Understanding the natural history of HPV infection and cervical cancer development among Indian women
Epidemiological studies have established a causal relationship between HPV infections and occurrence of cervical cancer (CaCx). It is observed that (i) CaCx incidence rates and (ii) prevalence of HPV infections at the population level are variable across the country. My research aims to gain insight into HPV incidence, prevalence, type distribution, persistence (in longitudinal follow-up of cohorts of women) in various regions of West Bengal and north-eastern States of India. This would be coupled with a genomics based approach to decipher the genetic underpinnings of the two known crucial stages in the natural history of cervical cancer – (i) viral persistence (population based) and (ii) progression to pre-cancer/cancer (hospital based).
Interrogating the intricacies of host pathogen interactions in HPV related cervical cancer pathogenesis through a genomics based approach
Recent functional studies have revealed that natural genetic variation modulates risks to common diseases including infectious diseases, through gene expression, that provides a link between the DNA sequence and the phenotypes that characterize clinical disease. Thus, quantification of transcript abundance could be used to provide insights into causal genomic underpinnings of diseases. Such differences in gene expressions have been correlated with the genetic variations in the cis and trans regulatory sequences/factors in populations. Epigenetic alterations on the other hand, including DNA methylation, histone modification and RNA mediated gene silencing, afford a level of transcriptional regulation above and beyond DNA sequence. The focus of my research is therefore to explore the association of coding and noncoding transcription (miRNA and long non-coding RNAs), uncharacterized transcripts and their function on gene regulation, genome control and their correlation with genetic variations in CaCx pathogenesis.
Molecular reasons why HPV infection is controlled in some women or instead progresses to subsequent stages of tumorigenesis are largely unknown. Methylation of cytosine residues at CpGs within promoters (at CpG Islands) loss of genome-wide methylation and the degree of hypomethylation have been observed in some cancers to be associated with tumorigenesis. The aim of my study is also to test the hypothesis that epigenetic changes (CpG methylation) in HPV16 and host genomes are crucial for the development of HPV16 related CaCx among Indian women and jointly influence disease risk by modulating the expression of key viral genes and host genes of relevant cellular pathways.
HPV16 E2 gene disruption, as a consequence of viral integration into the host genome, mediates the loss of negative feedback control of viral oncogene expression and hence is a critical event in cervical carcinogenesis. Interestingly, in many HPV-induced CaCx cases, we find the existence of intact E2 genes or lack of evidence of the canonical pathway of HPV-induced transformation. That is suggestive of the existence of alternative pathway(s) by which HPV induces cellular transformation in these CaCx cases. We therefore hypothesize that the genetic/epigenetic make-up of an individual could likely influence the mechanism by which HPV induces cellular transformation in cervical epithelial cells. Therefore, it becomes essential to focus on the elucidation of various mechanisms adopted by HPV16 in mediating cervical carcinogenesis, employing a genomics based approach followed up by functional assays to get insights into the molecular mechanisms of disease development., which could also lead to biomarker and therapeutic target development.
Projects: (extramurally funded)
Training Grant: (Extramurally Funded)
Enhancing Capacity in Genomics-Driven Research in Human Health & Disease in the North-East Region (Department of Biotechnology, Govt. of India, 2014)- as Principal Investigator along with Dr. Arindam Maitra as Co- Principal Investigator. The project is aimed at providing comprehensive training to NER scientists, research students (doctoral and post-doctoral) and clinicians engaged in “Biomedical Research”, to better equip them to undertake focused research leading towards understanding the molecular basis of diseases prevalent in NER of India.
Sen S., Mandal P., Bhattacharya A., R., Mondal, N.R., Chakravarty, B., Chatterjee, T., Roy, S., and Sengupta, S. (2017). Impact of viral and host DNA methylations on HPV16-related cervical cancer pathogenesis. Tumor Biology, DOI: 10.1177/1010428317699799 journals.sagepub.com/home/tub
Saha Sharma, S., Roy Chowdhury, R., Mandal, N.R., Roy, S.,and Sengupta, S (2017). Expression signatures of HOX cluster genes in cervical cancer pathogenesis: Impact of human papillomavirus type 16 oncoprotein E7. Oncotarget, DOI: 10.18632/oncotarget.16619 (Advance Publication). [Impact Factor 5.008].
Das Ghosh, D., Mukhopadhyay, I., Bhattacharya, A., Roy Chowdhury, R., Mandal, N.R., Roy, S.,and Sengupta, S (2017). Impact of genetic variations and transcriptional alterations of HLA class I genes on cervical cancer pathogenesis. International Journal of Cancer, DOI: 10.1002/ijc.30681 (epub ahead of publication).
Saha Sharma, S., Roy Chowdhury, R., Mondal, N.R., Chakravarty, B., Chatterjee, T., Roy, S., and Sengupta, S. (2016). Identification of genetic variation in the lncRNA HOTAIR associated with HPV16-related cervical cancer pathogenesis. Cellular Oncology 39, 559-572.
Sharma S, Mandal P, Sadhukhan T, Roy Chowdhury R, Mondal N.R., Chakravarty B, Chatterjee T, Roy S and Sengupta S (2015). Bridging Links between Long Noncoding RNA HOTAIR and HPV Oncoprotein E7 in Cervical Cancer Pathogenesis. Scientific Reports 5:11724/DOI: 10.1038/srep11724.
Mandal P, Bhattacharjee B, Das Ghosh D, Mondal N.R., Roy Chowdhury R, Roy S and Sengupta S (2013). Differential expression of HPV16 L2 gene in cervical cancers harboring episomal HPV16 genomes: influence of synonymous and non-coding region variations. PLoS ONE 8(6): e65647. DOI:10.1371/journal.pone. 0065647.