Genetic Evaluation of Hereditary Prostate Cancer

During much of the past 30 years, genetic tests for heritable disorders have assessed limited numbers of genes and have often employed serial testing algorithms in which the next test was determined by the results of the prior test.¹ The advent of next-generation (also known as massively parallel high-throughput) sequencing has transformed this picture by making it possible to sequence the entire human genome for less than $1,000.1,2 Companies have developed multigene panels that screen for numerous cancer-associated germline mutations at the same time.

As urologists, we can use these tests to help elucidate hereditary risks and guide surveillance and treatment. But, these tests require informed use and interpretation. In this article, I review the types of cancer risk, mutations linked to prostate cancer, available tests for hereditary prostate cancer, and the impact of multigene testing on urology care.

Cancer Risk

Most experts distinguish three major types of cancer risk. General population risk describes sporadic cancers occurring by chance. In this case, affected patients test negative for any known deleterious mutations within their family, and their close relatives typically do not have the same cancer(s).

Familial cancer risk describes the risk for cancers that arises from both genetic and environmental factors. These cancers tend to cluster within families and show no specific inheritance pattern.3 In contrast, in hereditary cancers, mutations occur in germ cells and present in every cell in the body. Hereditary cancers occur when a parent passes an altered gene (germline mutation) to a child. Hereditary cancers are often diagnosed at an earlier age than is otherwise typical and affected patients may develop more than one type of cancer. Patients with hereditary cancer(s) often have relatives with the same or related cancers. Only about 5% to 20% of cancers are hereditary.4-6 Finally, germline mutations differ from somatic mutations, which are confined to tumors and are not heritable. All tumors have multiple somatic mutations.

Cancer epidemiologists and geneticists have refined our understanding of hereditary prostate cancer. Published in 1993, the Johns Hopkins criteria defined hereditary prostate cancers as occurring in at least three first-degree family members, across at least three generations, and with at least two cases diagnosed before age 55 years.7Other early studies linked prostate cancer to autosomal dominant and X-linked patterns of inheritance, often involving variants in chromosomes 1 and 17.8-11

Genes Linked to Hereditary Prostate Cancer

Recently, further research has implicated specific mutations in hereditary prostate cancer and has found that men with these variants are at greater risk for high-grade disease. In the Genetic Evaluation of Men study, researchers used multigene sequencing in 200 men who had prostate cancer or were at increased risk.12 A total of 5.5% had detectable mutations, which usually involved the DNA repair genes BRCA1, BRCA2, ATM, BRIP1, and MSH6. Patients whose families met strict criteria for hereditary cancer syndrome had the highest rates of germline mutations (10.5% and 3.7%, respectively). Interestingly, the next-highest rates of 17 mutations in this study were from men whose Gleason scores exceeded 7 (8.7% mutation rate) or who had T3 or metastatic disease (8.2%). This finding has been echoed by another recent prospective study of men with metastatic prostate cancer who were unselected as to family history.5 A total of 11.8% of these men had germline DNA-repair mutations,5 a substantially higher prevalence than that in unselected men with localized prostate cancer (4.6%).13

BRCA

Among known germline mutations linked to prostate cancer, all available evidence suggests that germline mutations of BRCA, and especially BRCA2, play the strongest role.5,14 Patients with germline BRCA mutations have a higher incidence of aggressive disease, a greater risk of progression on local therapy, and shorter overall survival (OS) times.14-16

Germline BRCA mutations are associated with a higher risk of nodal involvement, distant metastasis, and death from prostate cancer. In a study of 2,019 patients with prostate cancer, those with germline BRCA1/2 mutations were significantly more likely than noncarriers to have Gleason scores of at least 8 (P = .00003), T3/T4 disease (P = .003), nodal involvement (P = .00005), metastases at diagnosis (P = .005).15 Men with BRCA2 mutations were at significantly greater risk of death from any cause (HR, 1.87; 95% CI, 1.54 to 3.07) and from prostate cancer (HR, 1.92; 95% CI, 1.09 to 3.39) compared to men without BRCA1/2 mutations.15

Further evidence for the role of BRCA comes from studies showing that men from breast cancer-prone families are at increased risk for aggressive prostate cancer.17 In a study of 148 men with prostate cancer, nearly 78% of BRCA2+ men had high-risk prostate cancer compared with approximately 59% of noncarriers.17 Two-thirds of BRCA2+ patients had Gleason scores of 8 or higher versus only one-third of noncarriers. Additionally, BRCA2 mutations are correlated with a significantly poorer OS, cancer-specific survival, and cause-specific survival.17

