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Five Genetic Variants Predict Aggressive Prostate Cancer

Five Genetic Variants Predict Aggressive Prostate Cancer

August 19, 2011 — Prostate cancer is the second leading cause of cancer-related deaths in men, but one of the challenges in this disease has been the inability to differentiate between men who have aggressive tumors and those who have indolent tumors that might never become clinically significant.

However, researchers have now identified 5 genetic variants that are strongly associated with aggressive, lethal prostate cancer.

Published online August 16 in Cancer Epidemiology, Biomarkers and Prevention, this is the first population-based study to demonstrate that germline genetic variants provide prognostic information for prostate cancer-specific survival.

"It is really promising as we now have identified inherited genetic variants that provide prognostic information for prostate cancer," said lead study author Janet L. Stanford, PhD, codirector of the Program in Prostate Cancer Research at the Fred Hutchinson Cancer Research Center in Seattle, Washington.

She told Medscape Medical News that they hoped that this panel of markers, along with others that may be identified in the future, "can help complement the existing clinical and pathological features of prostate cancer to better stratify patients according to the likelihood of having a more aggressive type of prostate cancer."

The Five SNPs

In this study, 5 single-nucleotide polymorphisms (SNPs) were validated as being significantly associated with prostate cancer–specific mortality (P ≤ .05). The 5 SNPs were located, one each, in the following 5 genes:

  • LEPR, the strongest marker associated with prostate cancer mortality in the study, is a cytokine receptor that is highly expressed in normal and malignant prostate tissue. The binding of leptin to its receptor leads to several downstream effects that may affect prostate carcinogenesis, including stimulation of tissue growth, inflammation, angiogenesis, and bone mass regulation. The latter effect, note the study authors, makes LEPR an interesting candidate for disease progression because the primary metastatic site for prostate cancer is the bone and bony metastases are predictive of fatal prostate cancer;
  • CRY1, the cryptochrome 1 gene, is in the circadian rhythm pathway, and circadian clock genes regulate androgen levels, which are known to affect prostate cancer progression and may also function as tumor suppressors through regulation of cell proliferation, apoptosis, and response to DNA damage;
  • RNASEL is associated with hereditary prostate cancer and is associated with apoptosis, inflammation, and cell proliferation and adhesion;
  • IL4 plays a role in cancer via activation of the Stat6 transcription factor; and
  • ARVCF is a member of the p120 catenin family of proteins, and increased expression has been shown to disrupt cell adhesion, which may facilitate cancer progression.

Patients with 4 to 5 at-risk genotypes had a 50% higher risk for prostate cancer–specific mortality than patients who had only 2 or fewer of these genotypes. After adjusting for clinicopathological factors know to affect prognosis, the risk for mortality increased with the number of at-risk genotypes (P for trend = .001).

Results Too Early

Similar to other malignant tumors, prostate cancer is a complex disease that results from an interaction between genetic and nongenetic factors. As previously reported by Medscape Medical News, a number of studies have identified genetic variants that may be associated with prostate cancer risk or more aggressive disease.

In one of those previous studies, Rosalind Eeles, MA, PhD, FRCP, FRCR, head of the Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, in Surrey, United Kingdom, and colleagues, identified 7 loci that were significantly associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19, and X and confirmed reports of common loci associated with prostate cancer at 8q24 and 17q.

Commenting on her work at that time, Dr. Eeles emphasized that it was still too early to consider marketing genetic tests to the public, and further research was needed. When approached for independent commentary about the current study, she felt that it was also too soon to draw conclusions.

"It is too early to say if this study will be useful as it needs validation, and this is in progress," she told Medscape Medical News.

Study Details

Dr. Stanford and colleagues analyzed DNA in blood samples obtained from 1309 prostate cancer patients residing in the Seattle area. A total of 937 SNPs were genotyped from this cohort, and a total of 22 SNPs were found to be significantly associated with prostate cancer–specific mortality.