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Prostate Cancer Fusion Details May Inform Progression Risk

NEW YORK (GenomeWeb) – A new study suggests taking a closer look at a relatively common gene fusion in prostate cancer tumors may help in distinguishing low-risk cases from more aggressive forms of the disease.

Researchers from the Mayo Clinic used whole-genome mate-pair sequencing to characterize TMPRSS2-ERG gene fusions in 133 tumor samples from individuals with prostate cancer classified as very low-, low-, intermediate- or high-risk based on Gleason scores. As they reported online today in Cancer Research, nearly half of the tumors contained fusions involving the chromosome 21 genes TMPRSS2 and ERG.

Consistent with past reports, "the presence or absence of a TMPRSS2-ERG gene fusion was not predictive of outcome," senior author John Cheville, a biomarker discovery, laboratory medicine, and pathology researcher at the Mayo Clinic, said in a statement. But, he added, results from the latest analysis suggest the nature of the fusion and the way it formed did appear to have some ties to prostate cancer outcomes.

The TMPRSS2-ERG fusions did appear to be less common in the tumors deemed high-risk for progression, the team noted. But prostate cancer progression also tended to differ with the presence or absence of the genes falling between TMPRSS2 and ERG in the fusions. Those interstitial genes were more frequently retained in fusions from low-risk or very-low risk cases compared to cases with intermediate or high risk of progression, where interstitial gene deletions were more common.

"[T]he retention of interstitial genes during the fusion event was more common in very low-risk and low-risk cancers, and there may be genes in this region that suppress or limit tumor growth," Cheville explained.

Building on past hints from animal model studies, the team set out to profile TMPRSS2-ERG gene fusions in prostate tumor samples collected from 133 prostate cancer patients during radical prostatectomy surgery. The set included 53 tumors classified as very low progression risk, along with 26 low-risk tumors, 29 tumors classified as intermediate-risk, and 25 high-risk tumors.

Based on analyses of whole-genome mate pair read sequence data generated with an Illumina mate-pair kit and HiSeq2000 instrument, the researchers identified TMPRSS2-ERG gene fusions in 60 of the 133 tumors, or 45 percent of cases. The fusion was somewhat less common in the high-risk cases, but still turned up in 24 percent of those cases.

Some 52 percent of intermediate-risk prostate tumors contained the TMPRSS2-ERG gene fusion compared to around 43 percent and 59 percent of the very low-risk and low-risk tumors, respectively.

Even so, the team noted that tumors at the lower end of the progression risk spectrum tended to retain interstitial genes between TMPRSS2 and ERG: 18 of the 21 interstitial gene-containing TMPRSS2-ERG gene fusions fell in tumors from the low- or very low-risk tumors.

In a subset of 34 prostate cancer cases with available biochemical recurrence data, the researchers found that the 22 individuals with interstitial genes in the fusion had lower cancer recurrence rates than the 12 individuals with interstitial gene-free TMPRSS2-ERG gene fusions in their tumors.

Though more research is required before such results can inform clinical practice, Cheville said that the results so far hint at "potential utility for determining the status of interstitial genes in stratifying men with prostate cancer into more well-defined risk groups."