A higher frequency of germline BRCA1 and BRCA2 mutations has been identified among African-American men with prostate cancer.18 In a study of more than 1,000 prostate cancer patients in an equal-access health care system, BRCA mutations were found in 7.3% of African-Americans and 2.2% of Caucasians.18 The presence of BRCA mutations was correlated with a higher risk and a shorter time to metastases. This is an important study because African-Americans have been found to be nearly twice as likely to die from low-grade prostate cancer and researchers have failed to link discrepancies in healthcare access to observed racial differences in prostate cancer outcomes.19,20

Men with known BRCA1/2 mutations are strong candidates for early prostate cancer screening. In one prospective screening study, among 199 men with PSA>3/0 ng/mL, 119 had confirmed BRCA mutations.21 The presence of BRCA1/2 mutations significantly increased the positive predictive value of biopsy.21

Other genes

Several other important germline mutations are implicated in prostate cancer. Mutations of DNA mismatch repair (MMR) genes, which are associated with Lynch syndrome, also confer a twofold increase in the risk of prostate cancer, amounting to a 30% lifetime risk.22 Mutations of MMR genes also increase the risk of transitional cell carcinoma of the upper urinary tract.23 The current recommendation for patients with these mutations is to begin prostate cancer screening at age 40.24  

The HOX genes belong to the homeobox superfamily of transcription factors that are important for prostatic development.25 Among them, homeobox B13 (HOXB13), located in the chromosome 17q21-22 region, is expressed during embryonic development, continues to be expressed at high levels in the normal adult prostate, and suppresses hormone-mediated androgen receptor activity and prostate tumor cell growth.25,26 A single-nucleotide polymorphism (rs339331) has been found to increase HOXB13 binding to a transcriptional enhancer, which may, in turn, upregulate the RFX6 gene that plays an important role in prostate tumor progression and metastasis, as well as in the risk of biochemical relapse.27

Accordingly, HOXB13 mutations are associated with a heightened risk for earlier-onset and more aggressive prostate cancer.25,28 A multigene sequencing study identified HOXB13 mutations in 3.1% of men with early-onset familial prostate cancer, versus only 0.6% of other men with prostate cancer and 0.1% of controls.25 In another large study, 1.3% of men with prostate cancer had the HOXB13 variant G84E versus only 0.4% of controls, and the variant was associated with more aggressive and advanced disease.29

ATM, another tumor suppressor gene involved in DNA repair, helps maintain telomere length and integrity.30,31 Germline ATM mutations have been associated with earlier metastasis of prostate cancer and shorter prostate cancer-specific survival.16 Treatment with poly (ADP-ribose) polymerase (PARP) inhibitor therapy has also shown promise for these tumors.32 Finally, the tumor suppressor gene CHEK2 is an upstream regulator of p53 in the DNA-damage repair pathway.33 Mutations of this gene are linked to both familial and sporadic prostate cancer.33 In one Finnish study, CHEK2 variants produced a threefold
greater odds of unselected prostate cancer and an eight-fold greater odds of hereditary prostate cancer.34 Subsequent studies have confirmed these associations.5,35  

Impact on Patient Care  

Genetic evaluation for hereditary prostate cancer has important implications for patient care. As has been discussed, several germline mutations increase the risk of early death from prostate cancer.16 Based on what is known to date, it is appropriate to consider earlier and more frequent prostate-specific antigen (PSA) screening for men with known personal or familial mutations of BRCA2, HOXB13, or MMR genes linked to Lynch syndrome.

Data indicate that prostate cancer patients with BRCA1/2 mutations should strongly consider therapy with a PARP inhibitor.21,32,36,37 In a study of BRCA1/2+ patients with advanced cancers, the PARP inhibitor olaparib produced prolonged tumor responses, especially in men with prostate cancer (median OS, 7.2 months; median progression-free survival [PFS], 18.4 months).36 Conversely, radiation therapy increases the risk of secondary cancers in patients with certain MMR mutations or TP53 mutations and should be avoided whenever possible.38

When prostate cancer is diagnosed, recent consensus guidelines from more than 70 experts in prostate cancer recommend factoring BRCA2 mutation status into treatment discussions for early-stage or localized prostate cancer, BRCA2 and ATM mutation status into treatment discussions for high-risk or advanced disease, and BRCA1, BRCA2, and ATM mutation status into treatment discussions for metastatic disease.24

These experts had more mixed opinions on how to use genetic test results to guide prospective prostate cancer screening, but most agreed that men with a known BRCA2 or HOXB13 mutation should have a baseline PSA test at age 40 years or 10 years before the youngest case of prostate cancer in the family, followed by interval screening annually or guided by baseline PSA.

