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Updated: Jun 6, 2026
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Investigation of DNA damage response and apoptotic gene methylation pattern in sporadic breast tumors using high
Ranjana Pal1, Niloo Srivastava, Rupali Chopra
1National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, Aruna Asafali Road, New Delhi-110067, India.
Background:
Sporadic breast cancer like many other cancers is proposed to be a manifestation of abnormal genetic and epigenetic changes. For the past decade our laboratory has identified genes involved in DNA damage response (DDR), apoptosis and immunosurveillance pathways to influence sporadic breast cancer risk in north Indian population. Further to enhance our knowledge at the epigenetic level, we performed DNA methylation study involving 17 gene promoter regions belonging to DNA damage response (DDR) and death receptor apoptotic pathway in 162 paired normal and cancerous breast tissues from 81 sporadic breast cancer patients, using a high throughput quantitative DNA methylation analysis technology.
Results:
The study identified five genes with statistically significant difference between normal and tumor tissues. Hypermethylation of DR5 (P=0.001), DCR1 (P=0.00001), DCR2 (P=0.0000000005) and BRCA2 (P=0.007) and hypomethylation of DR4 (P=0.011) in sporadic breast tumor tissues suggested a weak/aberrant activation of the DDR/apoptotic pathway in breast tumorigenesis. Negative correlation was observed between methylation status and transcript expression levels for TRAIL, DR4, CASP8, ATM, CHEK2, BRCA1 and BRCA2 CpG sites. Categorization of the gene methylation with respect to the clinicopathological parameters showed an increase in aberrant methylation pattern in advanced tumors. These uncharacteristic methylation patterns corresponded with decreased death receptor apoptosis (P=0.047) and DNA damage repair potential (P=0.004) in advanced tumors. The observation of BRCA2 -26 G/A 5'UTR polymorphism concomitant with the presence of methylation in the promoter region was novel and emerged as a strong candidate for susceptibility to sporadic breast tumors.
Conclusion:
Our study indicates that methylation of DDR-apoptotic gene promoters in sporadic breast cancer is not a random phenomenon. Progressive epigenetic alterations in advancing tumors result in aberrant DDR-apoptotic pathway thereby promoting tumor development. We propose, since pathological epigenetic changes of the DDR-apoptotic genes are reversible modifications, these could further be targeted for therapeutic interventions.
Insights
Epigenetic changes in DNA damage response (DDR) and apoptosis genes are linked to sporadic breast cancer development. Aberrant methylation patterns in these genes progress with tumors and may be reversible therapeutic targets.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Sporadic breast cancer is associated with genetic and epigenetic alterations.
- Previous research identified genes in DNA damage response (DDR), apoptosis, and immunosurveillance pathways influencing breast cancer risk.
- Epigenetic modifications, specifically DNA methylation, were investigated in relation to DDR and apoptotic pathways.
Purpose of the Study:
- To investigate DNA methylation patterns in promoter regions of 17 genes involved in DDR and death receptor apoptotic pathways.
- To correlate epigenetic alterations with gene expression and clinicopathological parameters in sporadic breast cancer.
- To identify potential epigenetic targets for breast cancer therapy.
Main Methods:
- DNA methylation analysis of 17 gene promoter regions in 162 paired normal and cancerous breast tissues from 81 sporadic breast cancer patients.
- High-throughput quantitative DNA methylation analysis technology was employed.
- Correlation analysis between methylation status, transcript expression, and clinicopathological parameters.
Main Results:
- Five genes showed statistically significant methylation differences between normal and tumor tissues: hypermethylation of DR5, DCR1, DCR2, BRCA2, and hypomethylation of DR4.
- Negative correlation observed between methylation and transcript expression for TRAIL, DR4, CASP8, ATM, CHEK2, BRCA1, and BRCA2.
- Aberrant methylation patterns increased in advanced tumors, correlating with decreased apoptosis and DNA repair capacity. A novel finding was the association of BRCA2 promoter methylation with a 5'UTR polymorphism, suggesting susceptibility to sporadic breast tumors.
Conclusions:
- Methylation of DDR-apoptotic gene promoters is a significant factor in sporadic breast cancer development, not a random occurrence.
- Progressive epigenetic alterations in advancing tumors lead to aberrant DDR-apoptotic pathways, promoting tumor growth.
- Reversible epigenetic modifications in DDR-apoptotic genes present potential therapeutic targets.
