Investigator: Sarah Holt, PhD – Staff Scientist, Fred Hutchinson Cancer Center, University of Washington

Using Genetic Variants in Candidate Gene Pathways to Measure Prostate Cancer Risk and Prognosis

Within the ~3 billion letters of DNA that make up the human genome there are ~23,000 genes that code for a specific protein. Genetic alterations, changes in the sequence of letters in DNA, can significantly alter the production and/or function of proteins. A common genetic alteration is called single nucleotide polymorphisms (SNPs), which occurs when one letter is changed. Cancer researchers have found that certain SNPs can predict for cancer risk and cancer progression. Dr. Holt’s research focus is on identifying SNPs that predict prostate cancer risk and prognosis.

During her first two years as a PCF Young Investigator, Dr. Holt analyzed DNA from ~1400 prostate cancer patients and ~1300 healthy controls. She chose to examine genes that code for proteins which control how estrogen is used in the cell. Previous reports showed that altered levels of estrogen and expression of the genes involved in estrogen signaling were associated with prostate cancer in human prostate cancer tissue specimens. In her current study she identified several SNPs located in estrogen pathway genes that confer an increased risk for prostate cancer.

After identifying these SNPs, Dr. Holt is more fully investigating how these genetic alterations may impact the function and/or production of other genes within the same signaling network. It is important to recognize that every protein works within a system, like a piston in an engine. This phenomenon that a genetic alteration in one gene can impact another gene is called epistasis (a genetic interaction). Dr. Holt has generated a novel mathematical model to test for epistasis in the estrogen signaling pathway in prostate cancer. She plans to publish a detailed description of these methods for the cancer community at large. Understanding epistasis will be critical in understanding the complexities of heritable prostate cancer which is the cause of ~10% of all cases.