Fusion transcript shows potential for prostate cancer biomarker

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Researchers have described a new class of pseudogene-associated fusion transcript in prostate cancer that has potential application as a therapeutic target and biomarker for early prostate cancer detection.

The fusion transcript KLK4-KLKP1 is a urine biomarker that is formed when the protein coding gene KLK4 fuses with the noncoding pseudogene KLKP1.

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The research, which was published in Neoplasia (2019; 21:989-1002), was carried out at the Henry Ford Health System. The authors screened 659 radical prostatectomy samples and found the expression of KLK4-KLKP1 fusion gene in 32% of patients. Interestingly, they discovered that KLK4-KLKP1 expression was notably higher in younger prostate cancer patients under 50 years of age.

They also confirmed KLK4-KLKP1’s role in cell proliferation, cell invasion, intravasation, and tumor formation using in vitro and in vivo functional assays.

“The significant and novel aspect of this gene fusion is the conversion of the non-coding KLKP1 pseudogene into a protein coding unit after the fusion. KLKP1 pseudogene without fusion is expressed only in normal prostate tissue, but the fusion gene is expressed only in prostate cancer,” said study author Nallasivam Palanisamy, MSc, MPhil, PhD, of Henry Ford Health System, Detroit and the University of Michigan Medical School, Ann Arbor.

The study also points to a long-held misconception about the role of pseudogenes in diseases like cancer.

“It is for the first time we show the prostate cancer-specific expression of a pseudogene, KLKP1. Pseudogenes were once thought to be junk DNA without any known functions. However, we were able to show the importance of pseudogenes in cancer using the new technologies and approaches available in the next generation sequencing and precision medicine era.” he said.

Continue to the next page for more.The research also describes a unique subset of prostate cancer cases. It is important to discover new molecular markers enabling the molecular classification of cancer into distinct subtypes. Expression of cancer-specific markers and the ability to detect them in urine is advantageous for non-invasive detection and to avoid painful biopsy procedures, according to Dr. Palanisamy.

Discoveries like this are important steps toward more personalized prostate cancer treatment.

Morphologic classification of prostate cancer based on Gleason score has been the norm. Given the multifocal nature of prostate cancer and extensive morphologic molecular heterogeneity of prostate cancer, as well as researchers’ identification of new molecular markers and their associations with clinical outcomes, it is time to use these markers to make informed decisions on active surveillance and treatment options, according to Dr. Palanisamy.

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These and other findings of molecular cancer classifications will help urologists at the initial diagnosis of cancer, he said.

“Since some of the markers are associated with aggressive type of prostate cancer, molecular screening along with pathological examinations will help clinicians and patients to make informed decisions to treat or not to treat at the initial stage of diagnosis, rather than enter into watchful waiting to allow cancer to metastasize, which is difficult to manage,” Dr. Palanisamy said. “Our finding is unique for reasons that the KLK4-KLKP1 is prostate cancer-specific gene fusion and not found in any other solid cancer. Given the controversies associated with PSA testing, it is useful to have additional prostate cancer-specific markers for accurate diagnosis of cancer at early stage.”

The fusion gene could be used in combination with other prostate cancer molecular markers for detection. And it could be detected not only in urine but also in needle biopsy tissue samples by using a specific antibody, according to a Henry Ford Health System press release on the study.

Initial results are encouraging and promising, according to Dr. Palanisamy. The next step for these researchers is to conduct a large-scale study using urine screening and matching tissues with and without prostate cancer to develop a clinical test for KLK4-KLKP1 expression.