PSA Gene Variants Distinguish Patients with Highly Aggressive Prostate Cancer

Cancer researchers have identified three mutations in the KLK3 (kallikrein-related peptidase 3) gene, which codes for prostate specific antigen (PSA), associated with biopsy-proven high-aggressive prostate cancer.

The three mutations or single nucleotide polymorphisms (SNPs) were among 72 prostate cancer susceptibility SNPs identified during genome-wide association studies of 1,827 white men with histologically confirmed prostate adenocarcinoma. SNPs associated with disease aggressiveness were identified by comparing high-aggressive (GS ≥8) and low-aggressive (GS ≤6) cases.

Investigators at The University of Texas MD Anderson Cancer Center (Houston, USA) reported that the three SNPs - rs2735839, rs10486567, and rs103294 -were associated with biopsy-proven high-aggressive (GS ≥8) prostate cancer. Furthermore, the frequency of the variant allele (A) at rs2735839 was significantly higher in patients with biopsy-proven GS4+3 disease than in those with GS3+4 disease.

The rs2735839 SNP is located 600 base pairs downstream of the KLK3 gene (encoding PSA) on chromosome 19q13.33 and has been shown to modulate PSA level, providing strong biologic plausibility for its association with prostate cancer aggressiveness.

The investigators also showed that rs2735839 could stratify patients with GS7 cancer, which is an intermediate grade of cancer accounting for 30 to 40% of all prostate cancers. This would be clinically important for more accurately assessing the clinical behavior of the intermediate-grade prostate cancer and for tailoring personalized treatment and post-treatment management.

"This is the first report that I am aware of that indicates a genetic variant can stratify GS7 prostate cancer patients," said contributing author Dr. Jian Gu, associate professor of epidemiology at the MD Anderson Cancer Center. "This is important because this group with heterogeneous prognosis is difficult to predict and there are no reliable biomarkers to stratify this group."

"Treatment options for the GS7 disease are controversial because the burden of combined treatment modalities may outweigh the potential benefit in some patients," said senior author Dr. Xifeng Wu, professor of epidemiology at the MD Anderson Cancer Center. "It is critical that we develop personalized treatments based on additional biomarkers to stratify GS7 prostate cancers. Additional biomarkers may help us achieve personalized clinical management of low and intermediate risk prostate cancer patients."

The study was published in the October 1, 2014, issue of the journal Clinical Cancer Research.

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The University of Texas MD Anderson Cancer Center