SjD Laboratory
Cancer Genomics and Systems Biology  


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Research
We are the cancer genomics and systems biology group at Rutgers CINJ. We develop new methods and work in close collaboration with bench scientists and clinicians on relevant projects. We provide brief overview of some of the recent works below. Additional details and latest news can be found on our webpage www.sjdlab.org

Genomic instability in cancer

Genomic instability and somatic mutations are hallmarks of all cancers. We use a combination of genomics, and molecular biology techniques to study genomic instability and DNA repair defects that arise due to endogenous processes and environmental exposure. We have shown that nuclear localization, DNA replication timing and genomic context play critical roles in shaping the landscape of amplifications, deletions, point mutations, and loss of heterozygosity in cancer genomes. Our findings provide insights into different mutagenic processes during aging and tumorigenesis, and has implications for identifying driver and passenger mutations in the cancer genomes. 

Hu et al. Nucleic Acids Res- Cancer, 2021
Singh et al. Comm Biol. 2020
Clements et al. Nature Comm. 2020
He et al. Nature. 2018
Smith et al. Nature Str Mol Biol. 2017
De et al. Nature Biotech.. 2011
De et al. Nature Str. Mol. Biol. 2011


Somatic mutations in benign human tissues


From the fertilization of an egg until the death of an individual, somatic cells can accumulate genetic changes, such that cells from different tissues or even within the same tissue differ genetically. The presence of multiple cell clones with distinct genotypes in the same individual is referred to as 'somatic mosaicism'. Many endogenous factors such as mobile elements, DNA polymerase slippage, DNA double-strand break, inefficient DNA repair, unbalanced chromosomal segregation and some exogenous factors such as nicotine and UV exposure can contribute to the generation of somatic mutations, thereby leading to somatic mosaicism. Such changes can potentially affect the epigenetic patterns and levels of gene expression, and ultimately the phenotypes of cells. Although recent studies suggest that somatic mosaicism is widespread during normal development and aging, its implications for heightened disease risks are incompletely understood. We found that somatic mutations in benign somatic tissues carry signatures of relaxed purifying selection.

Hu et al. NAR Caner. 2020
Yadav et al. Nucleic Acids Res. 2016
Aghili et al. Cell Rep. 2014
De. Trends Genet 2011 (cover story)


Intra-tumor heterogeneity and evolutionary dynamics of cancer
Despite growing from a single, renegade somatic cell, by the time of detection, a tumor typically comprises of billions of cells that show considerable genetic and non-genetic differences among them, a phenomenon known as intra-tumor heterogeneity (ITH). Genetic and non-genetic ITH appear to be hallmarks of nearly all types of malignancies, providing substrates for evolvability and emergence of drug resistance and leading to unpredictable prognosis. We use a combination of computational, genomics, and mathematical approaches to study intra-tumor heterogeneity and clonal evolution in cancer, including order of mutation events and emergence of resistance. We report that non-genetic intra-tumor heterogeneity is a predictor of phenotypic heterogeneity and ongoing evolutionary dynamics in tumors. 
 
Biswas et al. in press.
Sharma et al. Cell Rep. 2019 
Balaparya et al. Nature Genetics. 2018
Martins et al. Cancer Discovery. 2012.(cover story)



Regulatory alterations in cancer

Quantifying the effects of different sources of gene expression variation in Pan-cancer cohorts using computational approaches, we found that copy number alterations, epigenetic changes, transcription factors and microRNAs collectively explain, on average, only 31-38% and 18-26% expression variation for cancer-associated and other genes, respectively, and that among these factors copy number alteration has the highest effect. We identified a novel signature of accelerated somatic evolution in many types of cancer, which is marked by clusters of somatic mutations in a hotspot region in multiple tumors; this signature is frequently associated with non-coding regulatory changes leading to deregulation of oncogenic pathways and adverse clinical outcome. We also found that epigenetic heterogeneity in B cell lymphoma is increases markedly with disease aggressiveness, and is associated with unfavorable clinical outcome. Our findings provide mechanistic insights into the biology of regulatory alterations in cancer. 

Sharma et al. Nucleic Acids Res. 2018
Smith KS et al. Nucleic Acids Res. 2015
Shaknovich, De, Michor. Biochim Biophys Acta. 2014.
De, Shaknovich, Riester et al. PLoS Genetics. 2013
Shaknovich et al. Blood. 2011