The KLK3 gene encodes prostate-specific antigen (PSA), a serine protease secreted by the prostate gland that plays a key role in semen liquefaction and is a widely used biomarker for prostate cancer.
While PSA testing is a cornerstone of prostate cancer screening and monitoring, its interpretation requires clinical context due to elevations in benign conditions and individual genetic variation.
The KLK3 gene, short for Kallikrein-Related Peptidase 3, is located on chromosome 19q13.33.
It encodes a protein known as Prostate-Specific Antigen (PSA). PSA is a serine protease—a type of enzyme that breaks down proteins—and is produced almost entirely by the epithelial cells of the prostate gland.
In the body, PSA is secreted into seminal fluid, where it plays a key role in semen liquefaction by breaking down proteins that cause seminal coagulation. This helps sperm move more freely after ejaculation.
While most PSA remains in the prostate or semen, small amounts circulate in the bloodstream, and clinicians measure these in PSA blood tests.
PSA testing may be relevant in the following scenario
The most common use of PSA testing is in the detection and monitoring of prostate cancer. An elevated PSA can lead to further evaluation, such as prostate MRI or biopsy.
PSA is also used to track response to treatment after surgery, radiation, or hormone therapy: a rising PSA after treatment may indicate cancer recurrence.
While PSA testing has helped detect prostate cancer early, its routine use remains debated: for example, PSA is not cancer-specific and can be elevated in non-cancer conditions.
Additionally, overdiagnosis of slow-growing cancers can lead to unnecessary treatment. Guidelines differ by organization, so shared decision-making with patients is essential.
Elevated PSA levels can also occur with:
PSA testing is primarily used for the early detection, monitoring, and risk stratification of prostate cancer. While highly sensitive, it is not cancer-specific and must be interpreted in clinical context.
Guidelines vary according to sources, but general recommendations may include:
Testing should follow shared decision-making. Discuss the risks of overdiagnosis, overtreatment, and false positives, particularly in men with benign prostatic conditions.
Test procedure typically includes:
Higher PSA levels may suggest prostate cancer, but they are not specific and require clinical context. Most men with elevated PSA do not have cancer; a biopsy is needed for diagnosis.
The following factors are known to influence PSA levels:
Low PSA levels usually mean a lower risk of prostate cancer, but do not rule it out completely. Some men with prostate cancer may have low PSA.
After successful prostate cancer treatment, PSA should fall to very low or undetectable levels. A rising PSA post-treatment can be an early sign of recurrence.
The KLK3 gene is located on chromosome 19q13.33 and is part of the kallikrein gene family. It is regulated by androgens, including dihydrotestosterone (DHT), through the androgen receptor (AR) pathway.
PSA exists in multiple forms in the blood:
Several single nucleotide polymorphisms (SNPs) in the KLK3 gene affect PSA levels and cancer risk, including:
These variants can explain up to 40–45% of individual PSA level differences, even in men without prostate disease.
Some studies suggest that combining KLK3 SNPs with other genetic markers may help:
In prostate cancer, KLK3 (PSA) has complex roles: for example, it may suppress tumor growth by inhibiting new blood vessel formation (anti-angiogenic).
However, KLK3 can also activate VEGF-C and VEGF-D, which promote angiogenesis and lymphangiogenesis, potentially aiding metastasis in advanced cancers.
The impact of KLK3 on tumor progression appears to depend on the tumor environment, androgen signaling, and the balance of VEGF isoforms present.
KLK3 is involved in:
It is highly expressed in prostate epithelial cells and secreted into seminal plasma. It can also be detected at low levels in nucleus and cytosol, though its primary action is extracellular.
Testing for KLK3 is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.
Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types.
A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.
Normal reference ranges for KLK3 genetic testing are considered to be without mutations that can alter the activity of the KLK3 proteins.
KLK3 (PSA) testing remains a cornerstone of prostate cancer care but requires contextual interpretation.
Genetic variation in KLK3 affects PSA levels and prostate cancer risk. Incorporating genetic data may improve screening accuracy.
PSA metrics such as velocity, density, and free/total ratios enhance diagnostic value.
While PSA is an essential diagnostic and monitoring tool, it should not be used in isolation. Shared decision-making with patients is key.
Understanding the biological, genetic, and clinical dimensions of KLK3 will help clinicians use PSA more effectively and reduce unnecessary interventions.
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