Physicians should also keep in mind that some prostate cancer-associated germline mutations significantly increase patients’ risk for secondary malignancies. In particular, BRCA2 mutations are associated with a 36% risk of pancreatic cancer (the general population risk is 0.5%), up to a 76% risk for melanoma, and a heightened risk for male breast cancer.39 Additionally, mutations in MSH, an MMR gene, increase risk of both colon cancer and upper tract transitional cell carcinoma. Clinicians should consider regular cancer screening in patients with high-risk germline mutations.

Whom to Test and How?

The diverse implications of genetic testing on prostate cancer management have spurred several guidance documents on genetic testing.24,40 The recently published consensus document recommends genetic testing for men with prostate cancer who have strong family histories (e.g. hereditary breast and ovarian cancer syndrome, hereditary prostate cancer, and/or Lynch syndrome), metastatic prostate cancer, and/or if their tumor sequencing tests show mutations in cancer risk genes.24 The authors most strongly agree on testing for mutations of BRCA2/BRCA1, HOXB13, MMR genes, and ATM, with specific test choice guided by clinical and familial factors.24

The National Comprehensive Cancer Network (NCCN) also recently updated its guidelines to recommend considering multigene testing for all men with regional, metastatic, high-risk, or very high-risk prostate cancer.40 Additionally, the guidelines suggest considering testing men with lower-risk prostate cancer if they have a strong family history (i.e. a brother, father, or multiple family members diagnosed with prostate cancer before age 60), known germline mutations of DNA repair genes (especially BRCA2 or Lynch syndrome), or more than one relative with breast, ovarian, or pancreatic cancer or Lynch syndrome.40

Studies support such guidance by indicating that significant proportions of unselected patients have a family history significant for cancer. In my own practice, we have found that 17% of patients had a significant family cancer history. This prevalence rose to 35% when physicians and research coordinators began administering an intensive family history questionnaire. Should this hold true in other practices, increasing the utilization and comprehensiveness of family history evaluations could potentially double the percentage of our patients for whom we should consider multigene testing for prostate cancer.

Multiple commercial genetic tests are now available for prostate cancer that utilize blood, saliva, or buccal swabs. Most incorporate genetic counseling into the price of the test. Table 1 summarizes some of the most frequently used panels.  

Caveats and Counseling   

As Table 1 shows, genetic testing for prostate cancer has reached a point where it can and should be incorporated into urology practice. However, there are several caveats to keep in mind. Only approximately 10% to 15% of prostate cancers involve germline mutations, only about 4% to 16% of men will test positive for a deleterious mutation, and most deleterious mutations associated with prostate cancer show only 20% to 40% penetrance (likelihood of phenotypic expression).5

table 1 genetic evaluation hereditary prostate cancer
Another caveat is that a positive result is not necessarily clinically actionable. Commercially available panels include moderate-risk genes for which we have only limited data on cancer risk. Not all mutations involve protein-encoding regions of a gene, and not all mutations of coding regions affect gene function. The more mutations screened for, the greater the likelihood of identifying variants of unknown significance.

Another issue is that even established clinical laboratories can disagree on whether variants are clinically relevant. In a study of nearly 1,200 individuals tested by multiple clinical laboratories for cancer-linked germline mutations, 603 variants were identified, of which 37% were of unknown significance.41 Not only were 26% of laboratory interpretations discordant, but 11% of patients received conflicting results as to whether variants were pathogenic or of unknown significance, which would affect surveillance and treatment. Discordance was highest for CHEK2 and ATM, followed by RAD15, PALB2, BARD1, NBN, and BRIP1. The situation with direct-to-consumer tests is even less reliable: One study found that multigene tests had up to a 40% rate of false positivity and that false positives were a problem across a range of genes, not just one or two.42 

