PPM1D is a potential therapeutic target in ovarian clear cell carcinomas.
OBJECTIVE
To identify therapeutic targets in ovarian clear cell carcinomas, a chemoresistant and aggressive type of ovarian cancer.


METHODS
Twelve ovarian clear cell carcinoma cell lines were subjected to tiling path microarray comparative genomic hybridization and genome-wide expression profiling analysis. Regions of high-level amplification were defined and genes whose expression levels were determined by copy number and correlated with gene amplification were identified. The effects of inhibition of PPM1D were assessed using short hairpin RNA constructs and a small-molecule inhibitor (CCT007093). The prevalence of PPM1D amplification and mRNA expression was determined using chromogenic in situ hybridization and quantitative real-time reverse transcription-PCR in a cohort of pure ovarian clear cell carcinomas and on an independent series of unselected epithelial ovarian cancers.


RESULTS
Array-based comparative genomic hybridization analysis revealed regions of high-level amplification on 1q32, 1q42, 2q11, 3q24-q26, 5p15, 7p21-p22, 11q13.2-q13.4, 11q22, 17q21-q22, 17q23.2, 19q12-q13, and 20q13.2. Thirty-four genes mapping to these regions displayed expression levels that correlated with copy number gains/amplification. PPM1D had significantly higher levels of mRNA expression in ovarian clear cell carcinoma cell lines harboring gains/amplifications of 17q23.2. PPM1D inhibition revealed that PPM1D expression and phosphatase activity are selectively required for the survival of ovarian clear cell carcinoma cell lines with 17q23.2 amplification. PPM1D amplification was significantly associated with ovarian clear cell carcinoma histology (P = 0.0003) and found in 10% of primary ovarian clear cell carcinomas. PPM1D expression levels were significantly correlated with PPM1D gene amplification in primary ovarian clear cell carcinomas.


CONCLUSIONS
Our data provide strong circumstantial evidence that PPM1D is a potential therapeutic target for a subgroup of ovarian clear cell carcinomas.
Tan
David S P
DS
Department of Histopathology and Gynecologic Oncology, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Royal Marsden Hospital, London, United Kingdom.
Lambros
Maryou B K
MB
Rayter
Sydonia
S
Natrajan
Rachael
R
Vatcheva
Radost
R
Gao
Qiong
Q
Marchiò
Caterina
C
Geyer
Felipe C
FC
Savage
Kay
K
Parry
Suzanne
S
Fenwick
Kerry
K
Tamber
Narinder
N
Mackay
Alan
A
Dexter
Tim
T
Jameson
Charles
C
McCluggage
W Glenn
WG
Williams
Alistair
A
Graham
Ashley
A
Faratian
Dana
D
El-Bahrawy
Mona
M
Paige
Adam J
AJ
Gabra
Hani
H
Gore
Martin E
ME
Zvelebil
Marketa
M
Lord
Christopher J
CJ
Kaye
Stanley B
SB
Ashworth
Alan
A
Reis-Filho
Jorge S
JS
D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002886:Chromosomes, Human, Pair 17; D055028:Comparative Genomic Hybridization; D003517:Cyclopentanes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D034622:RNA Interference; D013876:Thiophenes / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C000591540:CCT007093; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D013876:Thiophenes; D048051:p38 Mitogen-Activated Protein Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C