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Aggressive Prostate Cancer Harbors Genomic Patterns

NEW YORK (GenomeWeb) – A team of Canadian researchers has scoured prostate cancer genomes to find patterns associated with aggressive disease.

In a pair of studies out today, a team led by researchers at the Princess Margaret Cancer Center and the Ontario Institute for Cancer Research analyzed mutational events in both non-inherited and inherited forms of prostate cancer for clues as to why some patients develop aggressive disease while others do not. They uncovered a number of recurrent mutations — such as an ATM point mutation in sporadic prostate cancer and MED12/MED12L amplification in prostate cancer that developed in people with germline BRCA2 mutations — and found that some of these alterations could predict prognosis.

"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," Robert Bristow from Princess Margaret Cancer Center said in a statement. "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."

Bristow, along with senior author Paul Boutros from OICR and their colleagues, sequenced the whole genomes of 200 localized non-indolent prostate cancers with similar clinical risk profiles. They further folded in whole-exome sequencing data from 277 other prostate tumors and conducted RNA and methylation analyses on a subset of this sample.

As they reported in Nature, the researchers found that these tumors typically didn't harbor many clinically actionable single nucleotide variants. They noted that only six genes had coding SNVs in more than 2 percent of tumors, and instead found a number of non-coding changes, large-scale rearrangements, and local hypermutation events.

In the 200 samples that underwent whole-genome analysis, the researchers uncovered seven non-coding SNVs in at least seven samples, and 64 non-coding SNVs in four to six patients. In addition, as the researchers expected, the most common recurrent rearrangement was a TMPRSS2:ERG fusion on chromosome 21, which was present in 38 percent of tumors. Other rearrangements included a translocation of MMS22L and ARHGAP10 and of chr17p11.1 and chr1q21.2.

Some 20 percent of the tumors exhibited chromothripsis, the researchers reported, in which there are extensive rearrangements confined to a limited region and 23 percent exhibited kataegis, or localized regions of hyper-mutations.

With follow-up data on 130 of the 200 patients whose tumors were sequenced, the researchers connected a point mutation in the ATM gene to relapse as well as an inter-chromosomal translocation breakpoint at the chromosome 7 centromere and amplification of MYC to biochemical recurrence.

Methylation status, they noted, appeared more closely linked to outcomes. Hyper-methylation of a probe near the 5' end of TCERG1L was strongly linked to poor outcomes, while hypo-methylation at probe at its other end was linked to good outcomes.

Based on these findings, the researchers developed a multi-modal biomarker signature that they reported could predict differences in patient relapse and survival.

But as Bristow, Boutros, and their colleagues also reported in Nature Communications, familial prostate cancer samples have slightly different mutational profiles. For their second study, they profiled localized prostate cancer samples from 14 men with germline BRCA2 mutations and compared them to those 200 samples from the previous study.

In particular, they noted that the mutational profiles of these tumors resembled that of metastatic disease. For instance, these tumors had a higher percentage of genome alterations as well as increased numbers of SNVs and genomic rearrangements as compared to sporadic tumors.

Likewise, the researchers found that familial prostate cancers often had MED12/MED12L amplifications — changes not common among the sporadic cancers. However, these changes are seen among metastatic castrate-resistant prostate cancer, the researchers said, suggesting that they could drive aggressive disease. Such amplifications were present in 44 percent of the BRCA2-mutant prostate cancers samples, and they were more common among BRCA2-mutant prostate cancers samples with intraductal carcinoma (IDC).

BRCA2-mutant prostate cancers samples with IDC were also more likely to be associated with copy-number changes linked to poor outcomes, the researchers reported.

Bristow, Boutros, and their colleagues added that the molecular changes they identified could be developed into diagnostics and help guide treatment. They noted that men with disease deemed genomically to be aggressive might benefit from more intense treatment.

"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," Bristow said.