TY - JOUR
T1 - Aneuploidy Landscape in Precursors of Ovarian Cancer
AU - Wang, Yeh
AU - Douville, Christopher
AU - Chien, Yen Wei
AU - Wang, Brant G.
AU - Chen, Chi Long
AU - Pinto, Andre
AU - Smith, Saron Ann
AU - Drapkin, Ronny
AU - Chui, M. Herman
AU - Numan, Tricia
AU - Vang, Russell
AU - Papadopoulos, Nickolas
AU - Wang, Tian Li
AU - Shih, Ie Ming
N1 - Publisher Copyright:
©2023 American Association for Cancer Research.
PY - 2024/2/1
Y1 - 2024/2/1
N2 - 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 ¼ 85), and histologically unremarkable fallopian tube epithelium (HU-FTE; control, n ¼ 65). On the basis of a discovery set (n ¼ 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 ¼ 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.
AB - 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 ¼ 85), and histologically unremarkable fallopian tube epithelium (HU-FTE; control, n ¼ 65). On the basis of a discovery set (n ¼ 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 ¼ 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.
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U2 - 10.1158/1078-0432.CCR-23-0932
DO - 10.1158/1078-0432.CCR-23-0932
M3 - Article
C2 - 38048050
AN - SCOPUS:85184135012
SN - 1078-0432
VL - 30
SP - 600
EP - 615
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -