguish serous from endometrioid carcinomas.19 Approximately 85% of cases in the CN high cluster shared membership with the ‘mitotic’ mRNA subtype.

Figure 3
Gene expression across integrated subtypes in endometrial carcinomas

Supervised clustering of the RPPA expression data was consistent with loss of function for many of the mutated genes (Fig. 3b). TP53 was frequently mutated in the CN high group (P=2.5×10−27) and its protein expression was also elevated, suggesting these mutations are associated with increased expression. By contrast, PTEN (P=2.8×10−19) and ARID1A (P=1.2×10−6) had high mutation rates in the remaining groups, but their expression was decreased, suggesting inactivating mutations in both genes. The CN high group also had decreased levels of phospho-AKT, consistent with down regulation of the AKT pathway. The CN low group had elevated RAD50 expression, which is associated with DNA repair, explaining some of the differences between the CN high and CN low groups. The POLE group had high expression of ASNS and CCNB1, whereas the MSI tumors had both high phospho-AKT and low PTEN expression.

Unsupervised clustering of DNA methylation data generated from Illumina Infinium DNA methylation arrays revealed four unique subtypes (MC1-4) that support the four integrative clusters. A heavily methylated subtype (MC1) reminiscent of the CpG island methylator phenotype (CIMP) phenotype described in colon cancers and glioblastomas,2022 was associated with the MSI subtype and attributable to promoter hypermethylation of MLH1. A serous-like cluster (MC3) with minimal DNA methylation changes was composed primarily of serous tumors and some endometrioid tumors (Supplementary Fig. 7.1) and contained most of the CN high tumors.

Integrative clustering using the iCluster framework returned two major clusters split primarily on serous and endometrioid histology highlighting TP53 mutations, lack of PTEN mutation and encompassing almost exclusively CN high tumors (Supplementary Fig. 8.1).23 We developed a new clustering algorithm, called SuperCluster, to derive overall subtypes based on sample cluster memberships across all data types (Supplementary Fig. 9.1). SuperCluster identified 4 clusters that generally confirmed the contributions of individual platforms to the overall integrated clusters. No major batch effects were identified for any platform (Supplementary Methods S10).

Structural Aberrations

To identify somatic chromosomal aberrations, we performed low-pass, paired-end, whole-genome sequencing on 106 tumors with matched normals. We found recurrent translocations involving genes in several pathways including WNT, EGFR-RAS-MAPK, PI3K, Protein Kinase A, RB and apoptosis. The most frequent translocations (5/106) involved a member of the BCL family (BCL2, BCL7, BCL9 and BCL2L11). Four of these were confirmed by identification of the translocation junction point and two were also confirmed by RNA-Seq. In all cases the translocations result in in-frame fusions and predicted to result in activation or increased expression of the BCL family members (Supplementary Fig. 3.2). Translocations involving members of the BCL family leading to reduced apoptosis have been described in other tumor types24 and our results suggest that similar mechanisms may be operative here.

Pathway alterations

Multiple platform data were integrated to identify recurrently altered pathways in the four endometrial cancer integrated subgroups. Because of the high background mutation rate and small sample size, we excluded the POLE subgroup from this analysis. Considering all recurrently mutated, homozygously deleted, and amplified genes, we used MEMo25 to identify gene networks with mutually exclusive alteration patterns in each subgroup. The most significant module was found in the CN low group and contained CTNNB1, KRAS, and SOX17 (Fig. 4a). The very strong mutual exclusivity between mutations in these three genes suggests that alternative mechanisms activate WNT signaling in endometrioid endometrial cancer. Activating KRAS mutations have been shown to increase the stability of beta-catenin via GSK3beta leading to an alternative mechanism of beta-catenin activation to APC degradation.26 SOX17, which mediates proteasomal degradation of beta-catenin,27,28 is mutated exclusively in the CN low group (8%) at recurrent positions (A96G and S403I) not previously described. Other genes with mutually exclusive alteration patterns in this module were FBXW7, FGFR2, and ERBB2.29 ERBB2 was focally amplified with protein overexpression in 25% of the serous or serous-like tumors, suggesting a potential role for HER2 targeted inhibitors. A small clinical trial of trastuzumab found no activity in endometrial carcinoma, but accrued few HER2 FISH-amplified serous carcinomas.30

Figure 4
Pathway alterations in endometrial carcinomas

PIK3CA and PIK3R1 mutations were frequent and showed a strong tendency for mutual exclusivity in all subgroups, but unlike other tumor types, they co-occurred with PTEN mutations in the MSI and CN low subgroups as previously reported (Fig. 4b).5,9 The CN high subgroup showed mutual exclusivity between alterations of all three genes. Overall, 93% of endometrioid tumors had mutations that suggested potential for targeted therapy with PI3K/AKT pathway inhibitors.

