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Genetics and Genomic Testing for Urology - Genetic Aspects and Molecular Testing

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Genetic testing has been developed to test and evaluate single genes and is intended to detect uncommon inheritable diseases. Read this article to know more.

Written by

Dr. Chandana. P

Medically reviewed by

Dr. Rajesh Gulati

Published At May 25, 2023
Reviewed AtJanuary 12, 2024

Introduction

Prostate cancer (PC) is becoming more common in Asia. One in eight men are affected by prostate cancer during their lifespan. Few men with prostate cancer are asymptomatic (remain silent) and die due to other conditions rather than the disease itself. This might be attributed to advanced age during diagnosis, sluggish tumor development, or treatment response. Greater knowledge of the genetic and biological principles underlying why some prostate carcinomas are clinically quiet while others develop into severe life-threatening diseases is required.

Genetic testing is becoming more common in clinical nephrology as genetic sequencing tools become more widely available. A genetic diagnosis has major consequences for nephrology treatment since it can explain the patient's prognosis and selection of the treatment based on the prognosis, save patients from invasive diagnostic methods like kidney biopsy, and guide family planning.

What Is the Prevalence of Prostate Cancer?

The incidence of prostate cancer varies greatly among nations globally; the yearly estimated incidence of prostate cancer varies from 86.4 cases per 100,000 men in Australia and New Zealand to 5.0 incidences per 100,000 men in South Central Asia. Asian men have an extremely low occurrence of prostate cancer, with age-adjusted incidence rates varying from 5.0 to 13.9 in every 100,000 men. In general, Australia and New Zealand have the highest incidence rates, and African countries have lower rates of prostate cancer overall.

What Are the Risk Factors for Prostate Cancer?

  • Age: The patient's age is a significant risk factor for prostate cancer. Prostate cancer is uncommon in males under 40, and the prevalence increases significantly with each decade after that. Approximately ten percent of prostate cancer cases in males under the age of 56 are identified as early-onset prostate cancer. As per data from the surveillance, epidemiology, and end results (SEER) Study, early-onset prostate cancer is rising, and certain instances may be more severe. There is a global trend toward a rise in men under 40 diagnosed with prostate cancer, frequently with a bad prognosis. Because germline pathogenic mutations may cause early-onset malignancies, young men with prostate cancer are now being widely examined to uncover prostate cancer genes.

  • Family History of Cancer: Prostate cancer is purely genetic; it has been reported that the hereditary risk of prostate cancer is as high as 60 percent. Familial aggregation of prostate cancer has been carried out extensively, as it has with breast and colon cancer. Between five percent and ten percent of prostate cancer cases are thought to be caused by inherited high-risk genetic factors or genes susceptible to causing prostate cancer. A family history of prostate cancer in a brother or father raises the risk, which is inversely proportional to the affected member's age. However, at least some family aggregation is attributable to increased prostate cancer screening in high-risk families. Furthermore, the risk is raised as the number of close relatives affected by prostate cancer increases. When a first-degree relative (FDR) was diagnosed with prostate cancer before the age of 65, the risk increases.

What Are the Indications for Genetic Testing in Prostate Cancer?

A. Family History of Prostate Cancer and Other Related Cancers:

  • PC (other than localized Grade Group 1) in a brother, father, or multiple family members diagnosed above the age of sixty;

  • Any first-degree family members expired due to prostate cancer above 60 years.

  • BRCA1/2 or DNA mismatch repair (MMR) gene germline mutations in the family;

  • BRCA1/2 m-associated cancer or Lynch syndrome (bile duct, breast, colorectal, endometrial, gastric, kidney, melanoma, ovarian, pancreatic, prostate [except localized Grade Group 1], small bowel, or urothelial cancer) among three or more members of the same family.

B. Familial Risks of PC:

  • Family history of the prostate and associated malignancies should be investigated for individuals with recently diagnosed prostate cancer.

  • Cancer surveillance and prevention strategies should be considered with carriers of germline mutations.

  • PC screening may begin at the age of 40 for BRCA 2m carriers.

  • PC screening for BRCA 2m carriers may be conducted ten years before the family's youngest PC diagnosis.

C.Germline Testing Following Diagnosis of Prostate Cancer:

  • Germline testing should be taken into consideration in prostate cancer patients who have one or more of the following symptoms:

    • Metastatic conditions or illness.

