A mutation (G84E) in the homeobox transcription factor HOXB13 gene is associated with a 3- to 8-fold increase in prostate cancer risk overall. This particular mutation is almost exclusively observed among men of Northern European descent and is more common among men with early-onset disease and a family history of prostate cancer. The hereditary breast and ovarian cancer (HBOC) susceptibility genes (BRCA1 and BRCA2) have also been implicated in inherited prostate cancer. Mutations in BRCA2 in particular have been associated with more aggressive clinicopathologic characteristics in prostate cancer and worse outcomes (increased risk of recurrence and poorer survival). There is also increasing data of prostate cancer being a part of Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome) which can also be associated with increased risk of upper tract urothelial carcinoma. Mutations in the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2 and EPCAM) account for Lynch syndrome, and there is emerging data of increased risk for prostate cancer among male DNA mismatch repair mutation carriers as well as increased rates of prostate cancer in Lynch syndrome families. Finally, a number of more common gene variants of low penetrance have also been identified from Genome-Wide Association Studies (GWAS); however, the purported function in prostate cancer and clinical significance for the majority of these common variants is unknown. Thus, a spectrum of genes are now emerging as contributors to inherited prostate cancer for which clinical genetic testing is available, which warrants awareness among urologic providers for appropriate referrals for genetic consultation.
Implications for urologists to identify patients to refer for genetic evaluation. A positive family history of prostate cancer, particularly when diagnosed in a first-degree relative (brother, father), has been associated with an approximate two- to three-fold increase in the risk of prostate cancer; however, risk is also elevated when prostate cancer is diagnosed in second-degree (uncles, grandparents) or third-degree relatives (cousins). Risk generally increases with the number of affected relatives, relationship to the patient (prostate cancer is higher when brothers are affected as opposed to father or sons), and is inversely related to the age at diagnosis among affected relatives. Hereditary Prostate Cancer (HPC) has been used to characterize families with a particularly strong history of prostate cancer and includes those families with either: 1) three or more affected first-degree relatives, 2) prostate cancer diagnosed in three successive generations of the same lineage (paternal or maternal), or 3) two first-degree relatives both diagnosed with early-onset disease (≤ 55 years). It has been estimated that 5-10% of prostate cancer cases may meet HPC criteria. Furthermore, the presence of prostate cancer among along with a family history consistent with other hereditary cancer syndromes such as HBOC and Lynch syndrome expands the scope of consideration for genetic mutations common to other solid tumors. A number of studies have shown a positive family history of breast, colon and pancreatic cancer diagnosed among close relatives is associated with increased prostate cancer risk, even in the absence of prostate cancer diagnosed among family members. These observations reinforce the importance of capturing broad family cancer history, even among those of the opposite sex, for appropriate referral of men to genetic consultation. Urologic providers should now develop strong relationships with genetic consultation practices for discussion of referrals of males for evaluation of inherited prostate cancer.
Genetic consultation for prostate cancer. Genetic counseling is a cornerstone of genetic consultation. The purpose of genetic counseling is to provide individuals with personalized assessment of cancer risk based on their personal and/or family cancer history, provide education of cancer inheritance patterns, and discuss the options/benefits/risks/limitations of genetic testing in order to make an informed decision for genetic testing. Genetic counselors and Advanced Genetics Nurses have training and education in medical genetics and counseling to help educate patients and their families on the genetic component of disease and understand the implications of genetic testing.
