Investigation of DNA damage response and apoptotic gene methylation pattern in sporadic breast tumors using high throughput quantitative DNA methylation analysis technology

Molecular Cancer

Research

Pawan Gupta¹  Sailesh Gochhait²  Rameshwar NK Bamezai²  Ranjana Pal²  Niloo Srivastava²  Rupali Chopra²  Neeraj Prakash³  Gaurav Agarwal⁴ 

[1] Dharamshila Cancer Hospital and Research Centre, 96, Dharamshila Marg, Vasundhara Enclave, Delhi, India;National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, Aruna Asafali Road, 110067, New Delhi, India;Rajiv Gandhi Cancer Institute and Research Center, 110085, Sector V, Rohini, New Delhi, India;Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, 226 014, Lucknow, India;

关键词: Methylation Profile;    Sporadic Breast Cancer;    Trail Mediate Apoptosis;    Sporadic Breast Cancer Patient;    Sporadic Breast Tumor;   

DOI  :  10.1186/1476-4598-9-303

 received in 2010-07-15, accepted in 2010-11-23,  发布年份 2010

来源: Springer

【 摘 要 】

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 immunesurvelliance 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.

【 授权许可】

Unknown   
© Pal et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.