Evolutionary pathways in early-stage, non-myoinvasive endometrioid endometrial cancers of no specific molecular profile Journal Article

  


Authors: Moufarrij, S.; Lakhman, Y.; Aghajanian, C.; Abu-Rustum, N. R.; Ellenson, L. H.; Weigelt, B.; Momeni-Boroujeni, A.
Article Title: Evolutionary pathways in early-stage, non-myoinvasive endometrioid endometrial cancers of no specific molecular profile
Abstract: Objective: To characterize the genomic landscape of FIGO 2009 stage IA, non-myometrial invasive endometrioid endometrial cancers (ECs) of no specific molecular profile (NSMP) and define the earliest driver genetic alterations and subsequent tumor evolution. Methods: Early-stage (FIGO 2009 stage IA), non-myoinvasive endometrioid NSMP ECs subjected to clinical tumor-normal targeted sequencing between 2014 and 2022 were identified. ECs were dichotomized into low- and high-volume disease based on gross and histologic measurement using a cutoff of 1.8 cm3. Cancer cell fractions (CCF) of somatic mutations were determined. Results: A total of 171 noninvasive, FIGO 2009 stage I endometrioid ECs of NSMP subtype were identified, of which the majority (n = 139; 81 %) were FIGO grade 1. The median calculated volume of disease was 1.8 cm3 at diagnosis. The ECs had on average 6 pathogenic mutations, affecting known EC cancer-related genes, including PTEN (80 %), ARID1A (52 %), PIK3CA (52 %), CTNNB1 (39 %), PIK3R1 (37 %), and KRAS (29 %). Genomic alterations did not correlate with tumor volume. PTEN mutations had the highest CCFs. Unsupervised hierarchical clustering based on CCF revealed 4 main groups characterized by: 1. clonal alterations in PTEN accompanied by PIK3CA, PIK3R1, or ARID1A alterations, 2. mutations in PIK3CA co-occurring with ARID1A alterations, 3. KRAS mutations, particularly associated with 1q high-level gain, or 4. AKT1 mutations, which uniquely occurred without concurrent PTEN, PIK3CA, or PIK3R1 alterations. Conclusion: Stage IA non-myoinvasive NSMP ECs show genomic heterogeneity suggestive of multiple evolutionary pathways. Further studies are warranted to define whether this is a sign of early genomic drift. © 2024 Elsevier Inc.
Keywords: adult; controlled study; aged; gene mutation; gene sequence; major clinical study; somatic mutation; cancer staging; endometrium carcinoma; cancer grading; endometrium cancer; molecular evolution; cancer cell; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; k ras protein; beta catenin; endometrial carcinoma; tumor heterogeneity; retinoblastoma binding protein 2; human; female; article; tumor evolution; tumor-related gene
Journal Title: Gynecologic Oncology
Volume: 192
ISSN: 0090-8258
Publisher: Elsevier Inc.  
Date Published: 2025-01-01
Start Page: 8
End Page: 14
Language: English
DOI: 10.1016/j.ygyno.2024.10.029
PROVIDER: scopus
PUBMED: 39509805
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85208113945&doi=10.1016%2fj.ygyno.2024.10.029&partnerID=40&md5=982a68c288db9ad00bb6c0b2b4ab436e
Notes: PDF misspells MSK author: Yuliya Lakhman's first name The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Amir Momeni-Boroujeni -- Source: Scopus
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MSK Authors
  1. Yuliya Lakhman
    96 Lakhman
  2. Nadeem Abu-Rustum
    888 Abu-Rustum
  3. Carol A Aghajanian
    609 Aghajanian
  4. Britta Weigelt
    633 Weigelt
  5. Amir Momeni Boroujeni
    88 Momeni Boroujeni
  6. Lora Hedrick Ellenson
    109 Ellenson
  7. Sara Maria Moufarrij
    20 Moufarrij
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