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Researchers Shed Light on Previously Unidentified Commonly Mutated Genes in Prostate Cancer

Shannon Connelly
Published Online:8:22 PM, Tue April 25, 2017

Joshua Armenia, PhD

In an effort to shed light on the genetic differences between primary and metastatic prostate cancer, researchers recently analyzed a cohort of more than 900 prostate cancer patients to determine which genes and pathways are recurrently altered. The analysis uncovered 23 genes that have not been previously identified as significantly mutated in prostate cancer, lead researcher Joshua Armenia, PhD, shared.
Armenia, research fellow, Memorial Sloan Kettering Cancer Center, recently gave a presentation on the long tail of mutated genes in prostate cancer during the 2017 Genitourinary Cancers Symposium. He further discussed the findings of his research in an interview with Targeted Oncology.
TARGETED ONCOLOGY:  Can you give an overview of your presentation?
Armenia: In our project, we analyzed 918 patients with prostate cancer. We conducted a mutational significance analysis to detect novel genes and pathways in prostate cancer to redefine the genomic landscape. We found 23 novel genes with potential in prostate cancer that have not previously been found as significantly mutated in prostate cancer but that around found to be mutated in other cancers. These genes include SPEN, for example, which is a hormone-regulator gene that has a role in breast cancer, to regulate response to tamoxifen, and it’s usually deleted in breast cancer. We found that in prostate cancer, this gene is frequently mutated by loss-of-function mutations, and these mutations in SPEN are also significantly enriched in metastatic disease.
We also found another novel gene, which is CUL3, that is part of the E3 ubiquitin ligase complex. The mutations in this gene are significantly mutually exclusive with SPOP mutations and the copy number profile of these tumors resembles the copy number profile of SPOP-mutant tumors.
We also found an enrichment in splicing pathway alterations. In 4% of these tumors, we found alterations in genes such as SF3B1 and U2AF1. We also found a novel subclass of prostate cancer characterized by mutations in epigeneity regulators and chromatin modifiers.
Finally, we found that there is a set of genomic markers that selectively enrich the metastatic tumors, and this includes loss of p10 and p53, as well as loss of RB1, BRCA2, and APC. But it also includes mutations in genes such as KMT2C and KMT2D. On the other end, primary tumors seem to be enriched in mutations in SPOP and in deletions in FOXP1.
TARGETED ONCOLOGY:  Are there any plans to further study these newly discovered mutations?
Armenia: There definitely should be experimental validation of some of these targets to actually assess the role of these mutations in prostate cancer in vitro, and in in vivo models as well.
TARGETED ONCOLOGY: What impact do you see for analyzing genes in the larger scope of prostate cancer?
Armenia: The power of having a large cohort of prostate cancer patients is that it can allow us to define biomarkers of advanced disease. This is comparing primary metastatic tumors to study the evolution of this disease more in detail. It would also be interesting to identify markers of risk progression of advanced disease within primary tumors by comparing the genomic alterations across Gleason scores in primaries.
TARGETED ONCOLOGY:  What is the takeaway from this research?
Armenia: There are new opportunities for clinical applications for prostate cancer, in particular. We have genes that can be targeted, such as the splicing genes, for example. Even if it’s rare, there are still a fraction of patients that have these driver mutations in these genes. Twelve percent of these tumors show alterations in epigenetic regulators and chromatin modifiers, but we also have 11% of tumors with alterations in the Wnt/β-catenin pathway, and if you look more closely at metastatic disease, PI3K, DNA repair, as well as the Wnt/β-catenin pathway, these are strongly altered in more than 30% of metastatic disease and this opens up clinical application and opportunities in prostate cancer.

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