Aneuploidy Landscape in Precursors of Ovarian Cancer

Yeh Wang, Christopher Douville, Yen-Wei Chien, Brant G Wang, Chi-Long Chen, Andre Pinto, Saron Ann Smith, Ronny Drapkin, M Herman Chui, Tricia Numan, Russell Vang, Nickolas Papadopoulos, Tian-Li Wang, Ie-Ming Shih, Chien Chien

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

PURPOSE: Serous tubal intraepithelial carcinoma (STIC) is now recognized as the main precursor of ovarian high-grade serous carcinoma (HGSC). Other potential tubal lesions include p53 signatures and tubal intraepithelial lesions. We aimed to investigate the extent and pattern of aneuploidy in these epithelial lesions and HGSC to define the features that characterize stages of tumor initiation and progression.

EXPERIMENTAL DESIGN: We applied RealSeqS to compare genome-wide aneuploidy patterns among the precursors, HGSC (cases, n = 85), and histologically unremarkable fallopian tube epithelium (HU-FTE; control, n = 65). On the basis of a discovery set (n = 67), we developed an aneuploidy-based algorithm, REAL-FAST (Repetitive Element AneupLoidy Sequencing Fallopian Tube Aneuploidy in STIC), to correlate the molecular data with pathology diagnoses. We validated the result in an independent validation set (n = 83) to determine its performance. We correlated the molecularly defined precursor subgroups with proliferative activity and histology.

RESULTS: We found that nearly all p53 signatures lost the entire Chr17, offering a "two-hit" mechanism involving both TP53 and BRCA1 in BRCA1 germline mutation carriers. Proliferatively active STICs harbor gains of 19q12 (CCNE1), 19q13.2, 8q24 (MYC), or 8q arm, whereas proliferatively dormant STICs show 22q loss. REAL-FAST classified HU-FTE and STICs into 5 clusters and identified a STIC subgroup harboring unique aneuploidy that is associated with increased proliferation and discohesive growth. On the basis of a validation set, REAL-FAST showed 95.8% sensitivity and 97.1% specificity in detecting STIC/HGSC.

CONCLUSIONS: Morphologically similar STICs are molecularly distinct. The REAL-FAST assay identifies a potentially "aggressive" STIC subgroup harboring unique DNA aneuploidy that is associated with increased cellular proliferation and discohesive growth. REAL-FAST offers a highly reproducible adjunct technique to assist the diagnosis of STIC lesions.

Original languageEnglish
Pages (from-to)600-615
Number of pages16
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Volume30
Issue number3
DOIs
Publication statusPublished - Feb 1 2024

Keywords

  • Humans
  • Female
  • Tumor Suppressor Protein p53/genetics
  • Ovarian Neoplasms/pathology
  • Cystadenocarcinoma, Serous/genetics
  • Fallopian Tubes/pathology
  • Fallopian Tube Neoplasms/genetics
  • Carcinoma in Situ/pathology

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