Epigenetic Alteration by DNA Methylation of ESR1, MYOD1 and hTERT Gene Promoters is Useful for Prediction of Response in Patients of Locally Advanced Invasive Cervical Carcinoma Treated by Chemoradiation.
OBJECTIVE
Locally advanced invasive cervical cancer [International Federation of Gynecology and Obstetrics (FIGO) IIB/III] is treated by chemoradiation. The response to treatment is variable within a given FIGO stage. Therefore, the aim of the present study was to evaluate the gene promoter methylation profile and corresponding transcript expression of a panel of six genes to identify genes which could predict the response of patients treated by chemoradiation.


METHODS
In total, 100 patients with invasive cervical cancer in FIGO stage IIB/III who underwent chemoradiation treatment were evaluated. Ten patients developed systemic metastases during therapy and were excluded. On the basis of patient follow-up, 69 patients were chemoradiation-sensitive, whereas 21 were chemoradiation-resistant. Gene promoter methylation and gene expression was determined by TaqMan assay and quantitative real-time PCR, respectively, in tissue samples.


RESULTS
The methylation frequency of ESR1, BRCA1, RASSF1A, MLH1, MYOD1 and hTERT genes ranged from 40 to 70%. Univariate and hierarchical cluster analysis revealed that gene promoter methylation of MYOD1, ESR1 and hTERT could predict for chemoradiation response. A pattern of unmethylated MYOD1, unmethylated ESR1 and methylated hTERT promoter as well as lower ESR1 transcript levels predicted for chemoradiation resistance.


CONCLUSIONS
Methylation profiling of a panel of three genes that includes MYOD1, ESR1 and hTERT may be useful to predict the response of invasive cervical carcinoma patients treated with standard chemoradiation therapy.
Molecular Pathology Laboratory, Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
S
S
Sood
Department of Radiotherapy and Oncology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
F D
FD
Patel
Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
S
S
Ghosh
Scientist Fellow, Microbial Type Culture Collection and Gene Bank, Institute of Microbial Technology, Chandigarh, India.
A
A
Arora
Department of Obstetrics and Gynecology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
L K
LK
Dhaliwal
Molecular Pathology Laboratory, Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Electronic address: drsradhika@gmail.com.
R
R
Srinivasan
D000328:Adult; D000368:Aged; D059248:Chemoradiotherapy; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D017570:MyoD Protein / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C509186:TERT protein, human; D019098:Telomerase
Chemoradiation; ESR1; MYOD1; gene promoter methylation; hTERT; invasive cervical carcinoma