Abstract
In the largest genomic analysis of intermediate-risk prostate cancer samples to date, researchers have uncovered a five-element molecular signature that could help pinpoint patients whose disease is likely to recur and metastasize even after surgery or radiotherapy. They hope to develop a prognostic assay from this signature that can be used in the clinic.
In the largest genomic analysis of intermediate-risk prostate cancer samples to date, Canadian researchers have uncovered a molecular signature that could help pinpoint patients whose disease is likely to recur and metastasize even after precision surgery or radiotherapy (Nature 2017;541:359–64).
“I can have 100 men come through the door with what appears to be the same stage of cancer—localized and potentially curable—yet just by probability, I know roughly 30% will relapse after surgery or radiotherapy,” says co–senior author Robert Bristow, MD, PhD, of Princess Margaret Cancer Centre in Toronto. “We need to improve our ability to predict which patients fall in this higher-risk category.”
With Paul Boutros, PhD, of Toronto's Ontario Institute for Cancer Research, the team carried out whole-genome sequencing on 200 intermediate-risk prostate tumors, and whole-exome sequencing on another 277. They assessed the tumor samples for various markers of genomic instability, including point mutations, copy-number alterations, and DNA methylation status. Aided by available outcomes data from 130 patients, “we ranked the relative importance of these different indices,” Bristow explains, “and put together a five-element signature that is prognostic for disease recurrence, with greater than 85% accuracy.”
Epigenetic changes are key in this signature, notably hypomethylation of TCERGL1 and hypermethylation of ACTL6B. Point mutations in ATM, chromosome 7 rearrangements, and MYC amplification comprise the remaining three elements. The researchers are now investigating the functional consequences of these molecular alterations.
For men whose intermediate-risk prostate cancer contains these adverse genomic features, more intensive treatment up front is warranted, Bristow says. “There are much better hormone therapies now that really shut down androgen signaling, which we could incorporate earlier than the metastatic setting. For some cases, we could utilize PARP inhibition, exploiting mutant ATM-induced deficiencies in DNA repair.”
Whole-genome sequencing “is about as deep as you can go, and hadn't been done to this extent in prostate cancer,” observes Peter Nelson, MD, of Fred Hutchinson Cancer Research Center in Seattle, WA. He considers this study an “expansive, powerful analysis,” noting that ATM mutations, in particular, had been “a suspected feature of recurrence, but not really nailed down” until now.
“A key question that remains is determining this signature's frequency across a large patient population, which would give some indication of its utility,” Nelson says. “It also remains to be seen if, besides recurrence, this constellation of bad genomic hallmarks is consistently associated with mortality.”
Bristow, Boutros, and their team are collecting more information, including RNA-sequencing data, to further refine their signature. “Our goal is to develop an assay that simultaneously measures each individual element, then commercialize this platform once its prognostic utility has been validated in a new cohort of approximately 500 patients,” Bristow says.
Overall, “within 5 years, I think many more men diagnosed with prostate cancer will undergo genomic screening,” he adds. “To be more precise in our care of this disease, the lexicon needs to evolve so it's not only about Gleason scores and PSA levels, but also which molecular risk group a patient is in.” –Alissa Poh
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