Integrated genome-wide DNA copy number and expression analysis identifies distinct mechanisms of primary chemoresistance in ovarian carcinomas.
OBJECTIVE
A significant number of women with serous ovarian cancer are intrinsically refractory to platinum-based treatment. We analyzed somatic DNA copy number variation and gene expression data to identify key mechanisms associated with primary resistance in advanced-stage serous cancers.


METHODS
Genome-wide copy number variation was measured in 118 ovarian tumors using high-resolution oligonucleotide microarrays. A well-defined subset of 85 advanced-stage serous tumors was then used to relate copy number variation to primary resistance to treatment. The discovery-based approach was complemented by quantitative-PCR copy number analysis of 12 candidate genes as independent validation of previously reported associations with clinical outcome. Likely copy number variation targets and tumor molecular subtypes were further characterized by gene expression profiling.


RESULTS
Amplification of 19q12, containing cyclin E (CCNE1), and 20q11.22-q13.12, mapping immediately adjacent to the steroid receptor coactivator NCOA3, was significantly associated with poor response to primary treatment. Other genes previously associated with copy number variation and clinical outcome in ovarian cancer were not associated with primary treatment resistance. Chemoresistant tumors with high CCNE1 copy number and protein expression were associated with increased cellular proliferation but so too was a subset of treatment-responsive patients, suggesting a cell-cycle independent role for CCNE1 in modulating chemoresponse. Patients with a poor clinical outcome without CCNE1 amplification overexpressed genes involved in extracellular matrix deposition.


CONCLUSIONS
We have identified two distinct mechanisms of primary treatment failure in serous ovarian cancer, involving CCNE1 amplification and enhanced extracellular matrix deposition. CCNE1 copy number is validated as a dominant marker of patient outcome in ovarian cancer.
Etemadmoghadam
Dariush
D
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
deFazio
Anna
A
Beroukhim
Rameen
R
Mermel
Craig
C
George
Joshy
J
Getz
Gad
G
Tothill
Richard
R
Okamoto
Aikou
A
Raeder
Maria B
MB
Harnett
Paul
P
Lade
Stephen
S
Akslen
Lars A
LA
Tinker
Anna V
AV
Locandro
Bianca
B
Alsop
Kathryn
K
Chiew
Yoke-Eng
YE
Traficante
Nadia
N
Fereday
Sian
S
Johnson
Daryl
D
Fox
Stephen
S
Sellers
William
W
Urashima
Mitsuyoshi
M
Salvesen
Helga B
HB
Meyerson
Matthew
M
Bowtell
David
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019927:Cyclin E / Q000235:genetics / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005784:Gene Amplification; D017353:Gene Deletion; D018628:Gene Dosage; D051548:Histone Acetyltransferases / Q000235:genetics / Q000502:physiology; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008875:Middle Aged; D056921:Nuclear Receptor Coactivator 3; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology
C475820:CCNE1 protein, human; D019927:Cyclin E; D019394:Ki-67 Antigen; D015513:Oncogene Proteins; D015534:Trans-Activators; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3