Molecular profiling of indolent human prostate cancer: tackling technical challenges to achieve high-fidelity genome-wide data.

The contemporary problem of prostate cancer overtreatment can be partially attributed to the diagnosis of potentially indolent prostate cancers that pose low risk to aged men, and lack of sufficiently accurate risk stratification methods to reliably seek out men with indolent diseases. Since progressive acquisition and accumulation of genomic alterations, both genetic and epigenetic, is a defining feature of all human cancers at different stages of disease progression, it is hypothesized that RNA and DNA alterations characteristic of indolent prostate tumors may be different from those previously characterized in the setting of clinically significant prostate cancer. Approaches capable of detecting such alterations on a genome-wide level are the most promising. Such analysis may uncover molecular events defining early initiating stages along the natural history of prostate cancer progression, and ultimately lead to rational development of risk stratification methods for identification of men who can safely forego treatment. However, defining and characterizing indolent prostate cancer in a clinically relevant context remains a challenge, particularly when genome-wide approaches are employed to profile formalin-fixed paraffin-embedded (FFPE) tissue specimens. Here, we provide the conceptual basis underlying the importance of understanding indolent prostate cancer from molecular profiling studies, identify the key hurdles in sample acquisition and variables that affect molecular data derived from FFPE tissues, and highlight recent progresses in efforts to address these technical challenges.