The role of the project is to characterize the relationship between ductal prostate cancer and conventional prostate cancer. Ductal is thought to be more aggressive and less responsive to hormonal treatments, and it’s thought that following the PSA does not work well to monitor for relapse, which suggests that more frequent CT scans and bone scans are required. To date the findings of my study include:

Next generation sequencing from our first case showed that the ductal cancer is very closely related to conventional cancer, with very late divergence between them. The rest of the samples were submitted for sequencing in early April 2015 and are now scheduled to be sequenced.

Expression array has shown that there are very few differences between ductal and conventional prostate cancer in the expression levels of the genes. There are differences in a few genes that are usually expressed in smooth muscle, which we think may be related to their different appearances, but we do not think that they cause major differences in their behavior. We are following up on the significance of these changes.

Since the expression array is a developing technology, we are seeking to validate this using next-generation sequencing (RNA-seq, or transcriptome sequencing). Those data are still coming.

I have collaborated with Donald Vander Griend, PhD, in looking at gene expression at the level of individual cells, instead of the entire tumor, using something called RNA-in situ hybridization. Here, too, we’ve found very similar expression of PSA in both types of cancers.  

I’ve collaborated with colleagues in the Department of Urology to look at clinical data from large databases. There, we found that patients with ductal prostate cancer have very similar outcomes to those with high grade conventional prostate cancer.

An undergraduate working with me has looked at data from the University of Chicago and found that in patients with ductal cancer, no one has developed metastases without first having a rising PSA.

The data collection will be complete by July, at which point I am leaving the University of Chicago to pursue a position as an Assistant Clinical Investigator in the Laboratory of Genitourinary Cancer Pathogenesis at the at the National Cancer Institute. Once there, I will continue data analysis on this project as a part of my laboratory’s focus to investigate the heterogeneity and evolution of the prostate cancer genome. I understand that my Young Investigator Award cannot follow me to the NCI, so I have copied Callie Johnston, who can help return the balance of the award to the CRF.

With the data we have now, the conclusion is that ductal prostate cancer is very similar to aggressive conventional prostate cancer and should be managed as such. This includes aggressive front-line and adjuvant therapies, but does not include extra CT scans and bone scans. Thank you for your support of this science and my career as an early investigator. Your support has been critical in my transition to a role with the NCI.

My project seeks to characterize the molecular features of ductal adenocarcinoma of the prostate, an aggressive subtype of prostate adenocarcinoma. The research method is focused on molecular characterization of prostate cancer from patients harboring both acinar (conventional) and ductal adenocarcinoma. Once the cases are identified, the project involves evaluation of the cases to examine somatic point mutations, fusion genes, and copy number changes.

Identifying cases that were representative of each histology and had adequate tissue was was crucial for this study. I relied on a national tissue resource, the Prostate Cancer Biorepository Network, as a resource. However, they were able to supply only one case that matched the criteria required.

I supplemented this with cases from the tissue bank at the University of Chicago. I collaborated with the genitourinary pathologist Gladell Paner to review potential cases. We initially identified 26 potential cases of patients with both acinar and ductal histologies. We reviewed all the histologic blocks of each case, and identified 11 cases with sufficient histologic purity and tumor quantity for these studies (Figure 1). Ten of these cases have undergone macro- or microdissection.

Figure 1.  Representative images of acinar and ductal histologies from a single patient with mixed histologies.

DNA and RNA have been isolated from each dissected region of tumor. Initial quality evaluations have been performed, indicating that the DNA is of high quality. Sequencing libraries have been constructed using the NEB Next Ultra library preparation method. Screentape evaluation of sequencing libraries indicate that the initial libraries are of expected size and distribution (Figure 2). The project will focus on the five samples with the highest quality sequencing libraries.

Figure 2. Screentape plot of sequencing library constructed from ductal adenocarcinoma of the prostate DNA.

To avoid batch effects, remaining sequencing libraries are being constructed prior to submitting these samples for sequencing. Sequencing will include both whole genome sequencing to facilitate evaluation of copy number variation and identification of chromosomal rearrangements, and exome sequencing to identify somatic point mutations and small insertions and deletions. RNA-seq libraries will be made from stored isolated RNA for identification of gene fusions. The project is nearing completion of data gathering and transitioning into the data analysis phase.

In addition to the scientific proposal, this work has facilitated other projects to characterize ductal prostate cancer. I am collaborating Donald Vander Griend to perform RNAish, a method to fluorescently label RNA transcripts within a cell for quantification of RNA transcription at a cell-based level using microscopy and image analysis software. In addition, an undergraduate at the University of Chicago is working with me to perform a chart review to examine patterns of relapse and detection of relapse for patients with ductal adenocarcinoma. Both of these additional projects will help improve our method of disease surveillance and relapse detection for patients with ductal prostate cancer.