Recurrent Genomic Alterations Driving Clear Cell Renal Cell Carcinoma Development
Abstract
Hypothesis, Evidence, and Rationale: The human genome is organized into 23 pairs of chromosomes. Abnormalities in the number and/or structure of chromosomes are hallmark characteristics of cancer genomes. For example, loss of the short arm of chromosome 3 -- known as 3p -- occurs in nearly all cases of clear cell renal cell carcinoma (ccRCC). These recurrent alterations directly initiate ccRCC through the simultaneous loss of four genes located on chromosome 3p that normally act to suppress tumor formation. ccRCC development ensues when 3p loss is combined with mutations in one or more of the same genes located on the second chromosome 3p copy. The gain of an additional copy of chromosome 5q represents the second most frequent genomic abnormality. Instead of simple deletions and amplifications of these chromosome arms, as suspected for ~40 years, it was recently discovered that many 3p loss and 5q gain events in ccRCC tumors exhibit complex rearrangements known as chromothripsis. Chromothripsis of 3p occurs relatively early -- oftentimes between childhood and adolescence -- which predisposes young individuals to developing ccRCC. Unfortunately, we currently do not understand what causes these chromosome alterations and why they occur at such high frequency in ccRCC. I recently developed a unique platform that allows us to experimentally induce chromothripsis in a controlled manner. Using this strategy, I discovered that chromosome segregation defects during mitotic cell division can cause chromothripsis. I now propose to leverage our expertise and unique set of experimental approaches to develop new cellular models of chromothripsis in the context of ccRCC. First, I will establish novel strategies to trigger chromosome 3p and 5q chromothripsis in non-cancerous human kidney cells. Next, I will study the ability of these rearrangements to transform normal renal cells into malignant cancer cells. Lastly, I will use high-resolution microscopy and whole-genome DNA sequencing approaches to directly interrogate the structure of chromosomes 3p and 5q for recurrent patterns of alterations before, during, and after cancer development. This will also be examined in cells harboring 3p gene mutations that may accelerate ccRCC following chromothripsis. The proposed research will uncover patterns of genomic alterations that can transform a normal kidney cell into a malignant and/or metastatic tumor. My laboratory is exceptionally well-suited to conduct the proposed research given our expertise in studying the fundamental mechanisms of chromothripsis and genomic rearrangements. In addition, the promising preliminary data acquired over the past year through institutional pilot funds support a high degree of feasibility and likelihood for success. Career Goals in Kidney Cancer Research: My career goal is to establish a robust and rigorous research program aimed at tackling the most pressing questions regarding the molecular and genetic etiology of ccRCC. In the long term, I hope to discover how gene mutations and genomic rearrangements drive ccRCC in order to identify more effective patient options to eradicate or prevent kidney cancer development and metastasis. Future efforts will involve the identification of ccRCC-specific molecular vulnerabilities associated with chromosome 3p and 5q alterations as potential clinical targets. In addition, we will integrate our research program with the resources and expertise of the UT Southwestern Kidney Cancer Program as we transition our laboratory focus toward investigating ccRCC etiology. AKCI Participation: Support from the Academy of Kidney Cancer Investigators (AKCI) Early-Career Investigator Award will lay the foundation and accelerate progress on this exciting new direction into exploring critical, unanswered questions in kidney cancer biology. We currently do not have the funding, resources, and protected time to pursue this area of research. If awarded, I will
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210764
Entities
People
- Peter Ly
Organizations
- United States Army
- University of Texas Southwestern Medical Center