Genetics in Prostate Cancer: From Familial Risk to Targeted Treatment

Prostate cancer is the third most common cancer worldwide. While some factors such as age are determinant, genetics is known to play a crucial role. It is estimated that 5-15% of cases have a hereditary component, which shows new perspectives for the prevention and early diagnosis of this pathology.

Prostate cancer is a multifactorial and heterogeneous disease at the molecular and clinical levels, and there are currently no screening tests that can effectively segment men at higher risk. There are different tests such as the detection of PSA levels that provide information, but they are highly specific. Thanks to advances in sequencing technology, the study of genetic panels related to prostate cancer based on Whole Exome Sequencing (WES) makes it possible to detect hereditary cases, improving surveillance and follow-up of this and other related cancers.

The Genetics of Hereditary Prostate Cancer

The BRCA1 and BRCA2 genes are widely recognized for their association with the risk of developing hereditary breast and ovarian cancer. However, several investigations have shown their correlation with prostate cancer. Mutations in these genes, particularly in BRCA2, increase the risk of this type of neoplasm and are frequently associated with more aggressive tumors. It is crucial to underline that the genetic spectrum of prostate cancer is not restricted to these genes, but includes other genes involved in critical molecular pathways.

In addition to BRCA1/2, other genes related to this type of cancer are involved in DNA repair pathways, such as homologous recombination (ATM, CHEK2, PALB) or mating error repair (MLH1, MSH2, PMS2 and MSH6). When these repair pathways fail, tumor risk increases. There is another relevant gene associated with an increased risk of hereditary prostate cancer, the HOXB13 gene acts as a tumor suppressor and there are variants described in this gene that substantially increase the risk of prostate cancer.

There are different genes related to prostate cancer that provide valuable information for medical management. For the simultaneous study of the genes of interest, targeted panels, which only sequence the genes under study, or virtual panels based on the whole exome, are requested.

Whole Exome Sequencing (WES): A Panoramic View

Traditionally, the analysis of multiple genes was a challenge due to the complexity and lack of scalability of the available techniques. The evolution of sequencing techniques has made it possible to optimize this process achieving greater agility and a reduction in the cost of this type of analysis, increasing its efficiency. In this context, Whole Exome Sequencing (WES) has established itself as a robust and cost-effective strategy for the analysis of gene panels.

As mentioned in our blog Exome vs. genome: which type of test to choose? , it is estimated that approximately 85% of disease-causing pathogenic variants are located in the exome. WES is a tool that allows obtaining the information of a large number of coding genes in a single assay, thus providing its analysis and interpretation associated with a possible suspicion of hereditary pathology.

Virtual Panels Derived from WES: Accuracy and Flexibility

When performing a WES, a vast set of genomic data corresponding to coding regions is generated, from which the targeted panel is created. Instead of examining the approximately 20,000 genes in the exome, a list of specific genes of interest whose involvement in a particular pathology is well established is defined. In the case of prostate cancer, the panel of genes related to this type of cancer provides additional relevant information that is useful for the clinician to adapt the patient’s follow-up, in the event that a risk variant is found. This information is additional and complementary to traditional opportunistic screening tests.

This tool offers significant advantages:

• Efficiency: A single sequencing is performed, but in case new signs or symptoms arise in the patient, by having the complete exome sequenced, it is possible to analyze additional genes related to other pathologies such as another type of hereditary cancer or hereditary cardiovascular disease.
• Flexibility and Updating: If the implication of a new gene related to prostate cancer is discovered in scientific publications, it is possible to reanalyze the genomic data to determine if there are variants in the gene that increase the risk of this type of cancer.
• Comprehensive view: The whole exome genomic data is available for updates, study of secondary findings or other clinical uses.

Genetic analysis in the clinic

The decision to perform a genetic study for prostate cancer should always be individualized and supervised by a professional. International clinical guidelines, such as those of the NCCN (National Comprehensive Cancer Network) or ESMO (European Society for Medical Oncology), suggest considering this type of testing in men with a strong family history of prostate cancer or other related tumors (breast, ovarian, pancreatic or colorectal). It is also recommended in those patients diagnosed with metastatic prostate cancer, high risk, or with specific histological characteristics such as intraductal, as well as in individuals with Ashkenazi Jewish ancestry.

It is essential that the entire process, from the indication of the study to the interpretation and communication of the results, has genetic counseling by an expert. The integration of advanced genetics, through tools such as Whole Exome Sequencing and virtual panel analysis, is transforming our ability to understand, prevent and treat this disease. It allows us to move from a general approach to precision medicine, identifying risks, guiding therapies and protecting families.

At Veritas, through our WES-based targeted panels, we provide comprehensive genomic analysis, enabling accurate risk stratification, adoption of early detection strategies and personalization of the clinical and therapeutic approach. If you would like to learn more about how precision genetics can help you or your patients, please do not hesitate to conta