Germline mutations in the Kallikrein 6 (KLK6) region are associated with an increased risk of aggressive prostate cancer, according to data from two cohorts.
"We have found a new blood test which specifically predicts whether a man is highly susceptible to aggressive prostate cancer, very similar to what the BRCA test does for breast cancer,” said Dr. Alexandre R. Zlotta from Mount Sinai Hospital, University Health Network, in Toronto, Canada.
“The gene and associated germline variants identified are very close to the well-known PSA” gene (also known as the KLK3 gene), he told Reuters Health by email.
Several kallikreins, especially KLK2 and KLK3, play major roles in prostate cancer and have been studied as prostate cancer biomarkers, but with the exception of KLK3, the influence of other KLK gene variants on aggressive prostate cancer remains unclear.
Dr. Zlotta’s team performed a fine-mapping study of the entire KLK region, comparing results between case patients with aggressive prostate cancer (Gleason Score (GS) >= 8) versus those with less-aggressive prostate cancer (GS <7 p="">
Haplotype analyses identified the KLK6 locus as statistically significantly associated with prostate cancer aggressiveness, with six of seven KLK6 single nucleotide polymorphisms (SNPs) reaching very high statistical significance.
“The gene variants were observed in 6% to 14% of the male population and even considering the lower value represents a significant proportion of men,” Dr. Zlotta said.
None of the SNPs are predicted to change the KLK6 amino acid sequence, but bioinformatics characterization suggested that they may have regulatory functions, the team reports in the Journal of the National Cancer Institute, online March 14.
None of the variants were associated with serum KLK2, KLK3 (PSA), or KLK6 levels or age at diagnosis, but all were associated with GS.
One germline SNP showed a clear association with KLK6 methylation levels in determining the GS in radical prostatectomy specimens, and these noncoding SNPs in KLK6 provided prognostic information that was additive to existing molecular tools.
“The exact role of KLK6 in tumor progression remains elusive,” the researchers note. “It encodes for an enzyme with trypsin-like properties and can degrade components of the extracellular matrix. KLK6 is implicated in processes such as epithelial-to-mesenchymal transition, angiogenesis, and invasion, in keeping with biological functions required by tumors to display an aggressive phenotype.”
“If additional studies further confirm our results observed on 2,000 men for its association with Gleason 8 or more and on 130 patients with biochemical failure, it is very likely that these new variants will be integrated in prostate cancer risk stratification, maybe with the BRCA genes as well,” Dr. Zlotta said.
“We also need to do extra work to further our understanding of the biology and role of this KLK6 in prostate cancer,” he said. “We know from our results that one of the KLK6 variants is in relation with KLK6 methylation at the tissue level which adds to the functional story, as KLK6 methylation was associated in a previous report of ours with more aggressive prostate cancer.”
“Ultimately incorporating these SNPs or future rare variants in the KLK6 region into clinical practice may directly impact and improve PCa screening and early diagnosis strategies,” the authors conclude. “Moving from ‘indiscriminate’ to ‘personalized’ screening should be encouraged, including, for instance, BRCA2 and KLK6 variants, which might be integrated in future approaches.”
Dr. Andrew Vickers from Memorial Sloan Kettering Cancer Institute, New York, who has also studied the prognostic value of KLK variants in prostate cancer, told Reuters Health by email, “Research on SNPs has helped us learn a lot of biology, but actual clinical uses are few and far between. SNPs are generally pretty weak predictors of cancer because, in short, cancer is a disease of somatic mutations. This is especially true in prostate cancer because there are already a number of excellent markers available, notably, total PSA and free PSA.”
As for the current results, he said there is “nothing directly clinical here: it is exploratory work, interesting for thinking about prostate biology.”
To be of clinical use, Dr. Vickers added, there would have to be “extensive external validation, clear demonstration that using the SNPs would actually improve decision making.”