Research Projects
Read about some of our current research projects:
Project 1: Confirmation of SNPs associated with aggressive PCa in a GWA Study
We propose to identify inherited sequence variants in the genome that confer moderate risk to prostate cancer (PCa) using a genome-wide association (GWA) study among more than 10,000 subjects from multiple study populations. The identified genes may advance our understanding on the etiology of PCa and could be used to better predict the risk for developing PCa. The focus on aggressive PCa is particularly important because this is the most clinically relevant form of PCa.
Project 2: Genetic profiling in PCPT: PCa risk, PSA levels, and chemoprevention
The overall hypothesis of the study is that multiple genetic variants, when combined, can be used to predict men at increased risk for PCa. We will use data and samples from the PCPT study, a phase III randomized, double-blind, placebo-controlled trial of finasteride in the prevention of prostate cancer. Results from this study may potentially benefit millions of men. Men at highest risk for PCa could be identified at an early age for intensive screening and chemoprevention such as finasteride. Genetic variants could also be used in combination with PSA and other existing clinical variables to considerably improve their predictive accuracy for positive prostate biopsy.
Project 3: Genetic variants in the genome predisposing to aggressive PCa
Taking advantage of the publicly available CGEMS genome wide association data, as well as the large and unique PCa patient population at Johns Hopkins Hospital (JHH), we propose a systematic genetic association study to confirm, fine map, and better characterize genetic risk variants for aggressive PCa.
Project 4: Interaction of germline and somatic changes in PCa progression
Understanding factors associated with the progression of PCa will have a significant impact on management and treatment of the disease. This proposal intends to identify interaction effects on prostate cancer (PCa) progression for several known germline (PCa) risk variants genetic and somatic genetic and epigenetic changes identified in our study, using several global detection methods. We hypothesize that germline risk variants, combined with somatic genetic and epigenetic changes may increase the risk of prostate cancer progression. The results of this study may advance our understanding on the etiology of PCa progression and augment current methods to better predict which PCa patients are most likely to develop progressed disease at the time of diagnosis. The PCa patients with poor prognosis can receive intensive monitoring and treatment.
Project 5: Systematic search for gene-gene interaction effect on prostate cancer risk
In this proposal, we will apply two novel analytical methods that allow us to perform such gene-gene interaction analysis among millions of genetic changes in thousands of subjects. We will first utilize data (millions of genetic changes) from an existing and large National Cancer Institute Cancer Genetic Markers of Susceptibility (CGEMS) study to systematically discover gene-gene interactions in the genome among ~1,000 PCa patients and ~1,000 normal subjects. We then propose to confirm these discovered gene-gene interactions in our large population-based case-control study in Sweden (CAPS), with ~3,000 PCa patients and ~2,000 normal subjects. Such confirmation is necessary because many gene-gene interactions, whether true or by chance alone, will be found in the discovery stage. Only true gene-gene interactions will be replicated in independent study populations.
Project 6: Clinical validity and utility of genomic targeted chemoprevention of PCa
In this study, we hypothesize that targeted chemoprevention, based on 1) overall genetic risk [family history (FH) and PCa risk-associated genetic variants], and 2) polymorphisms that interact with 5ARIs, may be more efficacious and cost-effective, and thus more likely to be employed by physicians and their patients. The effectiveness of this genomic-targeted approach needs to be systematically evaluated and compared to non-genomic approaches using evidence-based methods such as those recommended by the EGAPP (Evaluation of Genomic Applications in Practice and Prevention) working group. We have assembled a multidisciplinary research team to address an overarching question of whether a genomic-targeted approach improves outcomes related to chemoprevention of PCa using 5ARIs compared to a non-targeted approach. We will evaluate and compare the efficacy, perception, decision making, and cost-effectiveness of genomic and non-genomic approaches in two existing large randomized clinical trials (REDUCE and PCPT), two new study populations of men at risk for PCa, and in a survey of physicians. The unique study design of REDUCE and PCPT, with end-of-study prostate biopsies, allows us to address two critical questions in this study: PSA detection-bias of PCa risk-associated SNPs and efficacy of genomic-targeted chemoprevention of PCa using 5ARIs. Results from this study will provide comprehensive data for evidence-based evaluation by the Center for Disease Control’s EGAPP working group, provide a proof of principle study of comparative effectiveness research (CER), and will help build a road map for future genomic and personalized medicine (GPM) in the 21st century.
Project 7: Gene-hormone interaction and risk of breast cancer
The overall hypothesis of this study is that common genetic variants can be used to classify women into low or neutral risk groups for developing breast cancer due to HT use (gene-hormone interaction). We will identify genetic variants using data and samples from the Hormone Therapy Trial (HT) of the Women's Health Initiative (WHI) study. Results from this study could benefit millions of women who suffer from menopausal symptoms. The identified genetic variants will be used to create a risk-benefit profile for HT treatment and may potentially improve clinical decision making for HT use. Individual HT-breast cancer risk assessment is important for identifying women for whom the benefits may outweigh the risks versus those women in whom the risks outweigh the benefits.
Project 8: The Role of CHD1 in DNA Rearrangements and Progression of PCa
The overall hypothesis of this study is that loss of the chromatin remodeler CHD1 leads to genomic
DNA rearrangement which results in DNA copy number alterations (CNAs) at other
critical genes, thereby driving cancer progression. The primary
goals in aim 1 are: 1) to confirm
the associations between deletion of CHD1
and CNAs identified in our pilot study, thereby to identify the CHD1 associated collaborative network in
PCa; 2) to determine whether loss of CHD1
is associated with tumorigenesis at early stages and/or cancer progression at
advanced stages. The goal of aim 2 is to evaluate the in vitro causal effects of
knockdown CHD1 expression in response to oxidative stress on DAN damage, genesis
of DNA rearrangement in terms of CNAs, differentially altered gene expression,
and cellular or growth characteristics.
In aim 3 we will explore the in vivo causal effects of loss
of CHD1 and MAP3K7 on tumorigenesis, pathological characteristics, invasion and
metastases.