TY - JOUR
T1 - CCNE1 and BRD4 co-amplification in high-grade serous ovarian cancer is associated with poor clinical outcomes
AU - Petersen, Shariska
AU - Wilson, Andrew J.
AU - Hirst, Jeff
AU - Roby, Katherine F.
AU - Fadare, Oluwole
AU - Crispens, Marta A.
AU - Beeghly-Fadiel, Alicia
AU - Khabele, Dineo
N1 - Funding Information:
Grant support: DK and AJW were supported in part by NIH grant R21 CA210210 . SP was supported by the Ovarian Cancer Research Alliance Ann and Sol Schreiber Mentored Investigator Award ( 600245 ) and a NIH Clinical and Translational Science Award ( TL1TR002368 ) to the University of Kansas. The Vanderbilt Translational Pathology Shared Resource is supported by NCI /NIH Cancer Center support grant 2P30 CA068485 .
Publisher Copyright:
© 2020 The Authors
PY - 2020/5
Y1 - 2020/5
N2 - Objective: High-grade serous ovarian cancer (HGSOC) is the most common and lethal histological subtype of epithelial ovarian cancer. HGSOC with cyclin E1 gene (CCNE1) amplification and bromodomain and extraterminal 4 (BRD4) amplification have been associated with poor outcomes. Our objective was to evaluate clinical outcomes of HGSOC with co-amplification of CCNE1 and BRD4 and high protein expression of cyclin E and BRD4. Methods: Copy number amplification data were extracted from The Cancer Genome Atlas (TCGA) for 579 HGSOC. Reverse phase protein array (RPPA) TCGA data were used to determine cyclin E and BRD4 protein expression in 482 HGSOC. Cyclin E and BRD4 protein expression by immunohistochemistry (IHC) was evaluated in a tissue microarray (TMA) of 110 HGSOC. Measured clinical outcomes were survival and platinum sensitivity. Results: Of 30% of HGSOC with amplifications in CCNE1 or BRD4, 8% have both CCNE1 and BRD4 amplification. Protein expression of cyclin E and BRD4 are positively correlated, both by RPPA (r = 0.23; p < 0.001) and by IHC (r = 0.21; p = 0.025). Patients with CCNE1 and BRD4 co-amplified HGSOC have worse overall survival than patients without amplifications, 39.94 vs 48.06 months (p = 0.029). High protein expression of cyclin E, but not BRD4, was associated with poor overall survival (HR 1.62, 1.04–2.53, p = 0.033) and platinum resistance (p = 0.016). Conclusion: HGSOC with CCNE1 and BRD4 co-amplification are associated with poor overall survival. Further studies are warranted to determine the use of protein expression by IHC as a surrogate marker for CCNE1 and BRD4 co-amplified HGSOC.
AB - Objective: High-grade serous ovarian cancer (HGSOC) is the most common and lethal histological subtype of epithelial ovarian cancer. HGSOC with cyclin E1 gene (CCNE1) amplification and bromodomain and extraterminal 4 (BRD4) amplification have been associated with poor outcomes. Our objective was to evaluate clinical outcomes of HGSOC with co-amplification of CCNE1 and BRD4 and high protein expression of cyclin E and BRD4. Methods: Copy number amplification data were extracted from The Cancer Genome Atlas (TCGA) for 579 HGSOC. Reverse phase protein array (RPPA) TCGA data were used to determine cyclin E and BRD4 protein expression in 482 HGSOC. Cyclin E and BRD4 protein expression by immunohistochemistry (IHC) was evaluated in a tissue microarray (TMA) of 110 HGSOC. Measured clinical outcomes were survival and platinum sensitivity. Results: Of 30% of HGSOC with amplifications in CCNE1 or BRD4, 8% have both CCNE1 and BRD4 amplification. Protein expression of cyclin E and BRD4 are positively correlated, both by RPPA (r = 0.23; p < 0.001) and by IHC (r = 0.21; p = 0.025). Patients with CCNE1 and BRD4 co-amplified HGSOC have worse overall survival than patients without amplifications, 39.94 vs 48.06 months (p = 0.029). High protein expression of cyclin E, but not BRD4, was associated with poor overall survival (HR 1.62, 1.04–2.53, p = 0.033) and platinum resistance (p = 0.016). Conclusion: HGSOC with CCNE1 and BRD4 co-amplification are associated with poor overall survival. Further studies are warranted to determine the use of protein expression by IHC as a surrogate marker for CCNE1 and BRD4 co-amplified HGSOC.
KW - BRD4
KW - CCNE1
KW - Cyclin E
KW - High-grade serous ovarian cancer
KW - Homologous recombination proficient
UR - http://www.scopus.com/inward/record.url?scp=85079045683&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2020.01.038
DO - 10.1016/j.ygyno.2020.01.038
M3 - Article
C2 - 32044108
AN - SCOPUS:85079045683
SN - 0090-8258
VL - 157
SP - 405
EP - 410
JO - Gynecologic oncology
JF - Gynecologic oncology
IS - 2
ER -