Five Genetic Variants Predict Aggressive Prostate Cancer

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;

RNASELis associated with hereditary prostate cancer and is associated with apoptosis, inflammation, and cell proliferation and adhesion;

IL4plays a role in cancer via activation of the Stat6 transcription factor; and
ARVCFis 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 (Pfor 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.

The 22 top ranking SNPs identified in the Seattle cohort were then genotyped in the validation cohort, which consisted of 2875 prostate cancer patients in Sweden. From the validation study, 5 of the 22 SNPs emerged as being significantly associated with death from prostate cancer. As compared to patients with 0 to 2 at-risk genotypes, those with all 5 SNP genotypes had the lowest prostate cancer–specific survival in both the Seattle (P < .001) and the Swedish (P = .004) cohorts.

On the basis of models that were adjusted for age at diagnosis and other clinicopathological variables, the most significant SNP in the Seattle dataset was rs1137100 (P = .001) in the LEPR gene and in the Swedish dataset was rs10778534 (P = .045) in the CRY1 gene.

The study authors also observed that a higher proportion of Swedish patients (17.4%) had died of prostate cancer relative to those from Seattle (4.6%) during a median follow-up period of 6.5 years. These data are consistent with the higher prostate cancer mortality rate in Sweden relative to the United States, they point out.

Further Validation Studies Needed

"We completed a validation study of the 22 SNPs that were identified as associated with prostate cancer mortality in our Seattle-based cohort and validated that 5 of those SNPs were also associated with prostate cancer mortality in the Swedish cohort," explained Dr. Stanford. "So the 5 individual SNPs are already validated."

They now hope to complete additional validation studies using the 22 SNPs and then undertake studies to validate the panel of 5 SNPs, along with any others that may be validated from the panel of 22, she added. "The published results represent the initial step in moving forward for finding and confirming that a patient's genetic background plays a role in determining the course of their prostate cancer."

As for the implications for clinical practice, she pointed out that a blood test to measure these SNPs would not be difficult to develop. "But we need to wait until further validation studies are completed before we will know how useful this panel of SNPs will be in complimenting Gleason score, stage, and PSA [prostate-specific antigen] for guiding decisions in the clinic," she said. "This initial study, however, provides the first validated evidence that a patient's inherited genetic background can affect prostate cancer aggressiveness and thereby outcomes."


Roxanne Nelson

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