Consensus clustering of copy number, mRNA expression, and pathway interaction data for 324 samples yielded 5 PARADIGM clusters with distinct pathway activation patterns (Fig. 4c, Supplementary Methods, S11).31 Paradigm cluster 1 had the lowest level of MYC pathway activation and highest level of WNT pathway activation, consistent with its composition of CN low cases having frequent CTNNB1 mutations. PARADIGM cluster 3 was composed predominantly of the CN high cases with relatively high MYC/Max but low ER/FOXA1 signaling and p53 activity. Only TP53 truncation and not missense mutations were implicated as loss-of-function mutations, suggesting different classes of p53 mutations may have distinct signaling consequences. Paradigm cluster 5 was enriched for hormone receptor expression.

Comparison to ovarian and breast cancers

The clinical and pathologic features of uterine serous carcinoma and high-grade serous ovarian carcinoma (HGSOC) are quite similar. HGSOC shares many similar molecular features with basal-like breast carcinoma.32 Focal SCNA patterns were similar between these three tumor subtypes and unsupervised clustering identified relatedness (Fig. 5a, Supplementary Fig. 12.1). Supervised analysis of transcriptome datasets showed high correlation between tumor subtypes (Supplementary Fig. 12.2). The MC3 DNA methylation subtype with minimal DNA methylation changes also was similar to basal-like breast and HGSOCs (Supplementary Fig. 12.3). High frequency of TP53 mutations is shared across these tumor subtypes (uterine serous, 91%; ovarian serous, 96%; basal-like breast, 84%),33,34 as is the very low frequency of PTEN mutations (uterine serous carcinoma, 2%; HGSOC, 1%; basal-like breast carcinoma, 1%). Differences include a higher frequency of FBXW7, PPP2R1A, and PIK3CA mutations in uterine serous compared to basal-like breast and HGSOCs (Fig. 5b). We show that uterine serous carcinomas share many molecular features with both HGSOC and basal-like breast carcinomas, despite more frequent mutations, suggesting new opportunities for overlapping treatment paradigms.

Figure 5
Genomic relationships between endometrial serous, ovarian serous, and basal-like breast carcinomas

Discussion

This integrated genomic and proteomic analysis of 373 endometrial cancers provides insights into disease biology and diagnostic classification that could have immediate therapeutic application. Our analysis identified four novel groups of tumors based on integrated genomic data, including a novel POLE subtype in ~10% of endometrioid tumors. Ultra-high somatic mutation frequency, MSS, and common, newly identified hotspot mutations in the exonuclease domain of POLE characterize this subtype. SCNAs add a layer of resolution, revealing that most endometrioid tumors have few SCNAs, most serous and serous-like tumors exhibit extensive SCNAs, and the extent of SCNA roughly correlates with PFS.

Endometrial cancer has more frequent mutations in the PI3K/AKT pathway than any other tumor type studied by TCGA to-date. Endometrioid endometrial carcinomas share many characteristics with colorectal carcinoma including a high frequency of MSI (40% and 11%, respectively), POLE mutations (7% and 3%, respectively) leading to ultrahigh mutation rates, and frequent activation of WNT/CTNNB1 signaling; yet endometrial carcinomas have novel exclusivity of KRAS and CTNNB1 mutation and a distinct mechanism of pathway activation. Uterine serous carcinomas share many similar characteristics with basal-like breast and HGSOCs; three tumor types with a high frequency non-silent TP53 mutations and extensive SCNA. However, the high frequency of PIK3CA, FBXW7, PPP2R1A, and ARID1A mutations in uterine serous carcinoma are not found in basal-like breast and HGSOCs. The frequency of mutations in PIK3CA, FBXW7, and PPP2R1A was ~30% higher than in a recently reported study of 76 uterine serous carcinomas,11 but similar to another study.12 Uterine serous carcinomas have ERBB2 amplification in 27% of tumors and PIK3CA mutations in 42%, which provide translational opportunities for targeted therapeutics.

