Hypothesis: In humans, gene expression is regulated through a system of chemical modifications that preserve the DNA structure but outwardly silence the expression of altered genes. These modifications are encompassed under the term "epigenetics." In this project, researchers will test the hypothesis that one of those epigenetic changes (cytosine modifications) occurs in a purposeful, organized process and not only through random events, as is currently believed. Understanding which areas of the genome (the whole set of genes in an organism) are more affected in a subtype of kidney cancer will help investigators to identify potential molecular targets for the design of new treatments or diagnostic tests. As such, this research could impact how we understand tumors that are more or less aggressive and lethal for patients.

Supporting Evidence: Some preliminary reports have shown that one of those epigenetics changes (cytosine hydroxymethylation) is less abundant in kidney tumors compared to normal kidneys. These reports are based on staining (how intense a dye is present in tumors under the microscope) and a few molecular tests (how a couple of genes are altered when measured directly using a calibrated instrument). However, we do not know whether these changes occur in one, a couple, or several genes or whether they occur randomly or in a coordinated fashion. We do not know, either, how much these changes alter gene regulation (i.e., how much a gene is translated into its product RNA-protein).

Scientific Rationale: Based on these reports, we can use tumor samples donated from patients and stored in a tumor bank (a hospital facility where these samples are stored) to understand how these alterations appear in multiple tumors (200 tumor samples) compared to normal kidney samples not affected by the tumor (50 samples). We have several tools to measure the degree to which these changes occur, and we can use this information to understand whether this phenomenon affects how long patients survive with kidney cancer, even under the same treatment conditions.

Proposed Project: This project will use 200 tumor samples that were collected from patients who have a subtype of kidney cancer (clear cell carcinoma) and compare the patterns of the epigenetic changes versus those of 50 normal kidney samples (from areas not affected by the tumor) using advanced technology to obtain good measurements of those changes. In this proposal, we will compare those changes using mathematical models to understand the relationship between tumor and normal measurements, and how they impact patients' survival after receiving their treatment.

Career Goals: My goal as a researcher is to tackle the problem of kidney cancer. To this end, I need to acquire as much knowledge about the disease and to exchange ideas with other colleagues. This program will provide the opportunity to bring together multiple scientists working on the kidney cancer problem through my mentors (Dr. Brugarolas and Dr. Christensen) and networking sessions (within the Academy of Kidney Cancer Investigators). Participating in that networking will nourish my early scientific career to bring innovative solutions for the people suffering from this devastating disease.

Applicability of the research (patients, clinical applications, health): If we can demonstrate that these alterations are occurring in specific patterns (e.g., following a specific order), this information will inform how to better design treatments and diagnostic tools for the patients with this subtype of kidney cancer.