Integrated genomic characterization of endometrial carcinoma

  title={Integrated genomic characterization of endometrial carcinoma},
  author={Douglas A. Levine and Gad Stacey B. Kristian Eric Andrey Carrie Mike Cyriac Getz Gabriel Cibulskis Lander Sivachenko Sougnez L and Gad Getz and S. Gabriel and Kristian Cibulskis and Eric S. Lander and Andrey Y. Sivachenko and Carrie Sougnez and Mike S Lawrence and Cyriac Kandoth and David J. Dooling and Robert S. Fulton and Lucinda Fulton and Joelle M. Kalicki-Veizer and Michael D. McLellan and Michelle D. O'Laughlin and Heather K. Schmidt and Richard K. Wilson and Kai Ye and Li Ding and Elaine R. Mardis and Adrian Ally and Miruna Balasundaram and Inanç Birol and Yaron S. N. Butterfield and Rebecca Carlsen and Candace D. Carter and Andy Chu and Eric Chuah and Hye-Jung E. Chun and Noreen Dhalla and Ranabir Guin and Carrie Hirst and Robert A. Holt and Steven J. M. Jones and Darlene Lee and Haiyan I. Li and Marco A. Marra and Michael Mayo and Richard A. Moore and Andrew J. Mungall and Patrick Plettner and Jacqueline E. Schein and Payal Sipahimalani and Angela Tam and Richard Varhol and A. Gordon Robertson and Andrew D. Cherniack and Itai M. Pashtan and Gordon Saksena and Roberto Onofrio and Steven E Schumacher and Barbara Tabak and Scott L. Carter and Bryan Hernandez and Jeff Gentry and Helga Birgitte Salvesen and Kristin G. Ardlie and Wendy Winckler and Rameen Beroukhim and Matthew L Meyerson and Angela Hadjipanayis and Semin Lee and Harshad S. Mahadeshwar and Peter J. Park and Alexei Protopopov and Xiaojia Ren and Sahil Seth and Xingzhi Song and Jiabin Tang and Ruibin Xi and Lixing Yang and Dong-zhu Zeng and Raju Kucherlapati and Lynda Chin and Jianhua Zhang and J. Todd Auman and Saianand Balu and Tom Bodenheimer and Elizabeth Buda and David Neil Hayes and Alan Hoyle and Stuart R. Jefferys and Corbin D. Jones and Shaowu Meng and Piotr A. Mieczkowski and Lisle E. Mose and Joel S. Parker and Charles M. Perou and Jeff Roach and Yan Shi and Janae V. Simons and Mathew G. Soloway and Donghui Tan and Michael D. Topal and Scot Michael Waring and Junyuan Wu and Katherine A. Hoadley and Stephen B. Baylin and Moiz S. Bootwalla and Phillip H. Lai and Timothy J. Triche Jr and David J. Van Den Berg and Daniel J. Weisenberger and Peter W. Laird and Hui Shen and Juok Cho and Danielle M. Dicara and Scott R. Frazer and David I. Heiman and Rui Jing and Pei Lin and William Mallard and Petar Stojanov and Douglas Voet and Hailei Zhang and Lihua Zou and Michael S. Noble and Sheila M. Reynolds and Ilya Shmulevich and B{\"u}lent Arman Aksoy and Yevgeniy Antipin and Giovanni Domenico Ciriello and Gideon Dresdner and Jianjiong Gao and Benjamin E. Gross and Anders S. Jacobsen and Marc Ladanyi and Boris Reva and Chris Sander and Rileen Sinha and Selcuk Onur Sumer and Barry S. Taylor and Ethan G. Cerami and Nils Weinhold and Nikolaus D. Schultz and Ronglai Shen and Stephen Charles Benz and Theodore Goldstein and David Haussler and Sam Ng and Christopher Szeto and Joshua M. Stuart and Christopher C. Benz and Christina Yau and Wei Zhang and Matti Annala and Bradley M. Broom and Tod D. Casasent and Zhenlin Ju and Han Liang and Guoyan Liu and Yiling Lu and Anna Unruh and Chris Wakefield and John N. Weinstein and Nianxiang Zhang and Yuexin Liu and Russell Broaddus and Rehan Akbani and Gordon B. Mills and Christopher Adams and Thomas Barr and Aaron D. Black and Jay Bowen and John Deardurff and Jessica Frick and Julie M. Gastier-Foster and Tom Grossman and Hollie A. Harper and Melissa Hart-Kothari and Carmen Helsel and Aaron Hobensack and Harkness C Kuck and Kelley Kneile and Kristen Leraas and Tara M. Lichtenberg and Cynthia Mcallister and Robert Pyatt and Nilsa C. Ramirez and Teresa R. Tabler and Nathan Vanhoose and Peter White and Lisa Wise and E J Zmuda and Nandita Barnabas and Charlenia Berry-Green and Victoria M. Blanc and L. Peter Boice and Michael Button and {\'A}d{\'a}m Farkas and Alex Green and J Mackenzie and Dana Nicholson and Steve E Kalloger and C. Blake Gilks and Beth Y. Karlan and Jenny Lester and Sandra Orsulic and Mark E. Borowsky and Mark G. Cadungog and Christine Czerwinski and Lori Huelsenbeck-Dill and Mary V. Iacocca and Nicholas Petrelli and Brenda Rabeno and Gary Witkin and Elena Nemirovich-Danchenko and Olga Potapova and Daniil Rotin and Andrew Berchuck and Michael Birrer and P J Disaia and Laura Monovich and Erin E. Curley and Johanna Gardner and David W Mallery and Robert J. Penny and Sean C. Dowdy and Boris J. Winterhoff and Linda N. Dao and Bobbie S. Gostout and Alexandra Meuter and Attila Teoman and Fanny Dao and Narciso Olvera and Faina Bogomolniy and Karuna Garg and Robert A. Soslow and Douglas A. Levine and Mikhail Abramov and John M. S. Bartlett and S. Kodeeswaran and Jeremy R. Parfitt and Fedor V. Moiseenko and Blaise Alexander Clarke and Marc T. Goodman and Michael E. Carney and Rayna K. Matsuno and Jennifer C. Fisher and M N Huang and W. Kimryn Rathmell and Leigh B. Thorne and Linda Van Le and Rajiv Dhir and Robert Edwards and Esther Elishaev and Kristin K. Zorn and Paul J. Goodfellow and David G. Mutch and Ari B. Kahn and Daphne W Bell and Pamela M Pollock and Chen Wang and David A.Wheeler and Eve Shinbrot and Brenda Ayala and Anna L. Chu and Mark A. Jensen and Prachi Kothiyal and Todd Pihl and Joan U. Pontius and D. Pot and E. E. Snyder and Deepak Srinivasan and Kenna R. Mills Shaw and Margi Sheth and Tanja Davidsen and Greg Eley Martin L. Ferguson and John A. Demchok and Liming Yang and Mark Guyer and Bradley A Ozenberger and Heidi J. Sofia},
  pages={67 - 73}
  • D. LevineGad Stacey B. Kristian Eric Andrey Carrie Mike Cyriac Getz Gabriel Cibulskis Lander Sivachenko Sougnez L H. Sofia
  • Published 1 May 2013
  • Biology, Medicine
  • Nature
We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1… 

