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ChIA-PET Sequencing Provides Insight into Prostate Cancer Genomics

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Research; Genitourinary Cancer

Prostate Cancer Breakthroughs

At UT Southwestern, we’re conducting research to prevent and mitigate the side effects of prostate cancer treatment, both in regard to surgical treatment and radiation therapy. We’re at the forefront of prostate cancer breakthroughs, and we’re conducting significant research in advanced prostate cancer.

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Recent findings by researchers at UT Southwestern could open up an entire new field focused on enhancers that could lead to novel prostate cancer therapies.

Recent advances in prostate cancer genomic sequencing have revealed that prostate cancer is associated with higher rates of recurrent genomic rearrangements and lower mutation rates. Most prostate cancer-associated recurrent genomic rearrangements are involved in the upregulation of transcription factor genes, including the upregulation of ETS transcription factor family genes, such as ERG and ETV1, which are found in more than 50% of prostate cancer tissue samples. Elucidating the genome architectural features of transcription control is essential to better characterize the role of transcriptional dysregulation in prostate cancer development. [1]

As an Assistant Professor with a joint appointment in the Departments of Pathology and Urology at UT Southwestern Medical Center, my research group is focused on the study of molecular genetic and epigenetic events associated with cancer development, with the underlying aim of translating this knowledge into novel diagnostic, prognostic and therapeutic strategies. We utilize integrative approaches that include cell-based assays, studies using animal models, analysis of human cancer specimens, and next-generation sequencing.

While one of the most common cancers, prostate cancer is also one of the most heritable cancers. Another unique feature is that prostate cancer has very few mutations. Unlike other cancers, such as lung cancer and melanoma, which are rich in mutations, prostate cancers have very few mutations, but is mainly driven by structural variation, the most common being a fusion between two genes, TMPRSS2 and ERG.

RNA Polymerase II–Associated Chromatin Interactions in Prostate Cancer

While two-dimensional genomic sequencing methods have contributed to the detection of thousands of enhancers in prostate cancer, the targets of the majority of these enhancers have not been well characterized. It remains uncertain whether individual enhancers regulate one or many genes and, contrarily, whether single genes are regulated by one or multiple enhancers in prostate cancer. This knowledge gap has hindered overall understanding of the regulatory targets of somatic mutations and germline risk alleles present in some intergenic regions. [1]

In a recent genomic study, my colleagues and I characterized the three-dimensional landscape of RNA polymerase II–associated chromatin interactions in normal prostate and malignant cells using a technique called ‘ChIA-PET,’ short for chromatin interaction analysis by paired-end tag sequencing, which allows pairing of enhancers to their gene targets. ChIA-PET sequencing is a technique used to map associations of particular proteins with DNA across the entire genome and can identify all the enhancers and their target gene at the same time. [1]

By pairing thousands of enhancers to their target genes, the researchers detected thousands of transcriptional network hubs functioning within the framework set by structural proteins, such as CTCF and cohesins. Further integrative analyses revealed numerous mechanisms of transcriptional regulation and dysregulation in prostate cancer. Furthermore, the team uncovered many germline and somatic DNA alterations that rewire the landscape of RNA Pol II interactions in prostate cancer.

The team also discovered a genetic interaction between the germline risk allele rs684232 and the somatically acquired TMPRSS2-ERG suggesting a potential role of epistasis and modifier genes in modulation of prostate cancer risk.

We defined a germline-somatic interplay between the prostate cancer risk allele rs684232 and the somatically acquired TMPRSS2-ERG gene fusion in the transcriptional regulation of multiple target genes, including VPS53, FAM57A, and GEMIN4.

“Looking ahead, we anticipate that this work will create fertile avenues for further research in transcriptional regulation and cancer development.”

Ram Mani, Ph.D.

Future Research

These findings have implications for the development of treatment strategies to prevent or delay the onset of prostate cancer. We are continuing to study the role of transcriptional regulation in prostate cancer development and anticipate the research will better optimize therapy for prostate cancer patients. [1-2]

We characterized the landscapes of transcription in prostate cancer and uncovered thousands of RNA polymerase II–associated long-range chromatin interactions. These results have multiple implications ranging from basic biology to cancer etiology and risk.

Our research group is actively engaged in identifying the DNA damage and repair pathways that mediate cancer-specific recurrent genomic rearrangements and resistance to targeted therapies, as well as the functional consequences of epigenetic and transcriptional deregulation in cancer development. Collectively, these studies will serve as the basis for early cancer detection and therapeutic targeting. [1-3] Looking ahead, we anticipate that this work will create fertile avenues for further research in transcriptional regulation and cancer development.

Footnotes

1. Ramanand SG, Chen Y, Yuan J, et al. The landscape of RNA polymerase II-associated chromatin interactions in prostate cancer. J Clin Invest. 2020;130(8):3987-4005.
2. Houlahan KE, Shiah YJ, Gusev A, et al. Genome-wide germline correlates of the epigenetic landscape of prostate cancer. Nat Med. 2019;25(10):1615-1626.
3. de Bono JS, Guo C, Gurel B, et al. Prostate carcinogenesis: inflammatory storms. Nat Rev Cancer. 2020;20(8):455-469.

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