Cancer starts years to decades before diagnosis. Yet, early stages of cancer development are poorly understood. In particular, the precancer landscape of chromosome instability is understudied. We investigate how the instability rate of the human genome, followed by selection, determines whether cancer develops. Using spatially aware and single-cell multiome methods that we developed, we dissect essential factors that lead to cancer development via chromosome instability.
Chromosome instability is characterized by an increased accumulation of changes in chromosome number and structure. We and others have shown that 60 to 80% of human cancers show chromosome instability. Even though point mutations have been studied extensively, the majority of cancer drivers arise from instability, not from point mutations.
Instability leads to intra-tumor heterogeneity, treatment resistance, metastases and ultimately poor clinical outcome – in fact, cancer genomes that are highly unstable offer very limited treatment options. For these hard-to-treat cancers, earlier detection and earlier intervention will increase survival rates. We want to identify potential etiologies and mechanisms of chromosome instability and with this, potential applications for early diagnosis, prevention and treatment.
Unknown before the next-generation sequencing era, chromothripsis is a unique type of chromosome instability, by which a single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Chromothripsis is frequent in cancer and linked with poor prognosis in a number of tumor types. The research in our group aims at achieving a better understanding of how chromothripsis arises and at assessing potential implications for cancer patients. More specifically, our goals are 1) to characterize in which context chromothripsis occurs and which evolutionary dynamics chromothriptic tumors may have 2) to decipher the mechanistic basis of chromothripsis 3) to target vulnerabilities of tumor cells with chromothripsis. For this, we employ approaches encompassing single-cell genomics, functional testing in model systems and pre-clinical studies in mice.