Early stage Type I endometrioid tumors are often treated with adjuvant radiotherapy, while similarly staged Type II serous tumors are treated with chemotherapy. High-grade serous and endometrioid endometrial carcinomas are difficult to correctly subtype, and intra-observer concordance among specialty pathologists is low.7,3436 Our molecular characterization data demonstrate that ~25% of tumors classified as high-grade endometrioid by pathologists have a molecular phenotype similar to uterine serous carcinoma, including frequent TP53 mutations and extensive SCNA. The compelling similarities between this subset of endometrioid tumors and uterine serous carcinomas suggest that genomic-based classification may lead to improved management of these patients. Clinicians should carefully consider treating copy number altered endometrioid patients with chemotherapy rather than adjuvant radiotherapy and formally test such hypotheses in prospective clinical trials. Further, the marked molecular differences between endometrioid and serous-like tumors suggest that these tumors warrant separate clinical trials to develop the independent treatment paradigms that have improved outcomes in other tumor types, such as breast cancer.

Methods Summary

Biospecimens were obtained from 373 patients after institutional review board-approved consents. DNA and RNA were co-isolated using a modified AllPrep kit (Qiagen). We used Affymetrix SNP 6.0 microarrays to detect SCNA in 363 samples and GISTIC analysis to identify recurrent events.37 The exomes of 248 tumors were sequenced to a read-depth of at least 20×. We performed low-pass whole-genome sequencing on 107 tumors to a mean depth of 6×. Consensus clustering was used to analyze mRNA, miRNA, RPPA, and methylation data with methods previously described.3840 Integrated cross-platform analyses were performed using MEMo, iCluster, and PARADIGM. 25,31

Supplementary Material

Acknowledgments

We wish to thank all patients and families who contributed to this study. We thank M. Sheth and L. Lund for administrative coordination of TCGA activities, G. Monemvasitis for editing the manuscript, and C. Gunter for critical reading of the manuscript. This work was supported by the following grants from the USA National Institutes of Health: 5U24CA143799-04, 5U24CA143835-04, 5U24CA143840-04, 5U24CA143843-04, 5U24CA143845-04, 5U24CA143848-04, 5U24CA143858-04, 5U24CA143866-04, 5U24CA143867-04, 5U24CA143882-04, 5U24CA143883-04, 5U24CA144025-04, U54HG003067, U54HG003079, and U54HG003273.

