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

<p>Abstract</p> <p>Background-</p> <p>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.</p> <p>Results-</p> <p>The study identified five genes with statistically significant difference between normal and tumor tissues. Hypermethylation of <it>DR5 </it>(P = 0.001)<it>, DCR1 </it>(P = 0.00001)<it>, DCR2 </it>(P = 0.0000000005) and <it>BRCA2 </it>(P = 0.007) and hypomethylation of <it>DR4 </it>(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 <it>TRAIL</it>, <it>DR4</it>, <it>CASP8</it>, <it>ATM</it>, <it>CHEK2</it>, <it>BRCA1 </it>and <it>BRCA2 </it>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.</p> <p>Conclusion-</p> <p>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.</p

Comparison of allelic imbalance in chromosomes 16 and 17 along with mutation in with -26 GA polymorphism background

<p><b>Copyright information:</b></p><p>Taken from "Implication of -26G>A 5' untranslated region polymorphism in susceptibility to sporadic breast cancer and its modulation by codon 72 Arg>Pro polymorphism"</p><p>http://breast-cancer-research.com/content/9/5/R71</p><p>Breast cancer research : BCR 2007;9(5):R71-R71.</p><p>Published online 18 Oct 2007</p><p>PMCID:PMC2242669.</p><p></p> values given are for overall distribution, G/G versus G/A, and A/A versus G/A

Effect of -26 G/A polymorphism on the 5' untranslated region secondary structure of RNA and stability analyzed by the RNAstructure program (version 4

<p><b>Copyright information:</b></p><p>Taken from "Implication of -26G>A 5' untranslated region polymorphism in susceptibility to sporadic breast cancer and its modulation by codon 72 Arg>Pro polymorphism"</p><p>http://breast-cancer-research.com/content/9/5/R71</p><p>Breast cancer research : BCR 2007;9(5):R71-R71.</p><p>Published online 18 Oct 2007</p><p>PMCID:PMC2242669.</p><p></p>3) and VRNAAFOLD (The European Molecular Biology Open Software Suite). The -26 position with G or A is indicated by arrows

Reporter gene assay with chimeric promoter and 5' untranslated region (UTR) with A or G at the -26 position (upper panel) and the effect of increasing the dose of adriamycin (0, 1, and 2

<p><b>Copyright information:</b></p><p>Taken from "Implication of -26G>A 5' untranslated region polymorphism in susceptibility to sporadic breast cancer and its modulation by codon 72 Arg>Pro polymorphism"</p><p>http://breast-cancer-research.com/content/9/5/R71</p><p>Breast cancer research : BCR 2007;9(5):R71-R71.</p><p>Published online 18 Oct 2007</p><p>PMCID:PMC2242669.</p><p></p>5 μM) (lower panel)

Leprosy and the adaptation of human Toll-like receptor 1

© 2010 Wong et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.DOI: 10.1371/journal.ppat.1000979Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control P = 5.7x10⁻⁸, OR = 0.31, 95% CI = 0.20–0.48, and HLA-DQA1 rs1071630, case-control P = 4.9x10⁻¹⁴, OR = 0.43, 95% CI = 0.35–0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases