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Current clinicopathologic indicators are insufficient to distinguish the small percentage of aggressive prostate cancer (PCa) from the vast majority of indolent disease at diagnosis, leading to overtreatment of PCa. A recent study reported and confirmed a strong association of PCa-specific mortality with somatic DNA copy number alterations (CNAs) in primary prostate tumors. If a sensitive, robust and low-cost method can be developed to measure these CNAs in biopsy specimens, it may help to stratify patients for more appropriate management at the time of diagnosis; aggressive treatment or active surveillance for patients with or without these CNAs, respectively.
A study on the association of somatic DNA copy number alterations (CNAs) in prostate tumors with lethal prostate cancer (PCa) by our collaborative group of Wake Forest University School of Medicine, the Brady Urological Institute of Johns Hopkins Medical Institutions, and the Karolinska Institute of Sweden was recently published in Cancer.1 Shortly after, two abstracts on the association of RNA expression of two different panels of genes with progression of PCa were presented by investigators from Mayo Clinic and University of California at San Francisco, respectively, in the 2013 American Urology Association Annual meeting.2,3 These studies all focused on the prognosis of PCa and received great attention in the scientific and clinical communities as well as in public, as evidenced by the news coverage. The excitement surrounding these studies is not surprising because distinguishing aggressive from indolent forms of PCa is probably the most important clinical task in managing and treating this heterogeneous disease. Most prostate tumors grow so slowly that they may never threaten a man's life; however, ~15% are lethal if not treated appropriately. Currently used clinical predictors such as Gleason score and tumor stages are useful but insufficient to discriminate between the two types of PCa at the time of diagnosis. This inability leads to unnecessary and intensive treatment of many PCa patients, reducing their quality of life, and incurring financial burden to patients, families and society. Novel biomarkers are urgently needed to better identify aggressive PCa at the time of diagnosis for selection of treatment strategy; a choice of active surveillance for indolent PCa or intensive treatment for aggressive PCa.
In this perspective piece, we highlight the key points of our Cancer paper on the association of CNAs with lethal PCa,1 discuss their advantages as markers for lethal PCa and describe the challenges for translating the genomic findings to clinics.
Using Affymetrix 6.0 SNP array to analyze tumor and matched normal DNA from 125 prostatectomy patients treated at Johns Hopkins Hospital and the algorithm of Genomic Identification of Significant Targets in Cancer, we uncovered seven regions in the tumor genome that were significantly associated with lethal PCa. These include CNAs of MYC at 8q24.21, SERPINB5 at 18q21.33, TPD52 at 8q21.13, USP10 at 16q24.1, PTEN at 10q23.31, TP53 at 17p13.1 and ADAR at 1q21.3. Note that these CNAs not only play a role in the development of PCa (comparing tumor versus normal), but more importantly they may play a role in progression of PCa (comparing lethal PCa patients versus patients that are still alive).
When adjusting for other known predictors of lethal PCa such as Gleason score and pathological stage using a multivariate logistic regression analysis, we found that two of these seven CNAs (PTEN deletion and MYC amplification) remained statistically significant. These results suggest that PTEN deletion and MYC amplification conferred additional prognostic value; therefore, they have potential to improve current clinical practice to distinguish lethal from indolent PCa.
Compared with patients without alterations at either PTEN or MYC, patients with both alterations had 53-fold higher risk for dying from the disease. It is important to note that although several prior studies had implicated PTEN loss in PCa metastasis,4,5 PTEN loss in death from hormone refractory PCa,6 and the loss of PTEN and gain of MYC in metastatic disease,7 our study was the first to demonstrate a stronger joint effect of PTEN and MYC on PCa-specific mortality.
An important aspect of the study was the further confirmation of the joint effect in 333 tumors from three additional distinct patient cohorts, including 103 patients who underwent prostatectomy at the Karolinska University Hospital in Sweden, 216 patients treated at Memorial Sloan Kettering Cancer Center and 14 autopsy patients from Johns Hopkins Hospital. For biomarker studies of whole genome analysis, independent confirmation is necessary to reduce the chance of false positive findings due to multiple-testing issues in the discovery stage.
Acquired DNA alterations in cancer cells accumulate and are preserved over time for as long as 10 years.8,9 Natural selection of somatic cells with DNA alterations that confer increased proliferation, decreased apoptosis or ability of invasion is the genetic basis of tumor development and clonal phenomena. In fact, monoclonal origins of lethal metastatic PCa have been observed.10 Because CNAs precede phenotypic presentations or histological changes, the discovery of CNAs associated with PCa-specific death may help identify a subset of patients with particularly aggressive cancers at an early stage, for targeted aggressive treatment.
In order to utilize these genomic findings for determining treatment options, these CNAs will most likely need to be detected in biopsy specimens at time of diagnosis. This poses significant challenges due to the multi-foci nature of PCa (heterogeneity), small amount of tumor cells in each cancer foci (insufficient tumor DNA and contamination of normal DNA), and the fragmentation of DNA molecules in formalin-fixed, paraffin-embedded biopsy specimens. Therefore, detection methods that are sensitive to small amounts of tumor DNA, robust to fragmented DNA, high-throughput for the measurement of all possible CNAs at the same time, and low cost, are needed in order to assay each needle biopsy core to identify signatures of CNAs that are associated with lethal PCa. Fortunately, quantitative PCR and multiplex ligation-dependent probe amplification may meet these criteria. However, studies are needed to demonstrate the capability of these methods to detect these CNAs in individual biopsy cores, and their predictive performance for the detection of lethal PCa.
With the discovery of CNAs associated with lethal PCa, there is hope that new diagnostic models can provide a more accurate prognosis at the time of PCa diagnosis. This in turn can inform treatment that is tailored to each patient, whereby patients with particular DNA signatures of lethal PCa can be targeted for more aggressive treatment, while patients without these CNAs may opt for active surveillance.