Dr.First NameLast NameInstitution #1 ADD ZIPCODEInstitution #2
Dr.ChristopherAdamsThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Mr.ThomasBarrThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Mr.Aaron D.BlackThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Mr.JayBowenThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Mr.JohnDeardurffThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Ms.JessicaFrickThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Dr.Julie M.Gastier-FosterThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205The Ohio State University, Columbus, OH 43210
Mr.ThomasGrossmanThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Ms.Hollie A.HarperThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Ms.MelissaHart-KothariThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Ms.CarmenHelselThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Mr.AaronHobensackThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Ms.HarknessKeckThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Ms.KelleyKneileThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Ms.Kristen M.LeraasThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Ms.Tara M.LichtenbergThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Ms.CynthiaMcAllisterThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Dr.Robert E.PyattThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Dr.Nilsa C.RamirezThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205The Ohio State University, Columbus, OH 43210
Ms.Teresa R.TablerThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Mr.NathanVanhooseThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Dr.PeterWhiteThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Ms.LisaWiseThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Dr.ErikZmudaThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Ms.BrendaAyalaSRA International, Fairfax, VA, USA
Ms.Anna L.ChuSRA International, Fairfax, VA, USA
Dr.Mark A.JensenSRA International, Fairfax, VA, USA
Dr.PrachiKothiyalSRA International, Fairfax, VA, USA
Dr.Todd D.PihlSRA International, Fairfax, VA, USA
Dr.JoanPontiusSRA International, Fairfax, VA, USA
Dr.David A.PotSRA International, Fairfax, VA, USA
Dr.Eric E.SnyderSRA International, Fairfax, VA, USA
Mr.DeepakSrinivasanSRA International, Fairfax, VA, USA
Dr.Ari B.KahnSRA International, Fairfax, VA, USA
Dr.Daphne W.BellCancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
DrPamelaPollockInstitute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 4059, Australia
Dr.ChenWangDepartment of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905
Dr.David A.WheelerHumanGenomeSequencing Center, Baylor College ofMedicine,Houston, Texas 77030,
Dr.EveShinbrotHumanGenomeSequencing Center, Baylor College ofMedicine,Houston, Texas 77030,
Dr.Beth Y.KarlanWomen’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Dr.AndrewBerchuckDuke University Medical Center, Duke Cancer Institute, Durham, NC 27710
Dr.Sean C.DowdyDepartment of OB Gyn, Division of Gynecologic Oncology, Mayo Clinic, Rochester, MN 55905
Dr.BorisWinterhoffDepartment of OB Gyn, Division of Gynecologic Oncology, Mayo Clinic, Rochester, MN 55905
Dr.InancBirolCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Mr.Yaron S.N.ButterfieldCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Ms.RebeccaCarlsenCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Ms.CandaceCarterCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Mr.AndyChuCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Mr.EricChuahCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Ms.Hye-Jung E.ChunCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Ms.NoreenDhallaCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Mr.RanabirGuinCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Ms.CarrieHirstCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Dr.Robert A.HoltCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Prof.Steven J.M.JonesCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Ms.DarleneLeeCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Ms.Haiyan I.LiCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Prof.Marco A.MarraCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Mr.MichaelMayoCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Dr.Richard A.MooreCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Dr.Andrew J.MungallCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Mr.PatrickPlettnerCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Ms.Jacqueline E.ScheinCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Ms.PayalSipahimalaniCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Ms.AngelaTamCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Mr.Richard J.VarholCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Dr.A. GordonRobertsonCanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z, Canada
Dr.AngelaHadjipanayisDepartment of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
Dr.SeminLeeCenter for Biomedical Informatics, Harvard Medical School, Boston, MA 02115
Mr.Harshad S.MahadeshwarInstitute for Applied Cancer Science, Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054
Dr.PeterParkCenter for Biomedical Informatics, Harvard Medical School, Boston, MA 02115Informatics Program, Boston Children’s Hospital, Boston, MA 02115
Dr.AlexeiProtopopovInstitute for Applied Cancer Science, Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054
Ms.XiaojiaRenDepartment of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
Mr.SahilSethInstitute for Applied Cancer Science, Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054
Dr.XingzhiSongInstitute for Applied Cancer Science, Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054
Dr.JiabinTangInstitute for Applied Cancer Science, Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054
Dr.RuibinXiCenter for Biomedical Informatics, Harvard Medical School, Boston, MA 02115
Dr.LixingYangCenter for Biomedical Informatics, Harvard Medical School, Boston, MA 02115
Mr.DongZengInstitute for Applied Cancer Science, Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054
Dr.JianhuaZhangInstitute for Applied Cancer Science, Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054
Dr.KristinArdlieThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Dr.ScottCarterThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Mr.JeffGentryThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Mr.BryanHernandezThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Dr.MatthewMeyersonThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Mr.RobertOnofrioThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Dr.GordonSaksenaThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Mr.Steven E.SchumacherThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Dr.BarbaraTabakThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Dr.WendyWincklerThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Dr.RameenBeroukimThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Dr.ItaiPashtanHarvard Radiation Oncology Program, Brigham and Womens Hospital, Boston, MA 02115The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Dr,Helga B.SalvesenDepartment of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, NorwayDepartment of Clinical Medicine, University of Bergen, Norway
