The genetic landscape of endometrial clear cell carcinomas Journal Article


Authors: DeLair, D. F.; Burke, K. A.; Selenica, P.; Lim, R. S.; Scott, S. N.; Middha, S.; Mohanty, A. S.; Cheng, D. T.; Berger, M. F.; Soslow, R. A.; Weigelt, B.
Article Title: The genetic landscape of endometrial clear cell carcinomas
Abstract: Clear cell carcinoma of the endometrium is a rare type of endometrial cancer that is generally associated with an aggressive clinical behaviour. Here, we sought to define the repertoire of somatic genetic alterations in endometrial clear cell carcinomas (ECCs), and whether ECCs could be classified into the molecular subtypes described for endometrial endometrioid and serous carcinomas. We performed a rigorous histopathological review, immunohistochemical analysis and massively parallel sequencing targeting 300 cancer-related genes of 32 pure ECCs. Eleven (34%), seven (22%) and six (19%) ECCs showed abnormal expression patterns for p53, ARID1A, and at least one DNA mismatch repair (MMR) protein, respectively. Targeted sequencing data were obtained from 30 of the 32 ECCs included in this study, and these revealed that two ECCs (7%) were ultramutated and harboured mutations affecting the exonuclease domain of POLE. In POLE wild-type ECCs, TP53 (46%), PIK3CA (36%), PPP2R1A (36%), FBXW7 (25%), ARID1A (21%), PIK3R1 (18%) and SPOP (18%) were the genes most commonly affected by mutations; 18% and 11% harboured CCNE1 and ERBB2 amplifications, respectively, and 11% showed DAXX homozygous deletions. ECCs less frequently harboured mutations affecting CTNNB1 and PTEN but more frequently harboured PPP2R1A and TP53 mutations than non-POLE endometrioid carcinomas from The Cancer Genome Atlas (TCGA). Compared to endometrial serous carcinomas (TCGA), ECCs less frequently harboured TP53 mutations. When a surrogate model for the molecular-based TCGA classification was used, 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 (endometrioid)/p53 wild-type, which were significantly associated with disease-free survival in univariate analysis. These findings demonstrate that ECCs constitute a histologically and genetically heterogeneous group of tumours with varying outcomes. Furthermore, our data suggest that the classification of ECCs as being generally ‘high-grade’ or ‘type II’ tumours may not be warranted. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Keywords: massively parallel sequencing; somatic mutations; molecular classification; copy number alterations; endometrial clear cell carcinoma
Journal Title: Journal of Pathology
Volume: 243
Issue: 2
ISSN: 0022-3417
Publisher: Wiley Blackwell  
Date Published: 2017-10-01
Start Page: 230
End Page: 241
Language: English
DOI: 10.1002/path.4947
PROVIDER: scopus
PUBMED: 28718916
PMCID: PMC5708127
DOI/URL:
Notes: Article -- Export Date: 2 October 2017 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Robert Soslow
    655 Soslow
  2. Michael Forman Berger
    412 Berger
  3. Deborah F DeLair
    91 DeLair
  4. Britta Weigelt
    269 Weigelt
  5. Donavan Tai Suan Cheng
    51 Cheng
  6. Sasinya Neka Scott
    67 Scott
  7. Raymond Sear Lim
    55 Lim
  8. Abhinita Subhadarshin Mohanty
    18 Mohanty
  9. Sumit   Middha
    60 Middha
  10. Kathleen   Burke
    55 Burke