A final caveat is privacy. Although the federal Genetic Information Nondiscrimination Act (GINA) prohibits companies from soliciting or using genetic information to decide whether to sell health insurance or how much to charge, these privacy protections do not extend to life insurance, disability insurance, or long-term care insurance.43

Patients and families should be aware of these details before they elect genetic testing. For this reason and the challenges of interpreting some test results, all patients would ideally undergo professional genetic counseling prior to testing. In reality, this is infeasible—there are not enough genetic counselors in the United States who are well-versed in oncology. Therefore, I recommend that urologists educate themselves or a specialized member of their care team to perform comprehensive pre-test counseling. Patients with positive tests results should then be referred to a genetic counselor for additional guidance.   

Remaining Questions 

Finally, several lines of inquiry require further discussion and investigation regarding hereditary evaluation of prostate cancer. The first is whether and how to test unaffected individuals from high-risk families. The NCCN addresses this question not only in its prostate cancer guidelines, but also in its guidelines on genetic and familial assessment of risk related to breast and ovarian cancer.44 These guidelines have recently broadened the criteria for genetic risk evaluation to include not only individuals with metastatic prostate cancer, but also unaffected individuals of any age whose family member(s) have known or probable pathogenic variant(s) in a cancer susceptibility gene or who have a strong family history of probable familial cancer.44 This guidance closely mirrors the NCCN’s prostate cancer guidelines and underscores the importance of using a robust family history questionnaire, which is ideally administered by a trained individual who can help respondents recall affected family members and their generational relationships.

The second major question is gene penetrance, which is much lower in prostate cancer than in breast or ovarian cancer, for example. The Michigan Urologic Surgery Improvement Collaborative (MUSIC) consortium is creating a statewide registry of prostate cancer patients with germline mutations on multigene testing.45 The aim is to correlate these mutations with data from tumor gene assays, active surveillance, and treatment outcomes in order to optimize a multigene prostate cancer panel for widespread use, just as we now use PSA testing to screen for prostate cancer. To do so, this effort will focus on genes with the highest penetrance in prostate cancer and use tumor markers to identify high-risk patients for whom surveillance should be considered.

Summary

 Like other cancers, prostate cancer can be sporadic (general population risk), can occur in families without specific inheritance pattern (familial risk), or can be hereditary (passed from parent to child through germline mutations). While only approximately 10% of prostate cancers are hereditary, up to 30% of men with prostate cancer meet criteria for multigene testing for hereditary mutations. Germline mutations of BRCA1/2, particularly BRCA2, are strongly associated with prostate cancer and also increase the risk of aggressive disease, early death from prostate cancer, and certain secondary cancers. Other important examples of germline mutations in prostate cancer affect the HOXB13, ATM, and CHEK2 genes, among others. Detecting clinically actionable mutations can help guide the choice between active surveillance and treatment, inform treatment planning, and help ensure earlier detection of secondary cancers. As most germline variants in prostate cancer show an autosomal dominant pattern of inheritance, multigene testing of diagnosed patients can also help identify family members who may benefit from enhanced screening.

The cons of hereditary evaluation in prostate cancer include a high rate of true negatives, variants of unknown or questionable clinical significance, relatively low penetrance, high rates of false positivity from direct-to-consumer tests, and privacy concerns. These issues make genetic counseling a priority. Despite the limitations of available multigene panels for prostate cancer, they are available for use now in our clinics and are NCCN-recommended. When used appropriately, they can guide surveillance, treatment, and enhanced screening for patients as well as family members. 

Written by: Sanjeev Kaul, MD, MCh, who completed his medical education and surgery residency at K.E.M hospital, Mumbai and urology residency at Nair Hospital, Mumbai. He served as a lecturer at Grant Medical College and J.J. Hospital in Mumbai before traveling to the United States in 2002 where he completed a fellowship in Robotic Urologic Oncology at the Vattikuti Urology Institute in Detroit, under the guidance of Professor Mani Menon, who is the pioneer of robotic surgery. Dr. Kaul has been practicing Robotic Surgery for prostate, kidney, and bladder cancer since 2003 and has performed more than 1,400 robotic surgeries, including radical prostatectomy, radical and partial nephrectomy, radical cystectomy, pyeloplasty, ureteral reimplantation, RPLND, etc. He is one of only two urologists in the world who has performed the excision of a kidney cancer extending into the inferior vena cava with the robot.

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