Dr.Andrew D.CherniackThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Dr.GadGetzThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Dr.Stacey B.GabrielThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Dr.J. ToddAumanEshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USAInstitute for Pharmacogenetics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Mr.SaianandBaluLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Mr.TomBodenheimerLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Ms.ElizabethBudaLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Dr.D. NeilHayesDepartment of Internal Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USALineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Mr.Alan P.HoyleLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Dr.Stuart R.JefferysLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Dr.Corbin D.JonesDepartment of Biology, University of North Carolina at Chapel Hill, NC 27599 USA
Dr.ShaowuMengLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Dr.Piotr A.MieczkowskiDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Mr.Lisle E.MoseLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Dr.Joel S.ParkerLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Dr.Charles M.PerouDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USADepartment of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, Chapel Hill, NC 27599 USA
Dr.JeffRoachResearch Computing Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Mrs.DonghuiTanLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Dr.Michael D.TopalDepartment of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, Chapel Hill, NC 27599 USALineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Dr.ScotWaringLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Mr.JunyuanWuLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Dr.Katherine A.HoadleyDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USALineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA
Dr.Stephen B.BaylinCancer Biology Division, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland 21231, USA.
Mr.Moiz S.BootwallaUniversity of Southern California Epigenome Center, University of Southern California, Los Angeles, California, 90089, USA.
Mr.Phillip H.LaiUniversity of Southern California Epigenome Center, University of Southern California, Los Angeles, California, 90089, USA.
Mr.Timothy J.Triche, Jr.University of Southern California Epigenome Center, University of Southern California, Los Angeles, California, 90089, USA.
Dr.David J.Van Den BergUniversity of Southern California Epigenome Center, University of Southern California, Los Angeles, California, 90089, USA.
Dr.Daniel J.WeisenbergerUniversity of Southern California Epigenome Center, University of Southern California, Los Angeles, California, 90089, USA.
Dr.Peter W.LairdUniversity of Southern California Epigenome Center, University of Southern California, Los Angeles, California, 90089 USA.
Ms.HuiShenUniversity of Southern California Epigenome Center, University of Southern California, Los Angeles, California, 90089, USA.
The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard
JuokChoUniversity Cambridge, Massachusetts 02142, USA.
DanielDiCaraThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
ScottFrazerThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
DavidHeimanThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
RuiJingThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
PeiLinThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
WillMallardThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
PetarStojanovThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
DougVoetThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
HaileiZhangThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Dr.LihuaZouThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
MichaelNobleThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Dr.Sheila M.ReynoldsInstitute for Systems Biology, Seattle, Washington 98109, USA
Dr.IlyaShmulevichInstitute for Systems Biology, Seattle, Washington 98109, USA
Dr.WeiZhangUniversity of Texas MD Anderson Cancer Center, Houston, TX 77054
Mr.B. ArmanAksoyComputational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Mr.YevgeniyAntipinComputational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Dr.GiovanniCirielloComputational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Mr.GideonDresdnerComputational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Dr.JianjiongGaoComputational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Dr.BenjaminGrossComputational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New
Dr.RileenSinhaComputational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Mr.S. OnurSumerComputational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Dr.Barry S.TaylorHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158
Dr.EthanCeramiComputational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Dr.NilsWeinholdComputational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Dr.NikolausSchultzComputational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Dr.RonglaiShenDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 USA
Mr.MattiAnnalaUniversity of Texas MD Anderson Cancer Center, Houston, TX 77054Tampere University of Technology Korkeakoulunkatu 10, FI-33720 Tampere, Finland
Dr.Bradley M.BroomDept. of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Mr.Tod D.CasasentDept. of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Dr.ZhenlinJuDept. of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Dr.HanLiangDept. of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Dr.GuoyanLiuUniversity of Texas MD Anderson Cancer Center, Houston, TX 77054
Dr.YilingLuDept. of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Ms.Anna K.UnruhDept. of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Mr.ChrisWakefieldDept. of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Dr.John N.WeinsteinDept. of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Dr.NianxiangZhangDept. of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Dr.YuexinLiuUniversity of Texas MD Anderson Cancer Center, Houston, TX 77054
Dr.RussellBroaddusDept. of Pathology, Unit 85 University of Texas M.D. Anderson Cancer Center 1515 Holcombe Blvd. Houston, Texas 77030
