The mechanism of DNA damage and chromothripsis from chromosome segregation errors

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Project Summary/Abstract Research: Tumorigenesis and resistance to therapy are generally believed to arise through gradual, multigenerational accrual of mutations. However, recent cancer genome sequencing suggests that many cancers may accumulate large number of mutations rapidly, perhaps during the course of a single cell cycle. The most dramatic example of such rapid genome evolution is chromothripsis, a new mutational process with massive chromosome rearrangements and a unique pattern DNA copy number that is curiously restricted to one or a few chromosomes. The mechanism(s) leading to chromothripsis have been unclear, but our group previously suggested that it could result from the physical isolation of chromosomes in abnormal nuclear structures called micronuclei. To test this hypothesis, I developed a procedure to combine live- cell imaging with single-cell whole genome sequencing. This has enabled me, with my collaborators, to recapitulate chromothripsis in the laboratory and demonstrate that it can occur via chromosome fragmentation in micronuclei. This experimental system now positions me to study the mechanism of chromothripsis in detail. I will also test my hypotheses that chromothripsis triggers a downstream cascade of genome instability and drives tumor formation through generation of double minute chromosomes, and that chromothriptic-like DNA damage may be an important facet of the tumor killing action of taxanes. Together, these experiments and the new hypotheses being tested will advance our understanding of the ways by which chromosome segregation errors shape cancer genomes, leading to development of novel therapeutic strategies. Candidate Career Goals: My long-term career objective is to obtain a tenure-track position as a physician-scientist in a radiation oncology department. The K08 award will provide the advanced training necessary to achieve this goal. This research proposal is part of a structured plan with scientific, technical, clinical, and career development components. Environment: DFCI and Harvard University are internationally recognized research programs with a number of expert researchers in the areas of cancer cell biology and genomics. Furthermore, DFCI Department of Radiation Oncology has a distinguished record of training successful physician-scientists. In order to achieve my goals, I will be mentored by two outstanding scientists, Dr. David Pellman and Dr. Matthew Meyerson. I have also assembled an excellent advisory committee, consisting of Dr. Alan D’Andrea, Dr. Tim Mitchison, Dr. Gad Getz and Dr. Harvey Mamon.