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Cited by 5,784Endometrial and Cervical Cancer TreatmentsCancer Genomics and DiagnosticsChromatin Remodeling and Cancer

The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.

Integrated genomic characterization of endometrial carcinoma

Open access
The Cancer Genome Atlas Research Network, Levine, Douglas A.·2013·Nature
DOI 10.1038/nature12113PMC PMC3704730
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Abstract

SummaryWe 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.

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Crossref · 10.1038/nature12113

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Figures

Figure 1 SCNAs in endometrial carcinomas. a, Tumours were hierarchically clustered into four groups based on SCNAs. The heat map shows SCNAs in each tumour (horizontal axis) plotted by chromosomal location (vertical axis). Chr., chromosome. b, Kaplan–Meier curves of progression-free survival for each copy-number cluster. PowerPoint slide
Figure 1 SCNAs in endometrial carcinomas. a, Tumours were hierarchically clustered into four groups based on SCNAs. The heat map shows SCNAs in each tumour (horizontal axis) plotted by chromosomal location (vertical axis). Chr., chromosome. b, Kaplan–Meier curves of progression-free survival for each copy-number cluster. PowerPoint slideCC BY-NC-SA · PubMed Central
Figure 2 Mutation spectra across endometrial carcinomas. a, Mutation frequencies (vertical axis, top panel) plotted for each tumour (horizontal axis). Nucleotide substitutions are shown in the middle panel, with a high frequency of C-to-A transversions in the samples with POLE exonuclease mutations. CN, copy number. b, Tumours were stratified into the four groups by (1) nucleotide substitution frequencies and patterns, (2) MSI status, and (3) copy-number cluster. SNV, single nucleotide variant. c, POLE-mutant tumours have significantly better progression-free survival, whereas copy-number high tumours have the poorest outcome. d, Recurrently mutated genes are different between the four subgroups. Shown are the mutation frequencies of all genes that were significantly mutated in at least one of the four subgroups (MUSiC, asterisk denotes FDR < 0.05). PowerPoint slide
Figure 2 Mutation spectra across endometrial carcinomas. a, Mutation frequencies (vertical axis, top panel) plotted for each tumour (horizontal axis). Nucleotide substitutions are shown in the middle panel, with a high frequency of C-to-A transversions in the samples with POLE exonuclease mutations. CN, copy number. b, Tumours were stratified into the four groups by (1) nucleotide substitution frequencies and patterns, (2) MSI status, and (3) copy-number cluster. SNV, single nucleotide variant. c, POLE-mutant tumours have significantly better progression-free survival, whereas copy-number high tumours have the poorest outcome. d, Recurrently mutated genes are different between the four subgroups. Shown are the mutation frequencies of all genes that were significantly mutated in at least one of the four subgroups (MUSiC, asterisk denotes FDR < 0.05). PowerPoint slideCC BY-NC-SA · PubMed Central
Figure 3 Gene expression across integrated subtypes in endometrial carcinomas. a, Supervised analysis of ∼1,500 genes significantly associated with integrated subtypes. b, Heat map of protein expression clusters, supervised by integrated subtypes. Samples are in columns; genes or proteins are in rows. PowerPoint slide
Figure 3 Gene expression across integrated subtypes in endometrial carcinomas. a, Supervised analysis of ∼1,500 genes significantly associated with integrated subtypes. b, Heat map of protein expression clusters, supervised by integrated subtypes. Samples are in columns; genes or proteins are in rows. PowerPoint slideCC BY-NC-SA · PubMed Central
Figure 4 Pathway alterations in endometrial carcinomas. a, The RTK/RAS/β-catenin pathway is altered through several mechanisms that exhibit mutually exclusive patterns. Alteration frequencies are expressed as a percentage of all cases. The right panel shows patterns of occurrence. b, The PI(3)K pathway has mutually exclusive PIK3CA and PIK3R1 alterations that frequently co-occur with PTEN alterations in the MSI and copy-number low subgroups. c, Heat map display of top 1,000 varying pathway features within PARADIGM consensus clusters. Samples were arranged in order of their consensus cluster membership. The genomic subtype for each sample is displayed below the consensus clusters. PowerPoint slide
Figure 4 Pathway alterations in endometrial carcinomas. a, The RTK/RAS/β-catenin pathway is altered through several mechanisms that exhibit mutually exclusive patterns. Alteration frequencies are expressed as a percentage of all cases. The right panel shows patterns of occurrence. b, The PI(3)K pathway has mutually exclusive PIK3CA and PIK3R1 alterations that frequently co-occur with PTEN alterations in the MSI and copy-number low subgroups. c, Heat map display of top 1,000 varying pathway features within PARADIGM consensus clusters. Samples were arranged in order of their consensus cluster membership. The genomic subtype for each sample is displayed below the consensus clusters. PowerPoint slideCC BY-NC-SA · PubMed Central
Figure 5 Genomic relationships between endometrial serous-like, ovarian serous, and basal-like breast carcinomas. a, SCNAs for each tumour type. b, Frequency of genomic alterations present in at least 10% of one tumour type. PowerPoint slide
Figure 5 Genomic relationships between endometrial serous-like, ovarian serous, and basal-like breast carcinomas. a, SCNAs for each tumour type. b, Frequency of genomic alterations present in at least 10% of one tumour type. PowerPoint slideCC BY-NC-SA · PubMed Central

