Prostate Cancer – Newly Discovered Biological Markers
Every year more than half of the 200,000 American men are diagnosed with prostate cancer by biopsy and are considered to be at low risk of progression to cancer and therefore they become potential candidates for active surveillance.
Genetic alterations in low-risk prostate cancer diagnosed by needle biopsy can identify men that harbor higher-risk cancer in their prostate glands, Mayo Clinic has discovered. The research, which is published in the January edition of Mayo Clinic Proceedings, found for the first time that genetic alterations associated with intermediate- and high-risk prostate cancer also may be present in some cases of low-risk prostate cancers.
The study found the needle biopsy procedure may miss higher-risk cancer that increases the risk of disease progression. Researchers say that men diagnosed with low-risk cancer may benefit from additional testing for these chromosomal alterations.
We have discovered new molecular markers that can help guide men in their decisions about the course of their prostate cancer care. Overtreatment has been issue for the group of men that our study targets. We found that the presence of genetic alterations in low-risk cancer can help men decide whether treatment or active surveillance is right for them.
George Vasmatzis, Ph.D., co-director of the Center for Individualized Medicine Biomarker Discovery Program and lead author on the study.
Prostate cancer is assessed by Gleason patterns and score that indicate grade. The Gleason patterns are strongly associated with risk of disease progression. Gleason pattern 3 prostate cancer is considered to be low-risk. Gleason patterns 4 and 5 cancer carry a higher risk of aggressive behavior.
Men whose tumor is composed entirely of Gleason pattern 3 may choose active surveillance. They are monitored closely with blood tests and needle biopsies, as necessary. Or they may be referred to treatment, such as surgery and radiation, particularly if they have Gleason pattern 4 or 5.
Men with a low-risk cancer sometimes choose surgery because they don’t want to risk disease progression. The study found that men who do not have these alterations in their cancers have a low risk of harboring aggressive disease. These men may feel more comfortable choosing active surveillance. Alternatively, if a man’s low-risk tumor shows these alterations, they have a higher risk that their cancer may progress. They may consider treatment, including surgery.
The objective of this research study was to test the hypothesis that chromosomal rearrangements (CRs) can distinguish low risk of progression (LRP) from intermediate and high risk of progression (IHRP) to prostate cancer (PCa) and if these CRs have the potential to identify men with LRP on needle biopsy that harbor IHRP PCa in the prostate gland.
Patients and Methods
Between August 14, 2001, and July 15, 2011, mate pair sequencing of amplified DNA from pure populations of Gleason patterns in 154 frozen specimens from 126 patients obtained was used to detect CRs including abnormal junctions and copy number variations. Potential CR biomarkers with higher incidence in IHRP than in LRP to cancer and having significance in PCa biology were identified. Independent validation was performed by fluorescence in situ hybridization in 152 specimens from 124 patients obtained between February 12, 2002, and July 12, 2008.
The number of abnormal junctions did not distinguish LRP from IHRP. Loci corresponding to genes implicated in PCa were more frequently altered in IHRP. Integrated analysis of copy number variations and microarray data yielded 6 potential markers that were more frequently detected in Gleason pattern 3 of a Gleason score 7 of PCa than in Gleason pattern 3 of a Gleason score 6 PCa. Five of those were cross-validated in an independent sample set with statistically significant areas under the receiver operating characteristic curves (AUCs) (P≤.01). Probes detecting deletions in PTEN and CHD1 had AUCs of 0.87 (95% CI, 0.77-0.97) and 0.73 (95% CI, 0.60-0.86), respectively, and probes detecting gains in ASAP1, MYC, and HDAC9 had AUCs of 0.71 (95% CI, 0.59-0.84), 0.82 (95% CI, 0.71-0.93), and 0.77 (95% CI, 0.66-0.89), respectively (for expansion of gene symbols, use search tool at www.genenames.org).
Copy number variations in regions encompassing important PCa genes were predictive of cancer significance and have the potential to identify men with LRP PCa by needle biopsy who have IHRP PCa in their prostate gland.
In this study, researchers performed DNA sequencing with a high-tech genomic tool known as mate-pair sequencing. This research was performed on specific Gleason patterns from frozen cancer specimens from 126 men who had their prostate glands removed. They found five genes are more frequently altered in Gleason patterns 4 and 5. These alterations were found more commonly in Gleason pattern 3 associated with higher Gleason patterns and not when Gleason pattern 3 was found alone.
The needle biopsy procedure samples only a small portion of the tumor. It is not uncommon that a man with a Gleason pattern 3 on needle biopsy specimen harbors a higher-grade cancer next to the pattern 3 that was missed by the procedure, therefore, if we identify these alterations in a Gleason pattern 3, there is a higher likelihood that Gleason pattern 4 is nearby.
John Cheville, M.D., co-director of the Center for Individualized Medicine Biomarker Discovery Program and co-author of the study.