First Functional Analysis of an Inherited SETD2 Mutation Associated with Renal Cell Carcinoma
Abstract
An estimated 63,000 new cases of kidney cancer will be diagnosed in the U.S. this year. An additional 15,000 people will die from kidney cancer. Cancer is driven by complex mechanisms at the DNA and cellular levels. One gene known to play a role in the development and progression of kidney cancer is SETD2. SETD2 is a protein that participates in the process of converting DNA to RNA, which can be converted into protein. In addition, it plays a role in cell division. It does this by modifying two proteins, histone and alpha-tubulin. Loss of SETD2 results in primary kidney cancer and metastases. We recently discovered an inherited change to the SETD2 protein that occurs more frequently in kidney cancer patients when compared to non-cancer controls and population controls. The role of this alteration is completely unknown. Our goal is to investigate whether the inherited change in question alters the function of SETD2, a key driver of kidney cancer. We will study this using the common fruit fly as a genetic model. Historically, gene discovery in fruit fly models has fundamentally shaped our understanding of human cancer. For example, several genes involved in colon cancer and metastasis were all primarily modeled in the fruit fly. Fruit fly Set2 has the same function as human SETD2. Studying the alteration in the common fruit fly will allow us to better understand how this mutation impacts human SETD2 function. The proposal is innovative because it involves the functional investigation of the first-ever inherited nonsynonomous SNV in SETD2 associated with RCC. The identification of a single point mutation that predisposes to RCC would have immediate clinical impact on Service members, Veterans, or members of the American public. This could occur in multiple situations. (1) Any patient that was diagnosed with RCC could be tested for the germline mutation. If it was found, screening of all family members for the mutation could be done and those that tested positive could undergo renal imaging to determine whether a renal mass was present. (2) Healthy individuals could be screened for the presence of the mutation. Those found to have the mutation could undergo immediate imaging and potentially additional follow-up imaging at intervals to aid in early detection of disease. (3) If patients with known RCC that have undergone curative surgery were found to harbor the germline mutation, the remaining kidney would remain at increased risk for development of a second tumor compared to patients with purely sporadic disease. These individuals would therefore justify lifelong follow-up and be considered to have high risk disease regardless of the tumor grade and stage. (4) RCC disproportionately affects African Americans, and this non-synonymous SNV is also found disproportionately in the African American population. It is therefore possible that some of the racial disparity of the disease could be accounted for by the presence of the mutation and that African Americans may especially benefit from this discovery through screening.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910859
Entities
People
- Rebecca Susan Arnold
Organizations
- Emory University
- United States Army