Dr.RehanAkbaniDept. of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Dr.Gordon B.MillsDept. of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Dr.StephenBenzDepartment of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Mr.TedGoldsteinDepartment of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Dr.DavidHausslerDepartment of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Mr.SamNgDepartment of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Mr.ChristopherSzetoDepartment of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Dr.JoshuaStuartDepartment of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA
Dr.Christopher CBenzBuck Institute for Age Research, Novato, California 94945, USA
Dr.ChristinaYauBuck Institute for Age Research, Novato, California 94945, USA
KristianCibulskisThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Dr.EricLanderThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Dr.AndreySivachenkoThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
CarrieSougnezThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Massachusetts 02142, USA.
Ms.MichelleO’LaughlinThe Genome Institute, Washington University, St. Louis, MO 63108
Ms.HeatherSchmidtThe Genome Institute, Washington University, St. Louis, MO 63108
Dr.Richard K.WilsonThe Genome Institute, Washington University, St. Louis, MO 63108
Dr.KaiYeThe Genome Institute, Washington University, St. Louis, MO 63108
Dr.LiDingThe Genome Institute, Washington University, St. Louis, MO 63108
Dr.CyriacKandothThe Genome Institute, Washington University, St. Louis, MO 63108
Dr.Elaine R.MardisThe Genome Institute, Washington University, St. Louis, MO 63108
Dr.GregEleyScimentis, LLC, Atlanta, GA 30666 USA
Dr.Martin L.FergusonMLF Consulting, Arlington, Maryland 02474, USA
Dr.TanjaDavidsenThe Cancer Genome Atlas Program Office, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Mr.John A.DemchokThe Cancer Genome Atlas Program Office, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Dr.Kenna R.Mills ShawThe Cancer Genome Atlas Program Office, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Ms.MargiShethThe Cancer Genome Atlas Program Office, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Dr.LimingYangThe Cancer Genome Atlas Program Office, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Dr.Mark S.GuyerNational Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Dr.Bradley A.OzenbergerNational Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Dr.Heidi J.SofiaNational Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
Dr.NanditaBarnabasAsterand, Detroit, MI 48202
Ms.CharleniaBerry-GreenAsterand, Detroit, MI 48202
Dr.VictoriaBlancAsterand, Detroit, MI 48202
Ms.LoriBoiceUniversity of North Carolina, Chapel Hill, NC 27599
Mr.MichaelButtonAsterand, Detroit, MI 48202
Mr.AdamFarkasAsterand, Detroit, MI 48202
Dr.AlexGreen, MD.Asterand, Detroit, MI 48202
Ms.JeanMacKenzieAsterand, Detroit, MI 48202
Ms.DanaNicholsonAsterand, Detroit, MI 48202
Mr.Steve E.KallogerOvCaRe British Columbia, British Columbia Cancer Agency, Vancouver British Columbia V5Z 4E6The University of British Columbia Department of Pathology & Laboratory Medicine Vancouver, British Columbia V6T 2B5
Dr.C. BlakeGilksOvCaRe British Columbia, British Columbia Cancer Agency, Vancouver British Columbia V5Z 4E6The University of British Columbia Department of Pathology & Laboratory Medicine Vancouver, British Columbia V6T 2B5
Mrs.JennyLesterWomen’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Dr.SandraOrsulicWomen’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
DrmarkborowskyHelen F Graham Cancer Center at Christiana Care, Newark, DE,19713
DrmarkcadungogHelen F Graham Cancer Center at Christiana Care, Newark, DE,19713
christineczerwinskiHelen F Graham Cancer Center at Christiana Care, Newark, DE,19713
lorihuelsenbeck-DillHelen F Graham Cancer Center at Christiana Care, Newark, DE,19713
DrmaryiacoccaHelen F Graham Cancer Center at Christiana Care, Newark, DE,19713
DrnicholaspetrelliHelen F Graham Cancer Center at Christiana Care, Newark, DE,19713
brendarabenoHelen F Graham Cancer Center at Christiana Care, Newark, DE,19713
DrgarywitkinHelen F Graham Cancer Center at Christiana Care, Newark, DE,19713
Dr.ElenaNemirovich-DanchenkoCureline, Inc., South San Francisco, CA 94080
Dr.OlgaPotapovaCureline, Inc., South San Francisco, CA 94080
Dr.DaniilRotinCureline, Inc., South San Francisco, CA 94080
Dr.MichaelBirrerHarvard Medical School, Massachusetts General Hospital Cancer Center, Boston, MA 02114
Dr.PhillipDiSaiaUniversity of California Medical Center, Irvine, Orange CA 92868 3298
Mrs.LauraMonovichGOG Tissue Bank, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205
Mrs.ErinCurleyInternaltional Genomics Consortium, Phoenix, AZ 85004
Mrs.JohannaGardnerInternaltional Genomics Consortium, Phoenix, AZ 85004
Mr.DavidMalleryInternaltional Genomics Consortium, Phoenix, AZ 85004
Mr.AttilaTeomanDepartment of OB Gyn, Division of Gynecologic Oncology, Mayo Clinic, Rochester, MN 55905
Mrs.FainaBogomolniyGynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
Ms.FannyDaoGynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
Dr.KarunaGargDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
Mr.NarcisoOlveraGynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
Dr.Robert A.SoslowDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
Dr.Douglas A.LevineGynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
Dr.MikhailAbramovN.N. Blokhin Russian Cancer Research Center RAMS, Moscow, Russia
Dr.John M.S.BartlettOntario Tumour Bank, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada
Ms.SugyKodeeswaranOntario Tumour Bank, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada
Dr.JeremyParfittOntario Tumour Bank, London Health Sciences Centre, London, Ontario N6A 5A5, Canada
Dr.FedorMoiseenkoSt. Petersburg Academic University, St. Petersburg, Russia
Dr.Blaise A.ClarkeDepartment of Pathology, University Health Network, Toronto, Ontario M5G 2C4 Canada
Dr.Michael E.CarneyUniversity of Hawaii Cancer Center, Honolulu, HI 96813
Dr.Rayna K.MatsunoUniversity of Hawaii, Honolulu HI 96813
Ms.JenniferFisherUniversity of North Carolina, Chapel Hill, NC 27599
Ms.MeiHuangUniversity of North Carolina, Chapel Hill, NC 27599
Dr.W. KimrynRathmellLineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599
Dr.LeighThorneUniversity of North Carolina, Chapel Hill, NC 27599
Dr.LindaVan LeUniversity of North Carolina, Chapel Hill, NC 27599
Dr.RajivDhirUniversity of Pittsburgh, Pittsburgh PA 15213
Dr.RobertEdwardsUniversity of Pittsburgh, Pittsburgh PA 15213
Dr.EstherElishaevUniversity of Pittsburgh, Pittsburgh PA 15213
Dr.KristinZornUniversity of Pittsburgh, Pittsburgh PA 15213
DrPaul J.GoodfellowWashington University School of Medicine, St Louis, MO.
DrDavidMutchWashington University School of Medicine, St Louis, MO.

