Genetic Alterations Linked to Poorer Prostate Cancer Prognosis

Wennuan Liu, PhD

Alterations in the chromosomes of two genes have been implicated in an increased risk of prostate cancer mortality, and the discovery holds promise for distinguishing which patients are candidates for more aggressive therapy, according to findings of an NIH-funded study published in the journal Cancer.

The goal of the research was to find out whether prognostic tumor markers exist that might help to identify patients with life-threatening disease—and thus needing more aggressive therapy—versus those whose slowly progressing disease could be treated more conservatively. While prostatectomy has been shown to prevent death, many patients have tumors that are not life-threatening; on the other hand, one of seven patients who undergo the surgery experiences a relapse and dies of the disease.

Investigators examined the DNA in tumor samples of 125 radical prostatectomy patients at Johns Hopkins Hospital (JHH) in Baltimore, Maryland, between the years 1988 and 2004 to identify any copy number alterations (CNAs) in the chromosomes. They used high-resolution, single-nucleotide polymorphism arrays and the algorithm Genome Identification of Significant Targets in Cancer (GISTIC) to determine any significant CNAs, and then correlated the presence of these abnormalities with other clinicopathologic features and clinical outcomes.

The analysis revealed 20 significant CNAs in the tumor DNA of patients with prostate cancer, 15 of which were chromosomal deletions and five of which were gains or amplifications. Four of these CNAs were deemed novel, seven were found to be significantly linked with early prostate cancer—specific mortality, and two of the seven (phosphatase and tensin homolog [PTEN] and v-myc myelocytomatosis viral oncogene homolog [MYC]) were found to provide valuable prognostic information, independent of other clinical variables, such as Gleason score, PSA level, and tumor stage.

Tumors with CNAs in both PTEN and MYC were associated with a marked increase in lethal prostate cancer, the researchers found. Whereas a borderline increase in risk was seen in tumors whose DNA had either abnormality, it was those tumors that harbored both that had the greatest risk of mortality (odds ratio [OR] = 53; 95% CI, 6.92-405; P = 1 x 10—4); of the two, gains of MYC were associated with the highest risk of prostate cancer mortality (OR = 4.75; P = .002).

Researchers confirmed these findings by also analyzing 333 tumors from three additional prostatectomy patient cohorts as follows: the Karolinska University Hospital in Sweden (n = 103), the Memorial Sloan-Kettering Cancer Center in New York City (n = 216), as well as tumor samples from the autopsies of 14 JHH prostate cancer patients who died of metastatic disease. All tumor tissues from the autopsy cohort harbored one or both of the abnormalities in PTEN or MYC. Eight of the 14 samples had alterations in both.

Although loss of PTEN and gains of MYC have previously been implicated in prostate cancer pathogenesis, “this study is the first to demonstrate a joint effect in clinical cohorts where CNAs of both PTEN and MYC in the tumor genome imposed the most significant risk for prostate cancer—specific mortality following prostatectomy,” noted Wennuan Liu, PhD, associate professor, Wake Forest School of Medicine, Winston-Salem, North Carolina, and colleagues.

The researchers said that if the relationship is confirmed through further study, genetic data can be used to determine which prostatectomy patients are most likely to benefit from adjuvant therapy.

Liu W, Xie CC, Thomas CY, et al. Genetic markers associated with early cancer-specific mortality following prostatectomy [published online ahead of print April 22, 2013]. Cancer. doi:10.1002/cncr.27954.