The Future of Germline Genetic Testing in Urology

Educational Objectives

The goal of this program is to improve diagnosis and management of urologic diseases using germline genetic testing. After hearing and assimilating this program, the clinician will be better able to:

1. Explain the difference between germline testing and somatic testing.
2. Use genetic testing to predict responsiveness to hormone therapy.
3. List genetic variants that result in different levels of disease aggressiveness in Black vs White men.

Summary

Types of genetic testing: 1) germline testing involves testing the deoxyribonucleic acid (DNA) that is inherited; such mutations are present in every cell of the patient's body; 2) somatic testing involves testing DNA present only within tumors; such mutations are very specific for tumors

Importance of genetic testing: the patient's genetic makeup enables clinicians to select screening, diagnostic, or treatment options that the patient will respond best to; it becomes a part of personalized medicine; individual susceptibility to prostate cancer is identified by germline testing; such patients may be screened at earlier time points; for patients with elevated prostate-specific antigen scores, a predisposition to prostate cancer aids in biopsy decision making; once patients are diagnosed with prostate cancer, germline testing aids in determining prognosis (aggressiveness); understanding the germline and somatic signatures in patients with advanced prostate cancer who are not responding to standard hormone therapy can result in a completely different therapeutic response; there is possibility to offer improved screening for family members (eg, individuals with the BRCA2 mutation and their family members are at risk for prostate, pancreatic, skin, and gastric cancer)

Inherited risk assessment: 1) obtain a family history of prostate cancer and other cancers (eg, breast, ovarian, endometrial, pancreatic, gastrointestinal, lymphoma, brain cancers); if yes, inquire about the patient's age at the time of diagnosis and whether the patient died as a result of the cancer; 2) perform evaluation of germline factors; identify rare pathogenic mutations that predispose to prostate cancer (eg, BRCA1, BRCA2, ATM, CHEK2); it is necessary to distinguish among genes that predispose to prostate cancer and those that predispose to aggressive cancer; 3) entails developing a polygenic risk score based on the presence of single nucleotide polymorphisms (SNPs) that increase the risk for prostate cancer; SNPs are variations in an individual's DNA; there are >300,000 of these variations throughout the DNA that increase risk for various diseases (eg, prostate cancer, heart disease, diabetes mellitus [DM]); the genetic risk score (GRS) is a polygenic risk score that is calculated and compared with the population; eg, a GRS score of 1 implies that the individual has average population risk of developing the disease; hence, scores personalized to each patient specifically estimate the risk of developing prostate cancer

Literature: GRS outperforms family history and rare pathogenic mutations in studies (prospective data based on UK Biobank) that compare their performance; GRS can estimate not only the risk for prostate cancer but also its aggressiveness; high-risk individuals are to be screened early; pathogenic mutations increase the risk for prostatic cancer and aggressive disease, but they are rare; family history imparts increased risk for prostate cancer, but not lethal prostate cancer

Calibration and racial variations: calibration of GRS score is critical; a race-specific risk score is more appropriate than a pan-race risk score; eg, Black men have increased risk for prostate cancer and lethal prostate cancer

Specific mutations: evidence of rare pathogenic mutations come from multigene panels; these can be useful for other physicians taking care of the patient as well; according to a study by the speaker's group of >90,000 patients with different rare pathogenic mutations, only 4 significant genes increase the risk for prostate cancer (HOXB13, BRCA2, ATM, CHEK2); BRCA1 confers a marginally increased risk for prostate cancer; a meta-analysis included in the above study revealed 5 genes increase the risk of developing more aggressive cancer; these include BRCA2, ATM, CHEK2, PALB2, and NBN

New mutations: the I179T mutation in the PSA gene known as KLK3 increases the risk for prostate cancer and for aggressive prostate cancer

Implications on therapy: patients who fail traditional hormone therapy and have DNA damage repair defects may respond better to certain medications (eg, poly ADP ribose polymerase [PARP] inhibitors, platinum-based therapy, immunotherapy); ≈20% of men with advanced prostate cancer harbor mutations in the germline and/or tumor DNA; identification of mutations may help to identify patients who are more sensitive to specific therapies

Response to hormone therapy: eg, a variation within the HSD3B1 gene, a testosterone processing-related gene, imparts decreased responsiveness to hormone therapy; patients with this variant develop castrate-resistant tumors at a much faster rate; identification of the variants may aid in the counselling of patients regarding potential responsiveness to hormone therapy and prognosis for men with aggressive prostate cancer

