Amplification of GNAS may be an independent, qualitative, and reproducible biomarker to predict progression-free survival in epithelial ovarian cancer.
OBJECTIVE
The purpose of this study was to identify genes that predict progression-free survival (PFS) in advanced epithelial ovarian cancer (aEOC) receiving standard therapy.


METHODS
We performed microarray analysis on laser microdissected aEOC cells. All cases received staging laparotomy and adjuvant chemotherapy (carboplatin+paclitaxel) as primary therapy.


RESULTS
Microarray analysis identified 50 genes differentially expressed between tumors of patients with no evidence of disease (NED) or evidence of disease (ED) (p<0.001). Six genes (13%) were located at 8q24, and 9 genes (19.6%), at 20q11-13. The ratio of selected gene set/analyzed gene set in chromosomes 8 and 20 are significantly higher than that in other chromosome regions (6/606 vs. 32/13656, p=0.01) and (12/383 vs. 32/13656, p=1.3 x 10(-)(16)). We speculate that the abnormal chromosomal distribution is due to genomic alteration and that these genes may play an important role in aEOC and choose GNAS (GNAS complex locus, NM_000516) on 20q13 based on the p value and fold change. Genomic PCR of aEOC cells also showed that amplification of GNAS was significantly correlated with unfavorable PFS (p=0.011). Real-time quantitative RT-PCR analysis of independent samples revealed that high mRNA expression levels of the GNAS genes, located at chromosome 20q13, was significantly unfavorable indicators of progression-free survival (PFS). Finally, GNAS amplification was an independent prognostic factor for PFS.


CONCLUSIONS
Our results suggest that GNAS gene amplification may be an independent, qualitative, and reproducible biomarker of PFS in aEOC.
Department of Obstetrics and Gynecology, School of Medicine, Keio University, 35 Shinanomachi, Shinjyuku-ku, Tokyo, Japan.
Ei-ichiro
E
Tominaga
Hiroshi
H
Tsuda
Tokuzo
T
Arao
Sadako
S
Nishimura
Masashi
M
Takano
Fumio
F
Kataoka
Hiroyuki
H
Nomura
Akira
A
Hirasawa
Daisuke
D
Aoki
Kazuto
K
Nishio
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D016190:Carboplatin / Q000008:administration & dosage; D017024:Chemotherapy, Adjuvant; D002864:Chromogranins; D018572:Disease-Free Survival; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000096:biosynthesis / Q000235:genetics*; D005784:Gene Amplification; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D017239:Paclitaxel / Q000008:administration & dosage; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction
D014408:Biomarkers, Tumor; D002864:Chromogranins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016190:Carboplatin; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D017239:Paclitaxel