Footnotes

The authors declare no competing financial interests. Readers are welcome to comment on the online version of the paper.

Reprints and permissions information is available at www.nature.com/reprints. This paper is distributed under the terms of the Creative Commons Attribution-Non-Commercial-Share Alike license, and the online version of the paper is freely available to all readers.

Author Contributions

The TCGA research network contributed collectively to this study. Biospecimens were provided by the tissue source sites and processed by the biospecimen core resource. Data generation and analyses were performed by the genome sequencing centers, cancer genome characterization centers and genome data analysis centers. All data were released through the data coordinating center. The National Cancer Institute and National Human Genome Research Institute project teams coordinated project activities. We also acknowledge the following TCGA investigators who made substantial contributions to the project: N.S. (manuscript coordinator); J.G. (data coordinator); C.K. and L.D. (DNA sequence analysis); W.Z. and Y.L. (mRNA sequence analysis); H.S. and P.W.L. (DNA methylation analysis); A.D.C., I.P. (copy number analysis); S.L. and A.H. (translocations); N.S., N.W. G.C., C.B, and C.Y. (pathway analysis); A.C. and A.G.R. (miRNA sequence analysis); R.B., P.J.G., G.B.M. and R.A.S. (pathology and clinical expertise); G.B.M. H.L. R.A. (reverse phase protein arrays); P.J.G. and R.B. (disease experts); G.B.M., and R.K. (manuscript editing); D.A.L. and E.R.M. (project chairs).

Supplementary Information is linked to the online version of the paper at www.nature.com/nature.

The Cancer Genome Atlas Research Network (Participants are arranged by area of contribution and then by institution.) See author list in excel spreadsheet.

The primary and processed data used to generate the analyses presented here are deposited at the Data Coordinating Center (https://tcga-data.nci.nih.gov/tcga/tcgaDownload.jsp); all of the primary sequence files are deposited in CGHub (https://cghub.ucsc.edu/). Sample lists, data matrices and supporting data can be found at: https://tcga-data.nci.nih.gov/docs/publications/ucec_2013/). The data can be explored via the cBio Cancer Genomics Portal (http://cbioportal.org).