    • Intraductal or ductal histology

    • Patients with a known positive family history of cancer.

D. Genetic Counseling and Consent:

  • For proper management, germline genetic testing should be combined with informed consent and genetic counseling.

  • Genetic counseling services are limited. There is a significant unmet demand for individuals with suspected cancer-related mutations who might benefit from authorized doctors' genetic counseling services.

E.Mutations in Hereditary Drivers:

In germline testing for patients with prostate cancer, homologous recombination repair (HRR) genes (BRCA1 and 2, ATM, PALB2) and mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) should be explored.

What Are the Testing Methods and Technical Considerations?

A. Germline versus Somatic Testing: Both germline and somatic mutations are important in the molecular pathogenesis of prostate cancer; genetic testing may be done in two steps: 1) germline testing, after genetic counseling and informed written consent (for patients with family history); or 2) somatic testing of tumor samples, following explanation to patients that any found probable germline mutation may necessitate additional confirming testing. When an HRR or MMR mutation is discovered, a peripheral blood sample must be tested for confirmation of germline genes so that adequate genetic counseling and cascade testing may be provided to family members.

B. Large Genomic Rearrangements (LGRs): Large, mainly deletions in the exon-level or other structural changes span megabase portions of the human genome are called LGRs. Large deletions are now identifiable by coverage depth analysis, obviating the need for routine multiplex ligation-dependent probe amplification (MLPA) because of the introduction of multi-gene next-generation sequencing (NGS) kits for germline testing that uses molecular barcodes and specialized bioinformatics approaches. LGR detection in somatic testing utilizing NGS on formalin-fixed paraffin-embedded (FFPE) tissue is difficult. However, not all NGS methods have been devised or refined to identify variations in copy numbers. An inter-laboratory study of FFPE tumor DNA samples revealed that the large insertion of BRCA1 exon 13 in 6kb, a disease-causing pathogenic variant, was not identified by any of the laboratories in the initial analysis. If a patient has a family history or is suspected of carrying hereditary cancer-causing genes, germline testing with a peripheral blood sample should be explored, even if NGS findings are negative.

C.Availability of the Tissue Samples: The histopathologist takes a unique place to improve the success rate of multi-gene NGS assays in PC. Formalin-fixed paraffin-embedded ( FFPE) samples for homologous recombination repair (HRR) gene mutation testing should be sufficiently cellular (greater than 5,000 cells = 30 ng of DNA) to generate the requisite amount of DNA (deoxyribonucleic acid) for testing. A minimum of neoplastic cell content is also necessary; tumor content should be at least 10 ten 20 percent to accurately identify somatic variations at greater than 5 percent allelic frequency and higher to identify LGRs.

D. Levels of testing and coverage: Multi-gene next generation sequencing (NGS) panels that include all forms of genetic variations, including single nucleotide variants, minor insertion or deletions, copy number variants such as massive deletions, and gene fusion, are used to undertake prostate cancer genomic profiling.

E. Ethnic Variations: Genetic mutations differ depending on ethnicity.

F. Homologous recombination repair (HRR) Gene Variations: HRR Gene Variations The existence of HRR gene mutations in a patient with Metastatic Castration-Resistant Prostate Cancer (mCRPC) aids in predicting responsiveness to poly ADP ribose polymerase (PARPi) therapy. Furthermore, MMR gene mutations, which are linked with the microsatellite instability (MSI)-high (MSI-H) phenotype, make patients more susceptible to immune checkpoint inhibitor (ICI) therapy, such as Programmed cell death protein (PD-1) inhibition.

Conclusion

Understanding the various genetic abnormalities that cause genitourinary cancers will lead to the creation of tailored therapy options. The primary driving mutations in familial syndromic malignancies have influenced research into important biological processes. The development of new molecular markers in testicular cancer may potentially suggest new therapeutic regimens for a subset of patients whose disease has relapsed or is resistant to cytotoxic chemotherapy. A deeper knowledge of the molecular etiology of urologic malignancies can help broaden the treatment armamentarium and enhance the outcomes of patients resistant to already authorized regimens.

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Dr. Rajesh Gulati
Dr. Rajesh Gulati

Family Physician

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