Association of variants with race: eg, SNP on the long arm of chromosome 8 confers increased aggressiveness specifically in Black men; knowledge of this variant may influence screening, counselling, and potential treatment decisions; some HOXB13 mutations are more common in White men, and some are more common in Black men; the X285K mutation, a HOXB13 mutation, increases the risk for prostate cancer and the risk for aggressiveness in Black men; the mutation in White men increases risk for prostate cancer but not aggressiveness

Bladder cancer: mismatch repair genes of Lynch syndrome (MLH1, MSH2, MSH6) increase risk for bladder cancer; MLH1 increases bladder cancer risk by 5 times; these are rare in general population; some of the DNA damage repair genes (eg, CHEK2, ATM, BRCA2) that increase the risk for prostate cancer and aggressiveness of disease also increase susceptibility to bladder cancer

Testosterone: a GRS is calculated based on SNPs that increase risk for low testosterone; this is used to counsel patients at increased risk for low testosterone; symptomatic patients with elevated GRS benefit from appropriate treatment

Benign prostatic hyperplasia (BPH): a GRS for BPH and prostate cancer can be used jointly; the benign growth of the prostate raises PSA levels, which can be confused with prostate cancer; a DNA test helps differentiate them; GRS values can be used to stratify patients and make decisions based on their genetic predisposition or heritability for BPH or prostate cancer

Interaction with other fields of medicine: the risk for development of venous thromboembolism events (VTE), pulmonary embolism (PE), and deep venous thrombosis (DVT) are important in general and also in the population of urologic patients; increased risk for VTE in patients with bladder cancer warrants use of prophylactic anticoagulant formulations; diseases like coronary artery disease (CAD) and type 2 DM intersect with urologic conditions; speaker's group showed in a prospective study that the risk of having VTE is much higher in patients with bladder cancer than prostate cancer; the creation of GRS specific for VTE is possible; the presence of factor V Leiden mutations increase the risk for VTE; the VTE GRS score can help predict who is at risk of developing a DVT or PE; aggressive therapy is recommended in patients who undergo surgery or chemotherapy and may have increased risk; populations of patients with BPH may have an increased risk for CAD; CAD overlaps with many different disease states (eg, lower urinary tract symptoms [LUTS], erectile dysfunction); it is recommended that a well-validated coronary artery GRS be considered to stratify patients who have risk for CAD; type 2 DM increases risk for many urologic diseases, eg, LUTS, overactive bladder; a validated GRS for type 2 DM can distinguish between type 1 and type 2 DM; this score performs as well or better than family history and any other currently available information

Future trends: it is anticipated there will be an increased implementation of germline genetic testing; personalized medicine assists in identifying patients who are at a higher risk for urologic and other diseases, as well as making appropriate decisions along the path of any of those diseases; there is potential to stratify patients based on the risk for various cancers

Readings

Chung JS, Morgan TM, Hong SK. Clinical implications of genomic evaluations for prostate cancer risk stratification, screening, and treatment: a narrative review. Prostate Int. 2020; 8(3):99-106. doi:10.1016/j.prnil.2020.09.001; He Y, Xu W, Xiao YT, et al. Targeting signaling pathways in prostate cancer: mechanisms and clinical trials. Signal Transduct Target Ther. 2022; 7(1):198. Published 2022 Jun 24. doi:10.1038/s41392-022-01042-7; Kulac I, Roudier MP, Haffner MC. Molecular pathology of prostate cancer. Surg Pathol Clin. 2021; 14(3):387-401. doi:10.1016/j.path.2021.05.004; Schiewer MJ, Knudsen KE. Basic science and molecular genetics of prostate cancer aggressiveness. Urol Clin North Am. 2021; 48(3):339-347. doi:10.1016/j.ucl.2021.04.004; Sokolova AO, Obeid EI, Cheng HH. Genetic contribution to metastatic prostate cancer. Urol Clin North Am. 2021; 48(3):349-363. doi:10.1016/j.ucl.2021.03.005; Shi Z, Lu L, Resurreccion WK, et al. Association of germline rare pathogenic mutations in guideline-recommended genes with prostate cancer progression: A meta-analysis. Prostate. 2022; 82(1):107-119. doi:10.1002/pros.24252; Weise N, Shaya J, Javier-Desloges J, Cheng HH, Madlensky L, McKay RR. Disparities in germline testing among racial minorities with prostate cancer. Prostate Cancer Prostatic Dis. 2022; 25(3):403-410. doi:10.1038/s41391-021-00469-3.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Helfand was recorded exclusively for Audio Digest on September 22, 2022. Audio Digest thanks the speakers for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

UR452302

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.