Molecular markers associated with prostate cancer

Avishek Roy

Scientific Liaison Manager
4baseCare

Prostate cancer develops in the prostate gland, a part of the male reproductive system. It is the second most commonly diagnosed cancer and the fifth most common cause of death from cancer in males, making it a major cause of morbidity and mortality globally. In 2018, worldwide there were 1.3 million new patients diagnosed with prostate cancer. While some men are diagnosed with early-stage cancer and the disease progresses slowly, many patients are diagnosed with locally advanced or metastatic disease. Less than one-third of men tested for prostate cancer through biopsy is diagnosed with cancer by histological analysis. The negative biopsies do little to reassure patients and clinicians of negative cancer status, and need to be repeated due to uncertainty of diagnosis. Researchers are eager to find molecular markers that will allow them to diagnose the disease early and correctly, reduce over-diagnosis, distinguish lesion types (to identify sub-classes of prostate cancer), select patients for different treatment options, increase life expectancy, and provide a better quality of life for the patient.

For the patient who has been diagnosed with prostate cancer, he now needs to make decisions. Since we are dealing with cancer, many of the decisions are perplexing and stressful. When it comes to something as serious as cancer, no one wants to provide the incorrect treatment, get the wrong therapy, or make the wrong decision. We also know that not all prostate cancers require treatment; therefore the difficulty in determining which prostate cancers requires intensive therapy. Fortunately, molecular or genetic markers found in prostate tumor cells can assist us in answering this issue. Not only will these markers assist to stratify a person’s risk, but they will also aid in the personalization of prostate cancer therapy.

Despite the facts that several biomarker tests have been established in the previous 10 years, efforts are continuously being made to enhance diagnostic tools in order to improve risk assessment, decrease overtreatment, and enable more targeted treatment for individuals with the high-risk illness. There has been remarkable progress in prostate cancer biomarker discovery, largely through advancements in genomic technologies.

Evidence has shown that somatic mutations observed in tumor tissue may change over time due to genetic alteration resulting in Genomic-Instability. All men with advanced metastatic prostate cancer who may be candidates for genomically-targeted therapy should have their tumor and germline DNA molecularly tested to discover possible therapeutic molecular targets. Understanding the importance of heritable (germline) mutations that affect prostate cancer risk, as well as acquired (somatic) mutations that occur in prostate cancer cells is becoming increasingly important for clinicians involved in the management of prostate cancer.

Genome wide association studies (GWAS) have identified >250 loci associated with prostate cancer risk. It has been observed that germline BRCA2 mutation carriers had a 2.5- to 8.6-fold increased chance of having prostate cancer by the age of 65. Retrospective studies suggest that men with BRCA2 mutations have higher Gleason grade tumors, greater rates of nodal involvement and distant metastases at diagnosis, and higher prostate cancer-specific mortality. BRCA1, ATM, CHEK2, and PALB2 are homologous recombination DNA repair genes that have been linked to a higher risk of prostate cancer. Targeting cancers that lack in homologous recombination repair (HRR) process, the mutation in HRR genes make them in-efficient, is one technique for treating advanced metastatic CRPC. BRCA1, BRCA2, CHEK2, ATM, PALB2, FANCA, and RAD51D are only a few of the genes that have been linked to HRR either directly or indirectly. HRR is a DNA repair system that is of therapeutic importance since HRR-deficient cells are sensitive to PARP inhibitors and perhaps platinum-containing chemotherapy. Studies have confirmed that molecularly targeted treatments such as PARP inhibitors have improved outcomes in men carrying somatic and/or germline DNA repair gene mutations.

It has been observed that microsatellite instability and mismatch repair failure, which can occur as a result of MLH1, MSH2, MSH6, and PMS2 mutations, imply PD-1 inhibitor sensitivity. New evidence suggests that germline variation HOXB13 G84E, NBS1, FANCA, and other DNA repair genes are linked to increased risk of prostate cancer. Therefore, germline genetic testing might be useful in the treatment and evaluation of family risk, while tumor-directed somatic sequencing could allow clinicians make treatment decisions.

Precision oncology is based on the development of successful treatment techniques for individual patient. The development of pathway inhibitors and the discovery of novel disease pathways have both contributed to the decline in prostate cancer mortality over the previous few decades. Nonetheless, these inhibitors have resulted in the development of resistance in patients over time. Therefore, the development of innovative medicines is the way forward for treating prostate cancer in the future. New genomic and proteomic technologies, gene editing technologies, non-coding RNA diagnostics and therapeutics, and liquid tumor profiling have the potential to captivate the promise of precision medicine. Genome editing has revolutionized science, with applications ranging from fundamental research to precision medicine, in which disease models have been designed to modify genetic variants. Liquid biopsy profiling has also opened up a new channel for extracting biomarkers like circulating tumor cells from bodily fluids, and this method could be used to assess recurrence in patients who have already started treatment and monitor treatment response, resulting in a more tailored approach to cancer treatment.