Mechanisms of Cancer Genome Rearrangements will focus on elucidating the sources and origins of structural genomic alterations arising throughout cancer genome evolution. Specifically, this meeting will serve as the first Forbeck Forum focused on bringing together a diverse group of researchers – ranging from computational cancer genomics to basic experimental biology – in an effort to understand the causes and consequences of complex rearrangements in human cancer genomes.

Rearrangements in the linear chromosome sequence order can directly drive cancer development, as exemplified by a single translocation between chromosomes 9 and 22 (the “Philadelphia chromosome”) in leukemia patients. While simple translocations have long been detectable by cytogenetic approaches, more recent cancer genome sequencing efforts have uncovered a spectrum of novel chromosomal rearrangement patterns across diverse adult and pediatric tumor types, including those with poor prognosis and limited treatment options. Such rearrangements – including chromothripsis and chromoplexy – are often caused by punctuated bursts of genomic instability, which can then promote cancer progression by triggering the loss of tumor suppressor genes, the generation of canonical driver gene fusions, the production of extrachromosomal DNA elements, and/or the development of resistance to chemotherapy. However, we currently have understanding about their mechanisms, functional consequences, and genetic and/or environmental factors that predispose individuals to cancer genome rearrangements. This lack of knowledge has limited our ability to interpret the complex patterns of alterations that are frequently observed in cancer patient genomes. A detailed understanding of these processes will be critical for identifying targetable genetic vulnerabilities associated with genome rearrangements, as well as their use as a potential clinical biomarker. Therefore, a Forum dedicated to bringing together researchers spanning currently disconnected fields (cancer genomics, DNA damage and repair, DNA replication, cell cycle regulation, and clinical oncology) is timely and holds great potential to address the biological basis and clinical implications of complex genomic rearrangements.

This meeting will be organized around four focused sessions addressing the mechanistic basis of complex genomic rearrangements in cancer. Key topics for discussion will include: i) the interpretation of structural variants in cancer patient genomes from DNA sequencing and computational methods; ii) how cells develop, respond to, and repair a spectrum of DNA lesions; iii) how defects throughout the cell cycle can trigger catastrophic consequences at the chromosomal level, and iv) hypotheses underpinning the punctuated evolution of cancer genomes. Junior, mid-career, and established investigators will have the opportunity to present their research in a rigorous yet collegial think-tank environment, which will be interleaved with discussions with a strong focus on biological mechanisms of genomic instability. As organizers, we will encourage the open discussion of unpublished work, concepts, and ideas to promote engagement and the establishment of new collaborations. We believe that the format of the Forbeck Forums is uniquely suited for a focused meeting on this topic, which has not been previously held. Given that diverse expertise and approaches are required to understand cancer genome aberrations, such a Forum holds great potential for unlocking creative thinking and promoting collaborative work. We anticipate that this Forum will foster new, multi-disciplinary interactions across participants who do not typically attend similar meetings, and therefore, we expect that the meeting will translate into synergistic interactions during the Forum and beyond.

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