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Research works printed but not linked: 2

  1. Lax, S. F. & Kurman, R. J. A dualistic model for endometrial carcinogenesis based on immunohistochemical and molecular genetic analyses. Verh. Dtsch. Ges. Pathol. 81, 228–232 (1997)
  2. Levine, R. L. et al. PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma. Cancer Res. 58, 3254–3258 (1998)

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Metadata

Authors
The Cancer Genome Atlas Research Network, & Levine, D. A.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Levine, Douglas A.
ORCID
Levine, Douglas A.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2013-05-01
Volume
497
Issue
7447
Pages
67-73
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature12113
PMC
PMC3704730
OpenAlex
W2041440766
Cited by
5,784
References
40
Citations by year
2026: 467 · 2025: 580 · 2024: 559 · 2023: 595 · 2022: 591 · 2021: 572 · 2020: 455 · 2019: 384 · 2018: 320 · 2017: 328 · 2016: 313 · 2015: 285 · 2014: 231 · 2013: 96
FWCI
345.78
Type
journal article
Language
en
Update notices
erratum (2013-06-12)
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institutes of Health
  • National Human Genome Research Institute (U54HG003067, U54HG003079, U54HG003273)
  • National Cancer Institute (P50CA098258, U24CA143882, R01CA180006, U24CA143843, U24CA143840, U24CA143858, U24CA144025, U24CA143866, U24CA143883, U24CA143845, U24CA143867, U24CA143848, U24CA143799, U24CA143835, P30CA008748, P30CA016672, P30CA016056, P30CA016086)
Topics
  • Health Sciences › Medicine › Obstetrics and Gynecology › Endometrial and Cervical Cancer Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
endometrial cancer, uterine serous carcinoma, endometrioid carcinoma, copy number alterations, TP53 mutation, POLE mutation, microsatellite instability, ARID5B, SWI/SNF chromatin remodeling, CTNNB1, PIK3CA, KRAS, PTEN, DNA methylation, oestrogen receptor, progesterone receptor, adjuvant therapy, genomic profiling
MeSH terms
Poly-ADP-Ribose Binding Proteins, Breast Neoplasms, Chromosome Aberrations, DNA Mutational Analysis, DNA Polymerase II, DNA-Binding Proteins, Female, Humans, Ovarian Neoplasms, Transcription Factors, Signal Transduction, Genome, Human, Gene Expression Regulation, Neoplastic, Endometrial Neoplasms, Genomics, DNA Copy Number Variations, Exome

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