Genetic and molecular subtype heterogeneity in newly diagnosed early- and advanced-stage endometrial cancer Journal Article


Authors: Da Cruz Paula, A.; DeLair, D. F.; Ferrando, L.; Fix, D. J.; Soslow, R. A.; Park, K. J.; Chiang, S.; Reis-Filho, J. S.; Zehir, A.; Donoghue, M. T. A.; Wu, M.; Brown, D. N.; Murali, R.; Friedman, C. F.; Zamarin, D.; Makker, V.; Mueller, J. J.; Leitao, M. M. Jr; Abu-Rustum, N. R.; Aghajanian, C.; Weigelt, B.
Article Title: Genetic and molecular subtype heterogeneity in newly diagnosed early- and advanced-stage endometrial cancer
Abstract: Objective: To characterize and compare the molecular subtypes and profiles of prospectively-accrued newly-diagnosed early- and advanced-stage endometrial cancers (ECs). Methods: EC patients consented to an IRB-approved protocol of massively parallel sequencing of 410–468 cancer-related genes; 175 ECs of 7 histologic types (n = 135 FIGO stages I/II, n = 40 FIGO stages III/IV) were included. Previously reported sequencing data from 99 additional advanced-stage ECs were retrieved for comparisons. Results: Irrespective of histologic type, all 175 ECs could be stratified into the molecular subtypes, with 75 (43%) being of p53 wild-type, 49 (28%) MMR-deficient, 39 (22%) p53 abnormal and 12 (7%) of POLE molecular subtypes. Subtype distribution, mutational and copy number profiles varied according to histologic type. In endometrioid ECs, genetic alterations varied according to histologic grade. Potential therapeutic targets, including high tumor mutational burden, ERBB2 amplification and PIK3CA hotspot mutations, were found across histologic types in 63% (n = 110) of all ECs. Compared to their early-stage counterparts, advanced-stage endometrioid ECs had a significantly higher fraction of genome altered (median 0.1% vs 12%, p < 0.001) and ARID1B mutations (0% vs 11%, p = 0.01), and advanced-stage serous ECs harbored more frequent ERBB2 amplification (18% vs 8%, p > 0.05) and PIK3CA mutations (46% vs 27%, p > 0.05). Whole-genome doubling was found in advanced- but not early-stage carcinosarcomas and clear cell carcinomas. Conclusions: Our findings demonstrate the molecular heterogeneity within and across histologic types of EC and the increased genomic complexity of advanced-stage ECs. Molecular subtypes are present across EC histologic types and may help stratify EC patients for prognostic and therapeutic purposes. © 2021 Elsevier Inc.
Keywords: endometrial cancer; massively parallel sequencing; molecular subtypes; whole-genome duplication
Journal Title: Gynecologic Oncology
Volume: 161
Issue: 2
ISSN: 0090-8258
Publisher: Elsevier Inc.  
Date Published: 2021-05-01
Start Page: 535
End Page: 544
Language: English
DOI: 10.1016/j.ygyno.2021.02.015
PUBMED: 33622519
PROVIDER: scopus
PMCID: PMC8085053
DOI/URL:
Notes: Article -- Export Date: 3 May 2021 -- Source: Scopus
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MSK Authors
  1. Vicky Makker
    139 Makker
  2. Mario Leitao
    433 Leitao
  3. Dmitriy Zamarin
    130 Zamarin
  4. Kay Jung Park
    245 Park
  5. Robert Soslow
    747 Soslow
  6. Ahmet Zehir
    281 Zehir
  7. Rajmohan Murali
    191 Murali
  8. Deborah F DeLair
    104 DeLair
  9. Britta Weigelt
    420 Weigelt
  10. Jorge Sergio Reis
    471 Reis
  11. Jennifer Jean Mueller
    94 Mueller
  12. Sarah   Chiang
    89 Chiang
  13. Daniel Jonas Fix
    10 Fix
  14. David Norman Brown
    55 Brown
  15. Michelle Wu
    7 Wu