Clear cell renal cell carcinomas (ccRCCs) are genetically characterized by the near-universal loss of chromosome 3p and gain of chromosome 5q. These recurrent genomic alterations are often driven by chromothripsis, a highly mutagenic process involving the catastrophic fragmentation of individual chromosomes followed by its reassembly through error-prone DNA repair mechanisms. Chromothripsis can be initiated by mitotic cell division errors that generate micronuclei, abnormal nuclear structures that entrap individual chromosomes and renders them susceptible to fragmentation. With the mentorship of Dr. James Brugarolas (University of Texas Southwestern Medical Center), Dr. Peter Ly aims to investigate the contributions of chromosome 3p and 5q chromothripsis to the development of ccRCC. Dr. Ly has previously established methods to induce chromosome-specific micronuclei and chromothripsis, and he plans to translate this expertise into reconstructing the genomic events underlying ccRCC evolution. The overall goal of this project is to identify recurrent patterns of 3p and 5q rearrangements that are capable of transforming normal diploid cells into malignant ccRCC tumors. The results of this research will advance our mechanistic understanding of how chromosome-specific alterations contribute to ccRCC tumorigenesis.