Two decades of research pay off as major PCA variant pinpointed

A team, including researchers at the University of North Carolina (UNC), Chapel Hill, Johns Hopkins University (JHU), University of Michigan, Wake Forest University and Translational Genomics Research Institute, has identified a rare, inherited mutation linked to a significantly higher risk of prostate cancer (PCA). The investigators looked for the same HOXB13 gene mutation among 5,100 men who had been treated for PCA; the mutation was found in 72 (1.4 per cent). These men were much more likely to have at least one first-degree relative who also had been diagnosed with PCA. The team also looked for the mutation in a control group of 1,400 men without PCA and only one of those carried the mutation. Men who were specifically enrolled in studies of early-onset or familial PCA were also studied.

Ethan Lange, UNC Chapel Hill Associate Professor of Genetics and Biostatistics, said that: “There is still work to be done regarding understanding the biological function of the mutation and the precise level of absolute risk for carriers of this mutation, a process that took years for the BRCA1 and BRCA2 genes. Still, our results strongly suggest this is the most clinically-important mutation identified for prostate cancer, to date”.

This particular mutation was found in families of European descent, while two different mutations on the HOXB13 gene were identified in families of African descent. An estimated 241,740 new cases of PCA will occur in the US during 2012, however, for reasons that remain unclear, incidence rates are significantly higher in African-Americans than Caucasians (241:100,000 vs 149:100,000 in 2008). Although death rates have decreased more rapidly among African-American than Caucasian men, rates in African-Americans remain more than twice as high as those in whites. Since only seven of the 94 families studied were of African descent, more research will be required before the significance of the mutations is known. James P Evans, Bryson Distinguished Professor of Genetics in the UNC School of Medicine, observed: “The genetics of prostate cancer have proven surprisingly difficult to unravel and this work represents significant and welcome progress. While fewer than 1 per cent of Caucasian men carry the described mutation in this particular gene, for those men who do carry it, the increased risk for developing prostate cancer is likely greater than for any previous mutation found, to date. Larger follow-up studies will be necessary to understand the importance of this finding for prostate cancer, and it remains to be seen whether this mutation is associated with other cancers”.

“It’s what we’ve been looking for over the past 20 years,” added Dr William B Isaacs, Professor of Urology and Oncology at the JHU School of Medicine. “It’s long been clear that prostate cancer can run in families, but pinpointing the underlying genetic basis has been challenging and previous studies have provided inconsistent results”. Indeed, the most recent data concerning PCA genes prior to this were presented in February 2011 from a PCA gene identification study by Genomic Health, which identified 295 genes strongly associated with clinical recurrence following radical prostatectomy with great consistency, but did not link these findings to any specific inherited mutation.

Article source: Cancer Drug News edited by Emily Halterman

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