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Genomic approaches to identify novel endogenous and exogenous genetic elements associated with human cancer

 

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Cancer is a complex disease characterized by somatic alterations (genetic and epigenetic), pathogenic infections, that are associated with more than 18% of the global cancer incidences. Pathogens, including viruses and bacteria are known to be associated with cancer by inducing chronic inflammation and interfering with host cellular mechanism. The discovery of cancer associated pathogens in cancer samples has been revolutionized with the advent of next generation sequencing (NGS) technology. For systematic detection and quantification of cancer associated pathogens in NGS samples, we have developed Cancer Pathogen Detector (CPD) -- a novel computational tool to detect the presence of 1070 pathogenic strains with high specificity and sensitivity using whole exome, whole genome, and transcriptome data. The identification of novel infectious agents will advance the understanding of the role of pathogens in disease progression and brings opportunities to prevent associated cancers by immunization or other public health measures.

Figure: Pathogen-derived signals modulate numerous hallmarks of cancer through diverse mechanisms.


Knowledge defining how the microbiota modulates host physiology and disease pathogenesis, particularly in the context of cancer, will provide a framework for the holobiont concept of cancer development and enable the identification of novel microbial targets for preventative and therapeutic strategies.Fulbright LE, Ellermann M, Arthur JC (2017)

Integrative biology of genome, epigenome and pathogens in human oral cancer

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Pathogenic infections have been associated with cancer worldwide. About 18-20% of the malignancies have been attributed to infections, such as Helicobacter pylori, Fusobacterium, human papillomaviruses (HPV), hepatitis virus, Epstein–Barr virus (EBV)/human herpes virus (HHV) 4 viruses, and others. However, lack of understanding of the underlying mechanism to establish causality of pathogenic infections to carcinogenesis lends itself to want of further research. Here, we propose to systematically elucidate pathogens associated with human oral cancer using the in-house developed Cancer Pathogen Detector tool, and characterize their role in carcinogenesis using in vitro and in vivo model systems by integrating the changing global landscape of co-occurring mutations and chromatin activation states. This study would further the understanding of the underlying cellular functions in context of its complex interactions with infectious agents through epigenomics. The identification of newer oncogenic infectious agents along with its concomitant effect of the genome and epigenome of the host cell – in state of transformation-- would lead to the molecular understanding of oncogenic mechanisms, better sub-classification of disease according to etiology, understanding of the role of pathogens in disease progression, prevention of associated cancers by immunization or public health measures, and to develop specific targeted treatments.

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Publications:

  1. Iyer P, Barreto SG, Sahoo B, Chandrani P, Ramadwar MR, Shrikhande SV, Dutt A. Non-typhoidal Salmonella DNA traces in gallbladder cancer. Infect Agent Cancer. PMID:  26941832

  2. Chandrani P, Kulkarni V, Iyer P, Upadhyay P, Chaubal R, Das P, Mulherkar R, Singh R, Dutt A. NGS-based approach to determine the presence of HPV and their sites of integration in human cancer genome. British of Journal Cancer.PMID:  25973533

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