High-resolution genome-wide mapping of structural mutations in prostate cancer

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DESCRIPTION (provided by applicant): Summary: As a physician with a PhD in structural biology, I aim to become an independent investigator studying the somatic genetics of prostate cancer while maintaining a small clinical practice in oncology. I am an Instructor in Oncology at the Dana-Farber Cancer Institute, receiving training in the laboratory of Dr. Matthew Meyerson, with additional access to the resources of the Broad Institute of Harvard and MIT. In addition to coursework, conference attendance, and mentoring by Dr. Meyerson and others, I propose a research project to characterize chromosomal aberrations in prostate cancer, relate them to cancer progression, and identify targeted oncogenes and tumor suppressor genes. Prostate cancer is distinguished by its clinical heterogeneity, with some cancers remaining indolent and others requiring local therapy to prevent metastasis and death. Unfortunately, we do not know the genetic bases of these differences. Understanding this may allow development of markers to distinguish between aggressive and indolent prostate cancer, and therapeutics to target the molecular alterations that give rise to progressive disease. We have developed techniques to characterize chromosomal aberrations in prostate cancer, including loss of heterozygosity (LOH) and copy number changes, at high resolution and throughout the genome, using single nucleotide polymorphism (SNP) arrays. We are able to identify known oncogene and tumor suppressor gene targets with high accuracy, and have small and intriguing candidate gene lists for other targeted regions. Here we propose to use this technology to address the somatic genetics of prostate cancer progression and validate those gene targets, with three specific aims: 1, Identify chromosomal aberrations, including LOH and copy number alterations, differing in prevalence between localized and metastatic prostate cancers; 2, Identify point mutations and insertion/deletion events in candidate oncogenes and tumor suppressor genes that appear targeted by these aberrations; and 3, Functionally validate selected candidate oncogenes from Aims 1 and 2. Relevance: Prostate cancer arises due to the accumulation of mutations in the DNA of a cell. We aim to identify mutations associated with its growth and spread outside of the prostate. Identifying them will potentially help us recognize in advance cancers that are likely to spread and develop therapies for them.