Identification of candidate epigenetic biomarkers for ovarian cancer detection.
Ovarian cancer ranks the most lethal among gynecologic neoplasms in women. To develop potential biomarkers for diagnosis, we have identified five novel genes (CYP39A1, GTF2A1, FOXD4L4, EBP, and HAAO) that are hypermethylated in ovarian tumors, compared with the non-malignant normal ovarian surface epithelia, using the quantitative methylation-specific polymerase chain reactions. Interestingly enough, multivariate Cox regression analysis has identified hypermethylation of CYP39A1 correlated with an increase rate of relapsing (P=0.032, hazard ratio >1). Concordant hypermethylation in at least three loci was observed in 50 out of 55 (91%) of ovarian tumors examined. The test sensitivity and specificity were assessed to be 96 and 67% for CYP39A1; 95 and 88% for GTF2A1; 93 and 67% for FOXD4L4; 81 and 67% for EBP; 89 and 82% for HAAO, respectively. Our data have identified, for the first time, GTF2A1 alone, or GTF2A1 plus HAAO are excellent candidate biomarkers for detecting this disease. Moreover, the known functions of these gene products further implicate dysregulated transcriptional control, cholesterol metabolism, or synthesis of quinolinic acids, may play important roles in attributing to ovarian neoplasm. Molecular therapies, by reversing the aberrant epigenomes using inhibitory agents or by abrogating the upstream signaling pathways that convey the epigenomic perturbations, may be developed into promising treatment regimens.
Huang
Yi-Wen
YW
Molecular Biology and Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Jansen
Rachel A
RA
Fabbri
Enrica
E
Potter
Dustin
D
Liyanarachchi
Sandya
S
Chan
Michael W Y
MW
Liu
Joseph C
JC
Crijns
Anne P G
AP
Brown
Robert
R
Nephew
Kenneth P
KP
van der Zee
Ate G J
AG
Cohn
David E
DE
Yan
Pearlly S
PS
Huang
Tim H-M
TH
Lin
Huey-Jen L
HJ
D050561:3-Hydroxyanthranilate 3,4-Dioxygenase / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D013250:Steroid Hydroxylases / Q000235:genetics; D013251:Steroid Isomerases / Q000235:genetics; D019473:Transcription Factors, TFII / Q000235:genetics
D014408:Biomarkers, Tumor; C470165:FOXD4 protein, human; D051858:Forkhead Transcription Factors; C104259:GTF2I protein, human; D019473:Transcription Factors, TFII; D050561:3-Hydroxyanthranilate 3,4-Dioxygenase; D013250:Steroid Hydroxylases; C499573:CYP39A1 protein, human; D013251:Steroid Isomerases; C090445:EBP protein, human