"DETERMINANTS OF INSTABILITY IN CANCER GENOMES"
Subhajyoti "Subho" De
Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute
Faculty Candidate in Genomics, Bioinformatics, and Computational Biology
Genomic alteration such as amplification or deletion of genetic material is a hallmark of many cancer types, but the mechanistic basis behind the genome-wide landscape of such events is poorly understood. Using cancer genomics and high dimensional data analysis approach we address this topic at the two levels – the 3D nuclear architecture and DNA secondary structure. In the first part of my talk, we show that the pairs of boundaries of genomic alterations are usually replicated concurrently and in spatial proximity of each other in the 3D nuclear space. This is noteworthy since the boundarypairs may be far apart on the linear DNA and the region in between may not be replicated at the same time. Our results provide mechanisms for generation of genomic alterations, and suggest that nuclear architecture and DNA replication timing data can help identify a significant proportion of such events. In the second part, we focus on the sequence context of the boundaries of the genomic alterations. We observe a significant enrichment for one type of DNA secondary structure, called G-quadruplex (G4) in the vicinity of the boundaries and find evidence for a causal role of G4s in generation of many of these events. Notably, abnormal loss of DNA methylation near G4-rich regions is a common signature for many such boundaries. We propose a mechanistic hypothesis that abnormal loss of methylation in genomic regions enriched for G4s acts as a mutagenic factor driving tissue-specific mutational landscapes in cancer. Together, our findings add momentum to the ongoing debate about epigenetic origin of cancer.
Subhajyoti De did his undergraduate in biotechnology and biochemical engineering from the Indian Institute of Technology-Kharagpur. He then went to the University of Cambridge in the UK to do his PhD on human genomics using computational biology approaches. After finishing PhD, he joined the King's College, Cambridge as an independent Research Fellow before moving to Harvard University to work with Dr. Franziska Michor on cancer genomics. Subhajyoti De has worked on diverse topics in genomics and cancer research using integration of high-dimensional data, computational biology, biostatistical techniques, in an interdisciplinary environment.