Title. What shapes the mutational landscapes of cancer genomes?

Summary. Genomic alteration such as point mutations, 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. Several factors have been identified in the recent years. In the first part of my talk, we show that DNA replication timing patterns, chromatin organization, and long-range interactions in the nucleus can help predict the genome-wide patterns of point mutations, amplifications, deletions, and also loss of heterozygosity events. This is noteworthy since the boundary-pairs of large genomic alterations 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. 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.