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Sequencing Study Reveals Recurrent Prostate Cancer Rearrangements

By Andrea Anderson

NEW YORK (GenomeWeb News) – A new genome sequencing study has uncovered recurrent rearrangements and mutations contributing to prostate cancer.

Researchers from the Broad Institute and elsewhere sequenced the genomes of seven primary prostate cancer and normal samples from the same individuals. Along with cancer-specific base changes, they also found several known and previously undetected rearrangements turning up in multiple samples. The study appears online today in Nature.

"Even in seven genomes, we did find recurrent patterns and we discovered new genes that were disrupted recurrently by rearrangements in multiple tumors," co-lead author Michael Berger told GenomeWeb Daily News. "It underscores the advantage of whole-genome sequencing for a disease like prostate cancer, where the rearrangements seem to be so important for the disease progression."

Berger, who participated in the study as a research scientist in senior author Levi Garraway's lab at the Broad Institute, is currently a pathology researcher at the Memorial Sloan-Kettering Cancer Center.

The team's findings are consistent with past studies hinting that rearrangements — including those leading to a fusion between TMPRSS2 and ERG genes — are a key feature of prostate cancer. In addition, they found clues that the TMPRSS2-ERG fusion in particular might be linked to rearrangements occurring in open chromatin context, while other fusions typically crop up in transcriptionally silent, closed chromatin regions.

Berger and his colleagues used the Illumina GAII to sequence primary tumor samples and matched normal tissue from seven individuals with high-risk prostate cancer to about 30 times coverage each.

"Prostate cancer has some well known gene fusions caused by chromosomal rearrangements which are particularly important for the biology," Berger noted. "Whole-genome sequencing seemed like a nice technique to apply in this particular case because these rearrangements wouldn't be detectable by exon capture or other low-resolution approaches … Basically, anything short of whole-genome sequencing wouldn't reveal these rearrangements."

In the process, the researchers found a median of nearly 3,900 somatic base mutations in the tumors tested — changes that were particularly common at so-called CpG positions in the genome where cytosine nucleotides neighbor guanine.

While the mutation rate is comparable to that detected in breast cancer and acute myeloid leukemia, the team noted, it's much lower than that reported for some other cancers, including melanoma and small cell lung cancer.

Among the genes that were mutated in two or more tumor samples: the scaffold protein coding gene SPTA1, SPOP, which codes for a protein involved in ubiquitination and transcription, as well as several chromatin-modifying genes and genes involved in stress response.

The researchers' search for prostate cancer-related rearrangements, meanwhile, uncovered a median of 90 such rearrangements in each tumor genome, including several rearrangements affecting PTEN pathway genes and other tumor suppressors.

Consistent with past studies pointing to recurrent TMPRSS2-ERG fusions in prostate cancer, the researchers found rearrangements producing such fusions in three of the seven tumors tested.

Even so, Berger noted, they found that this TMPRSS2-ERG fusion does not always stem from the sort of simple deletions found previously. Instead, some tumors show more complicated rearrangements that produce both TMPRSS2-ERG and other gene fusions, he said.

When the researchers incorporated epigenetic information into their analysis, they found clues that tumors carrying the TMPRSS2-ERG gene fusion also tend to have more breakpoints in the regions of the genome reported to have open chromatin and active transcription in prostate cancer studies.

On the other hand, tumors lacking this fusion have more breakpoints in parts of the genome with closed chromatin regions that are typically transcriptionally silent.

Nevertheless, Berger emphasized that more sequencing work is needed to determine whether these patterns hold in additional prostate tumors.

"It could just be an odd coincidence and by sequencing more genomes we'll see if the pattern holds up," he said. Even so, he added, "if it's not related to the gene fusion status, it suggests the rearrangements may be occurring in a particular compartment of the nucleus."

Researchers at the Broad Institute and elsewhere are using sequencing to tackle additional prostate cancer genomes, Berger said, in an effort to continue unraveling the biology of the disease. As with other cancer sequencing studies, he added, the goal is to eventually apply these and other genomic insights to improve cancer treatment.

"If we continue sequencing genomes of all [prostate cancer] risk categories, the genome sequence may be able to distinguish indolent from aggressive prostate cancer and potentially prevent unnecessary prostatectomies and over-treatment," Berger said. "But that's going to require additional sequencing of lots more tumors."