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Studies Explore Genetic Alterations Linked to Aggressive, Metastatic Prostate Cancer

NEW YORK (GenomeWeb) – In separate studies, two research teams have teased out genetic alterations linked to aggressive or metastatic prostate cancer.

Prostate cancer is the second most common cancer among men, and while the disease is often indolent and treatable, some cases are aggressive. Distinguishing between the two could guide treatment decisions.

In one study appearing today in Cell, an international team of researchers homed in on an allele on chromosome 19 that is associated with aggressive disease, and worked out how it might be influencing the expression of two genes involved in prostate cancer cell growth and tumor progression. Previous studies have implicated an allele located at 19q13 with aggressive prostate cancer, a link the University of Oulu's Gong-Hong Wei and his colleagues confirmed in their new analysis of nearly 3,000 Finnish prostate cancer cases.

The researchers conducted an expression quantitative trait locus analysis in three independent cohorts and found that the risk allele is linked to the expression levels of both CEACAM21 and PCAT19. Through knockdown, overexpression, and other assays, they found that not only are CEACAM21 and PCAT19 highly expressed in prostate cancer tissue as compared to control tissues, but also that knocking them down in prostate cancer cell lines is associated with decreased cell proliferation, migration, and invasion. This, the researchers said, suggests that the genes contribute to disease development.

The risk allele falls within an enhancer element and changes the binding site of HOXA2, which is itself an oncogene associated with poor prognosis, the researchers reported. This suggested to them that the risk allele works with HOXA2 to drive CEACAM21 and PCAT19 expression.

Within clinical data, Wei and his colleagues also noted a synergistic effect between the 19q13 risk allele and the expression of CEACAM21 and PCAT19 on prostate cancer prognosis.

"Thus, the findings may allow better prognostic prediction and distinguishing a more lethal phenotype to identify high-risk group patients that need radical treatment regimens because of their poorer treatment outcomes," they wrote in their paper.

Meanwhile, a team of US researchers also reported in Cell today on structural variants that contribute to metastatic castration-resistant prostate cancer. These variants also affect regulators of tumorigenesis and progression. Using whole-genome and whole-transcriptome analyses of metastatic prostate cancer samples from more than 100 men who had developed resistance to androgen deprivation therapy, the University of California, San Francisco's Felix Feng and his colleagues found that these recurrent structural variants affect key driver genes.

For instance, 81 percent of patients harbored an amplification nearly 67 megabases upstream of the androgen receptor (AR) gene. The androgen receptor, which is activated by male sex hormones, is the target of second-line prostate cancer treatments used after recurrence.

While tumors with this amplification also often had duplicated AR genes, the upstream amplification was, on its own, linked to increased AR expression levels. Overall, they found that 85 percent of their samples had pathogenic activating AR mutations, AR amplifications, or putative AR enhancer region amplifications. Twenty-nine percent of cases harbored alterations affecting other genes that modulated the AR pathway.

In addition, the researchers reported structural variations affecting MYC and FOXA, including in lncRNAs associated with MYC regulation.

Feng and his colleagues also noted links between certain DNA repair deficiencies and certain types of structural variations. Patients whose tumors had TP53 alterations, for example, were more likely to exhibit chromothripsis, while BRCA2 inactivations were linked to deletions.

"This study could aid the search for better therapies to treat aggressive prostate cancer," co-first author Christopher Maher from Washington University School of Medicine said in a statement. "More immediately, the new information could help doctors find ways to identify which patients may develop aggressive tumors, and help guide their treatment decisions."