“SPARK funding is very important because our hypothesis is in a very juvenile state and it requires validation through experimental data. This award will help us build our story, so we can get more funding in the future.”
Solving the puzzle of a shattered chromosome
FUNDED: JANUARY 2020
FUNDED BY: the generosity of François Ferré & Magda Marquet and 2019-20
Genomic rearrangements are one of the fundamental driving forces behind cancer development. Recently, cancer genome sequencing has uncovered a class of new complex rearrangement called ‘chromothripsis’, which is a catastrophic event leading to shattering of an individual chromosome into smaller fragments (i.e., thripsis) and rejoining the resulting fragments in an arbitrary order. Such an event may cause massive problems with the regular operation of a cell, especially regarding to control of gene expression. The complexity of chromothripsis is puzzling, and we have no clear understanding of what may be the trigger for it or how cells tolerate such a catastrophic event. The prevalence of chromothripsis-like events covers more than 100 cancer types, and some with particularly poor prognosis. Understanding the nature of this genomic rearrangement is thus crucial for coming up with more informed therapies for these patients.
Over the past decades, our understanding of the human genome 3D organization has grown rapidly, and we now know that the human genome is folded into multiple layers of hierarchically-organized and well-defined structures. Alterations in any one of these finely-tuned layers can lead to an unwanted cascade of molecular events and ultimately drive disease. The predominant method to study the 3D organization of the genome is chromosome conformation capture (Hi-C). Our laboratory has vast expertise in interpreting such data and we have developed some of the most used softwares in this field. We have also recently published the first method that systematically identifies genomic rearrangements from Hi-C data and co-led a pioneering study that combined the power of multiple experimental techniques to create the most comprehensive rearrangement maps for many cell lines used as model systems for different cancers.
Here, I propose to investigate chromothripsis and how it impacts gene expression and relate to cancer progression in two different cancer types. With a collaborator from UCSD, who is an expert in genomic studies of pediatric tumors, we will study a central nervous system tumor called ependymoma. Patients who develop a specific subtype of ependymoma, which has the most dismal outcome, also exhibit a recurrent chromothripsis event on their chromosome 11. We will examine the 3D chromatin organization and gene expression in these samples using sophisticated computational techniques we will develop with the SPARK support in hopes of finding new clues to molecular mechanisms underlying the aggressiveness of this subtype. In collaboration with a clinical team in the U.K., we will also screen existing tumor samples from a cohort of lung cancer patients for chromothripsis and perform similar analysis as described above. Our project will bring a systematic approach to a difficult problem that is not well-understood and has broad impact for patients suffering from aggressive forms of tumors harboring chromothripsis.
Six-Month Project Update
My project investigates chromothripsis events in cancer. Chromothripsis is a complex genomic rearrangement defined as the shattering and reconfiguration of a chromosome, and is associated with worse clinical outcomes in cancer patients. This project aims to highlight the epigenetic impact of such events on cancer and improve prognoses for patients. Since receiving funding, I’ve been establishing collaborations and working on high-risk patient sample collections. We have established a collaboration with an oncologist at Rady Children’s Hospital, San Diego, to study patients suffering from pediatric Acute Lymphoblastic Leukemia (ALL) involving amplification of chromosome 21 (iAMP21). We’ve recently received clearance from the Children’s Oncology Group biospecimen bank to receive more iAMP21 and non-iAMP21 samples for this project. We are also in the process of selecting lung cancer biopsy samples from our colleague, Dr. Vijayanand Pandurangan’s lab, to identify chromothripsis events. In parallel, we’ve purchased a breast and colon cancer cell line that has confirmed chromothripsis events and plan to use those to validate the novel computational algorithm we’ve developed to help advance this field. Once validated, we can confidently use our algorithm to analyze the patient samples, with the hope of finding new clues to molecular mechanisms underlying the aggressiveness of these cancers.