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Mapping PCa’s Genetic Landscape Just Got a Bit Easier and Potentially Less Expensive

January 14, 2013 -- Cancer genetics researchers study tumors for clues; they want to know how the tumor got there in the first place; how it differs from other tumors; how it differs from normal tissue; how it behaves over time; how it changes over time; what its presence does to its neighborhood, how it affects other cells and molecules, and ultimately, they hope to use these clues to deliver kill shots to tumors. These researchers meticulously chart the genomic landscape of tumors so they can make detailed maps to follow as they hunt for a tumor’s Achilles Heel. Each cancer presents its own unique challenges to genetics researchers; in prostate cancer one of those singular challenges has been the lack of cancer tissue to study once the disease has progressed to an advanced stage—most patients do not undergo biopsies late in the course of their disease. A recent study in the journal European Urology demonstrates for the first time the feasibility of using preserved biopsy tissue procured from prostate cancer patients early in the course of their disease to map the genomic characteristics of that patient’s tumor. Prior to now, researchers mostly required large amounts of tumor DNA taken from fresh or frozen biopsies, rather than the small amounts fixed in wax that are traditionally used to store biopsy samples.

This first-in-principal study was led by PCF Young Investigator Dr. Himisha Beltran at Weill Cornell Medical College, a cancer genetics researcher and physician. (Dr. Mark Rubin, also PCF-funded, was the senior author on the paper.) Beltran and colleagues used next-generation genomic sequencing technology (in collaboration with Foundation Medicine) on archived tumor samples that were chemically preserved and embedded in a waxy substance so they could map out all the clues found in those men’s tumors. The newer technology involves re-sequencing suspect regions of DNA repeatedly to map out an accurate readout of that genetic region using minute quantities of DNA. “As little as 55 ng of DNA was needed to achieve deep sequence coverage, which we believe is a major advance in the field of cancer genomics and one step toward bringing such technology realistically into routine clinical practice,” write the study authors. The approach can improve the cost effectiveness of personalized genome sequencing and can be done in a relatively short period of time (~21 days) which makes it useful in clinical applications, write the authors.

Beltran et al were able to use this new technique to accurately identify multiple types of cancer-associated mutations and gene fusions in a single test. Tumors from 45 men with a range of prostate cancer types—localized disease, metastatic disease and treatment-resistant metastatic disease—were assessed. And while the primary objective of this study was to prove that new sequencing methods work well and reliably on preserved biopsy samples, the study was also successful at pinpointing novel genomic alterations in advanced prostate cancers. For example, the researchers found that a mutation known as a point mutation, where a single unit of DNA is changed, is more common than previously thought in advanced prostate cancer and may be a factor in the development of treatment resistance. Also, of note, a highly aggressive form of prostate cancer that Dr. Beltran is studying, known as neuroendocrine prostate cancer, does not seem to make the androgen receptor (AR) protein, a finding that suggests, say the authors, that drugs that target the AR protein may not work well in this subset of patients.

The researchers report they identified more than half a dozen other novel mutations. And some of the mutations found are what researchers call actionable, meaning drugs are available or under development that can be used to amend the mutated gene’s function.

Beltran says her next steps will be to understand how gene changes in an individual patient’s original tumor change with disease progression and to correlate how this may affect response to specific therapies used to treat prostate cancer. The hope is that these genetic tests can guide a more personalized treatment approach and help improve outcomes for patients.

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