Clinicopathologic and Genomic Analysis of TP53-Mutated Endometrial Carcinomas

Although overall survival was similar across histologic types, serous carcinomas presented more frequently at stage IV, had more persistent and/or recurrent disease, and reduced disease-free survival, providing evidence to suggest performance of ERBB2 assessment in all TP53-mutated endometrial carcinomas.

Endometrial Carcinoma: Molecular Cytogenetics and Transcriptomic Profile

It is confirmed that a high degree of genetic heterogeneity characterizes EC tumors but highlights the nonrandom involvement of some loci, and some other genes and miRNAs of known importance in carcinogenesis and the immune response showed consistent deregulation.

Molecular characterization of endometrial cancer and therapeutic implications

The emerging comprehensive genomic classification of endometrial carcinoma is reviewed and mutational profiles that classify as copy-number high/‘serous-like’ and might benefit from treatment approaches similar to those for serous tumors are discussed.

An integrated molecular profile of endometrioid ovarian cancer.

Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma

For the first time, it is shown that mutations in chromatin remodelling‐related genes and in DNA‐repair‐ related genes are frequent in this subtype of endometrial cancer, highlighting the possible implication of these genes in this disease, creating opportunities for new therapeutic approaches.

Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas

Evaluation of HRD may help select patients that could benefit from treatments targeting this defect, including platinum compounds and PARP inhibitors, and is largely restricted to non-endometrioid, TP53-mutant endometrial cancers.

The genetic landscape of endometrial clear cell carcinomas

All molecular subtypes previously identified in endometrial endometrioid and serous carcinomas were present in the ECCs studied, including POLE, MMR‐deficient, copy‐ number high (serous‐like)/p53 abnormal, and copy‐number low (endometrioids)/p 53 wild‐type, which were significantly associated with disease‐free survival in univariate analysis.



Comprehensive molecular characterization of human colon and rectal cancer

Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.

Integrated Genomic Analyses of Ovarian Carcinoma

It is reported that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1,BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes.

Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation

An integrated analysis of genome-wide expression and copy-number data for primary endometrial carcinomas with extensive clinical and histopathological data distinguished 2 major clusters with strikingly different phenotypes, including significant differences in disease-free survival.

Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses.

  • E. KuhnR. Wu I. Shih
  • Medicine, Biology
    Journal of the National Cancer Institute
  • 2012
Molecular genetic aberrations involving the p53, cyclin E-FBXW7, and PI3K pathways represent major mechanisms in the development of uterine serous carcinoma.

Comprehensive molecular portraits of human breast tumors

The ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity.

Use of mutation profiles to refine the classification of endometrial carcinomas

Target enrichment sequencing on 393 endometrial carcinomas from two large cohorts suggested that the original morphological classification was incorrect in most instances, and a nine‐gene panel may prove useful as an adjunct to Morphological classification and serve as an aid in the classification of problematic cases.

Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes

High frequencies of somatic mutations are identified in CHD4, EP300, ARID1A, TSPYL2, FBXW7, SPOP, MAP3K4, and ABCC9, implicating frequent mutational disruption of these processes in the molecular pathogenesis of one of the deadliest forms of endometrial cancer.

Genome-scale analysis of aberrant DNA methylation in colorectal cancer.

Four DNA methylation-based subgroups of CRC are identified using model-based cluster analyses and novel insight is provided regarding the role of CIMP-specific DNA hypermethylation in gene silencing.

Microsatellite instability and epigenetic inactivation of MLH1 and outcome of patients with endometrial carcinomas of the endometrioid type.

MSI is not associated with survival in patients with endometrioid endometrial cancer, and associations with clinicopathologic variables and survival outcomes were evaluated.