Low-grade prostate cancer diverges early from high grade and metastatic disease.
Bottom Line: Notably, mutations in cancer-associated genes and the p53 signaling pathway were found exclusively in high-grade foci and metastases.The pattern of mutations is consistent with early divergence between low- and high-grade foci and late divergence between high-grade foci and metastases.These data provide insights into the development of high-grade and metastatic prostate cancer.
Affiliation: Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois, USA; Department of Medicine, University of Chicago, Chicago, Illinois, USA.Show MeSH
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Mentions: Given the disparate outcomes between men with low-grade prostate cancer and those with high-grade disease, a fundamental question in prostate cancer management is the possible molecular relationship among grades and metastatic disease. Multiple lines of evidence suggest multifocal disease is often independent.(30,31) However, recent reports have demonstrated shared molecular derangements of coincident low- and high-grade foci.(16,17) The present study identifies mutations shared between low- and high-grade cancer foci, supporting the ability of a single progenitor to give rise to both low- and high-grade disease. However, the relationship between these foci was distant relative to the relationship between high-grade disease and synchronous metastases. In fact, in two of the four cases it cannot be ruled out that the foci arose from independent origins. The early divergence of low- and high-grade disease may help explain distinct differences in their clinical behavior. Indeed, we found no evidence of direct progression from low grade to metastatic disease. Instead, there was an overwhelming fraction of shared mutations between high grade and metastatic disease, which is consistent with late divergence of these high-grade foci (Fig. 5).
Affiliation: Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois, USA; Department of Medicine, University of Chicago, Chicago, Illinois, USA.