At the present time, genetic evaluation guidelines for prostate cancer primarily focus on BRCA1 and BRCA2 testing. The National Comprehensive Cancer Network (NCCN) guideline in genetic and familial risk for breast and ovarian cancers states that a male warrants genetic counseling and to consider genetic testing if he has prostate cancer of Gleason score >=7 and one of the following: (1) at least one close blood relative with ovarian cancer or breast cancer at age <=50, or (2) at least two relatives with breast, ovarian, or prostate cancer (Gleason >=7) at any age. The NCCN states that an unaffected male may also consider genetic evaluation if their family history meets the same criteria, though testing of an affected relative is preferred if possible. For male BRCA mutation carriers without prostate cancer, the NCCN recommends prostate cancer screening start at age 45 for BRCA2 carriers and to consider screening for BRCA1 carriers. Due to additional risk for male breast cancer for BRCA mutation carriers, NCCN recommends breast self-exam training starting at age 35, and a yearly clinical breast exam also starting at age 35. BRCA mutation status in a male can provide useful information for male and female relatives, to consider their own genetic counseling and genetic testing including the known mutation in the family. Thus, female relatives can gain cancer risk information and personalized screening recommendations for breast and ovarian cancer, and both males and females can gain information regarding risks for pancreatic cancer and melanoma and discuss the current state and options for screening of these cancers. Therefore, genetic counseling for males concerned about inherited prostate cancer includes discussion of the role of BRCA1 and BRCA2 in prostate cancer risk and screening, as well as additional cancers associated with BRCA mutations relevant to males and females.
Additional larger prostate cancer risk-focused gene panels are also now available for genetic testing through a few commercial genetic testing laboratories. These panels include BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, and HOXB13 (in some of the panels). However, guidelines for prostate cancer screening currently only exist for BRCA1 and BRCA2. Testing these additional genes could provide information on risks and management of additional cancers such as colon cancer, ovarian cancer, endometrial cancer, or pancreatic cancer. Prostate cancer gene panels also include several other genes where there is early data in prostate cancer, or conflicting data for many genes regarding risk for prostate cancer. Therefore, genetic counseling includes discussion of genes available on these panels, cancer risks associated with these genes, potential findings and implications for men and their families. In particular, it is stressed that current guidelines for management of prostate cancer are only limited to BRCA1 and BRCA2, though genetic test results could inform of additional cancer risks for which many have management guidelines.
Also, discussion needs to include if the men would want to know this information. It can be difficult for some individuals to hear about future cancer risks while newly diagnosed or hear about cancer risks (i.e. pancreatic cancer) where screening guidelines are not available but screening modalities may exist.
Additional considerations for genetic testing. Current insurance coverage for genetic testing is primarily limited to BRCA1/2 testing if a man meets NCCN criteria (Genetic/Familial High-Risk Assessment: Breast and Ovarian). There may still be an out-of-pocket cost depending on the man’s insurance plan. Full payment out-of-pocket is also an option and can range from $249-$2436 depending on the laboratory. Thus, some men are opting to proceed with gene panel testing if the out-of-pocket cost can be afforded. Prior to testing, additional considerations to discuss in genetic counseling include genetic discrimination laws. The Genetic Information Non-discrimination Act (GINA) of 2008 provides protection from discrimination in health insurance and employment in most scenarios, but does not cover life insurance, long-term care, or disability insurance. Therefore, a male with no pre-existing conditions needs to understand these laws prior to proceeding with genetic testing in case he is found to carry a genetic mutation. Furthermore, genetic test results may have reproductive implications for offspring particularly for recessive conditions (such as Fanconi anemia related to two partners with BRCA2 mutations). Thus, this is also important to discuss prior to proceeding with genetic testing
Conclusion. Genetic evaluation for prostate cancer is now emerging to address the need to identify the basis of suspected inherited prostate cancer in families. Urologists need to develop strategies to capture comprehensive family cancer history to identify men to refer for genetic evaluation. Furthermore, referral of men with young onset prostate cancer, particularly diagnosed at age <=55, is important for men to undergo genetic counseling and make informed decisions for genetic testing. Strong partnership of urologic providers with the cancer genetics community will be needed for men to gain access to genetic consultation and to make progress in expanding our understanding of the genetic predisposition to prostate cancer. A national consensus conference is scheduled in Philadelphia in early 2017 to develop comprehensive genetic evaluation guidelines relevant to prostate cancer risk, which will have impact for men and their families regarding cancer risk and management.
1Veda N. Giri, MD, 2Jennifer Beebe-Dimmer, MPH, PhD, 1Colette Hyatt, MS, LCGC, and 3Leonard Gomella, MD
1Cancer Risk Assessment and Clinical Cancer Genetics Program, Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
2Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Department of Oncology, Detroit, MI
3Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson Universityee
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