References

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29. [PubMed]
2. Fleming GF, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2004;22:2159–2166. [PubMed]
3. Sutton G, et al. Whole abdominal radiotherapy in the adjuvant treatment of patients with stage III and IV endometrial cancer: a gynecologic oncology group study. Gynecol Oncol. 2005;97:755–763. [PubMed]
4. Lax SF, Kurman RJ. A dualistic model for endometrial carcinogenesis based on immunohistochemical and molecular genetic analyses. Verh Dtsch Ges Pathol. 1997;81:228–232. [PubMed]
5. Cheung LW, et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer discovery. 2011;1:170–185. [PMC free article] [PubMed]
6. Levine RL, et al. PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma. Cancer research. 1998;58:3254–3258. [PubMed]
7. McConechy MK, et al. Use of mutation profiles to refine the classification of endometrial carcinomas. J Pathol. 2012;228:20–30. [PMC free article] [PubMed]
8. Byron SA, et al. FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features. PLoS One. 2012;7:e30801. doi: 10.1371/journal.pone.0030801. [PMC free article] [PubMed] [Cross Ref]
9. Urick ME, et al. PIK3R1 (p85alpha) is somatically mutated at high frequency in primary endometrial cancer. Cancer research. 2011;71:4061–4067. [PMC free article] [PubMed]
10. Zighelboim I, et al. Microsatellite instability and epigenetic inactivation of MLH1 and outcome of patients with endometrial carcinomas of the endometrioid type. J Clin Oncol. 2007;25:2042–2048. [PubMed]
11. Kuhn E, et al. Identification of Molecular Pathway Aberrations in Uterine Serous Carcinoma by Genome-wide Analyses. J Natl Cancer Inst. 2012;104:1503–1513. [PMC free article] [PubMed]
12. Le Gallo M, et al. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet. 2012 doi: 10.1038/ng.2455. [PMC free article] [PubMed] [Cross Ref]
13. Salvesen HB, et al. Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proceedings of the National Academy of Sciences of the United States of America. 2009;106:4834–4839. [PMC free article] [PubMed]
14. Cowin PA, et al. LRP1B deletion in high-grade serous ovarian cancers is associated with acquired chemotherapy resistance to liposomal doxorubicin. Cancer research. 2012;72:4060–4073. [PubMed]
15. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–337. [PMC free article] [PubMed]
16. Govindan R, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 2012;150:1121–1134. [PMC free article] [PubMed]
17. Pleasance ED, et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. 2010;463:191–196. [PMC free article] [PubMed]
18. Palles C, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2012;45:136–144. [PMC free article] [PubMed]
19. Bartosch C, et al. Endometrial carcinomas: a review emphasizing overlapping and distinctive morphological and immunohistochemical features. Adv Anat Pathol. 2011;18:415–437. [PubMed]
20. Toyota M, et al. CpG island methylator phenotype in colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America. 1999;96:8681–8686. [PMC free article] [PubMed]
21. Hinoue T, et al. Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res. 2012;22:271–282. [PMC free article] [PubMed]
22. Noushmehr H, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17:510–522. [PMC free article] [PubMed]
23. Shen R, Olshen AB, Ladanyi M. Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis. Bioinformatics. 2009;25:2906–2912. [PMC free article] [PubMed]
24. Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990;348:334–336. [PubMed]
25. Ciriello G, Cerami E, Sander C, Schultz N. Mutual exclusivity analysis identifies oncogenic network modules. Genome Res. 2012;22:398–406. [PMC free article] [PubMed]
26. Li J, Mizukami Y, Zhang X, Jo WS, Chung DC. Oncogenic K-ras stimulates Wnt signaling in colon cancer through inhibition of GSK-3beta. Gastroenterology. 2005;128:1907–1918. [PubMed]
27. Zorn AM, et al. Regulation of Wnt signaling by Sox proteins: XSox17 alpha/beta and XSox3 physically interact with beta-catenin. Mol Cell. 1999;4:487–498. [PubMed]
28. Sinner D, et al. Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells. Mol Cell Biol. 2007;27:7802–7815. [PMC free article] [PubMed]
29. Pollock PM, et al. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene. 2007;26:7158–7162. [PMC free article] [PubMed]
30. Fleming GF, et al. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2010;116:15–20. [PMC free article] [PubMed]
31. Vaske CJ, et al. Inference of patient-specific pathway activities from multi-dimensional cancer genomics data using PARADIGM. Bioinformatics. 2010;26:i237–245. [PMC free article] [PubMed]
32. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70. [PMC free article] [PubMed]
33. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–615. [PMC free article] [PubMed]
34. Clarke BA, Gilks CB. Endometrial carcinoma: controversies in histopathological assessment of grade and tumour cell type. J Clin Pathol. 2010;63:410–415. [PubMed]
35. Yemelyanova A, et al. Utility of p16 expression for distinction of uterine serous carcinomas from endometrial endometrioid and endocervical adenocarcinomas: immunohistochemical analysis of 201 cases. Am J Surg Pathol. 2009;33:1504–1514. [PubMed]
36. Gilks CB, EO, Soslow RA. Poor Inter-Observer Reproducibility in the Diagnosis of High-Grade Endometrial Carcinoma. Am J Surg Pathol. 2012 in press. [PubMed]
37. Mermel CH, et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011;12:R41. [PMC free article] [PubMed]
38. Gaujoux R, Seoighe C. A flexible R package for nonnegative matrix factorization. BMC bioinformatics. 2010;11:367. [PMC free article] [PubMed]
39. Houseman EA, et al. Model-based clustering of DNA methylation array data: a recursive-partitioning algorithm for high-dimensional data arising as a mixture of beta distributions. BMC bioinformatics. 2008;9:365. [PMC free article] [PubMed]
40. Brunet JP, Tamayo P, Golub TR, Mesirov JP. Metagenes and molecular pattern discovery using matrix factorization. Proceedings of the National Academy of Sciences of the United States of America. 2004;101:4164–4169. [PMC free article] [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...