Aberrant Promoter Hypermethylation of RASSF1a and BRCA1 in Circulating Cell-Free Tumor DNA Serves as a Biomarker of Ovarian Carcinoma

Document Type : Research Articles


1 Department of Biochemistry, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka, India.

2 Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka, India.

3 Department of Gynaeconcology, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka, India.


Objective: Ovarian cancer is one of the leading causes of cancer deaths in women. Ovarian cancer is diagnosed at
the late stages and generally relapses within 12-14 months of cytoreductive surgery. This is attributed to lack of precise
molecular detection methodologies to detect and track the disease. Epigenetic alteration such as aberrant promoter
hypermethylation is an important early event that occurs during cancer development and progression. This study focuses
on development of a minimally invasive methylation marker that could be used for detection and prognosis of ovarian
cancer patients. Methods: Aberrant promoter hypermethylation of RASSF1a and BRCA1 was assessed in circulating
DNA of 72 EOC patients using methylation-specific PCR. The findings were correlated with various clinicopathological
parameters. Statistical analysis was done using the Fisher exact test and chi-square test. Results: The aberrant methylation
patterns of RASSF1a and BRCA1 was identified to be present in the cancerous samples. A total of 31.9 % and 56.9%
methylation was observed for RASSF1a and BRCA1 respectively. A striking 50% methylation of BRCA1 was identified
in the benign sample cohort, which marks the significance of assessing the hypermethylation pattern to detect cancer at
its early stages. Methylation of the two tumor suppressor genes was evident across various stages and grades of ovarian
tumors suggesting that this could also help as a prognostic marker. Conclusion: The results of the current study hold
significance since the hypermethylation patterns can be identified in the cell-free circulating tumor DNA from a small
volume of blood plasma and is a simple and minimally-invasive method. Assessment of hypermethylation patterns of
a panel of TSG along with the existing screening markers could aid in better diagnosis and management of the disease.
It could also aid in designing specifically tailored treatment strategies to fight the disease.


Main Subjects