Prostate cancer that seems highly curable at first can take a turn toward something that is more aggressive—and far deadlier. If this turn, which occurs about 30% of the time, could be predicted, physicians could intensify treatment straightaway and potentially effect cures in men who have a high risk of succumbing to prostate cancer that would come roaring back following radiotherapy or surgery.

It may soon be possible to predict which cases of prostate cancer are especially risky, assert Canadian researchers. These scientists, led by Robert Bristow, M.D., Ph.D., and Paul Boutros, Ph.D., both affiliated with the Canadian Prostate Cancer Genome Network (CPC-GENE), report findings that could help clinicians personalize effective, targeted therapies from the moment of diagnosis.

The findings appeared January 9 in Nature, in an article entitled, “Genomic Hallmarks of Localized, Non-Indolent Prostate Cancer.” The article describes how the scientific team led by Drs. Bristow and Boutros analyzed the tumors of 477 Canadian men in the general population with prostate cancer.

“We analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumors with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset,” wrote the authors. “Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers.”

Specifics included a paucity of clinically actionable single-nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumors harbored recurrent noncoding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, added the article’s authors, and correlated with specific genomic profiles.

In a related study (“Germline BRCA2 Mutations Drive Prostate Cancers with Distinct Evolutionary Trajectories”), also published January 9 and led by Drs. Bristow and Boutros, but appearing in Nature Communications, scientists described how BRCA2 inherited disease turns lethal in rare cases where men have inherited a BRCA2 gene mutation that affects the repair of DNA damage in cells.

To identify the drivers of aggression in BRCA2-mutant prostate cancer, the scientists characterized genomic alterations in localized prostate cancer tumor specimens from 14 men carrying a deleterious germline mutant BRCA2 allele using either whole-genome sequencing and/or single-nucleotide polymorphism array-based copy-number analyses.

“We find that BRCA2-mutant PCa [prostate cancer] harbours a mutational profile more akin to that of mCRPC [metastatic castration-resistant prostate cancer] than localized sporadic PCa, and shows broad dysregulation of pathways associated with aggressive disease, including the MED12/MED12L axis,” detailed the authors. “Micro-dissection and subclonal reconstruction shows distinct evolutionary trajectories and identifies a common precursor to IDC [intraductal carcinoma] and adjacent invasive carcinoma.”

Overall, the authors found that localized castration-sensitive BRCA2-mutant tumors are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease. Such tumors, the authors concluded, could justify aggressive initial treatment.

“We used specialized state-of-the-art DNA sequencing techniques to focus on the genetics of prostate cancers to better understand what is so different from one man's disease to another man's disease,” explained Dr. Bristow, who not only participates in the CPC-GENE program, but is a clinician-scientist at the Princess Margaret Cancer Centre, University Health Network.

“These genetic fingerprints had high accuracy in being able to discern those men who do well with surgery or radiotherapy and those men that already have early spread of their disease outside the prostate gland. This information gives us new precision about the treatment response of men with prostate cancer, and important clues as to how to better treat one set of men versus the other to improve cure rates overall.”

The next step will be to translate this research finding into a molecular diagnostic tool that can be used in the clinic. “We will be testing 500 more men over the next 2 to 3 years to accomplish that,” comments Dr. Bristow. “It is an exciting era in prostate cancer research. We will soon be able to identify in the clinic the exact genetic state of a man's cancer and react on a patient-to-patient basis to cure more men worldwide.”

Dr. Bristow says that although most men present with localized, potentially curable disease, more than 200,000 men die of it every year when tallied across all countries.

“The richness of information in our genetic findings today will enable us to further sort individual patients into appropriate groups of risk for spread of their disease and effect cures in men who otherwise might have been incurable.”

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