Abstract: Prostate cancer is a highly heritable cancer, with contributions from rare pathogenic variants in prostate cancer predisposition genes (eg, HOXB13, BRCA2) and from common genetic variants throughout the genome. Only HOXB13 has been identified as a prostate cancer risk gene through linkage disequilibrium studies. Cancer predisposition genes in DNA damage repair pathways have been found to contribute to prostate cancer risk—particularly high-risk or metastatic prostate cancers—in family-based, clinic-based, and population-based studies. Polygenic and genomic risk scores based on common genetic variants identified in genome-wide association studies may have greater power to determine cancer risk than scores based on rare pathogenic variants, but the utility of these scores has yet to be rigorously studied prospectively. Individuals with high-risk or metastatic prostate cancers should be offered germline genetic testing to inform familial risk and screening practices, and to identify biomarker-based treatment options such as platinum-based chemotherapy or poly(ADP-ribose) polymerase inhibitors. Much work is needed to increase the use of germline genetic testing in individuals with prostate cancer, to improve equitable access to testing across all ethnic and racial groups, and to study the genomes of non-European ancestral populations in greater numbers to identify additional ancestry-specific risk variants.
Introduction
Prostate cancer is the most common non-skin cancer and the second most common lethal cancer among males in the United States.1 Prostate cancer is a highly heritable cancer, with evidence from twin studies demonstrating that up 42% to 57% of prostate cancer risk can be attributed to heritability.2,3 Further evidence suggests that disease aggressiveness among males with prostate cancer may be heritable in terms of both disease risk group at diagnosis and prostate cancer–specific survival.4,5 Linkage studies have identified chromosomal loci (eg, 17q21—the location of the prostate cancer risk gene HOXB13—and 8q24) as risk loci for prostate cancer,6-10 and additional family-based and population-based studies have identified risk genes in the homologous recombination repair (HRR) pathway, most notably BRCA2.11,12 The genetics of prostate cancer have several screening, prognostic, and therapeutic implications. In this review, we discuss the role of genetics in prostate cancer risk and how to incorporate genetic information in the routine care of individuals with, or at risk for, prostate cancer.
Genetic Risk of Prostate Cancer
Rare Pathogenic Variants and Other Risk Loci
Rare pathogenic variants and other risk loci include HOXB13, DNA damage repair genes, TP53, and 8q24.
HOXB13. In the nascent field of prostate cancer genetics, linkage disequilibrium studies identified several genetic loci associated with prostate cancer risk, including 17q21 and 8q24.6,7,10 An in-depth analysis of genes in the 17q21-22 candidate region among families with prostate cancer linked to this region identified a recurrent variant in HOXB13 that is associated with prostate cancer—namely, G84E.8 Many follow-up studies in different populations have confirmed the association between the G84E variant of HOXB13 and prostate cancer risk, especially in men with early-onset prostate cancer and men with a family history of the disease.13-15 The G84E variant is thought to represent a founder allele typically seen in populations of European ancestry, a stop-loss variant (X285K) has been identified in men of West African genetic ancestry,16-18 and ancestry-specific variants have been identified in men of Japanese19 and Chinese20 ancestries. Notably, the G84E variant is associated with an increased risk in prostate cancer that is independent of disease phenotype, whereas the stop-loss variant in populations with African ancestry is associated with an increase in aggressive prostate cancers, potentially through excess MYC and cyclin B1 expression.21,22 The work of elucidating the mechanisms of HOXB13 carcinogenesis is ongoing,23 but currently no precision therapeutics are available for individuals harboring pathogenic variants in HOXB13.
DNA Damage Repair Genes. Several clinically ascertained studies have identified an enrichment of DNA damage repair (DDR) genes, such as BRCA1 and BRCA2, and of mismatch repair (MMR) genes among individuals with prostate cancer, particularly those with early-onset, aggressive, or metastatic prostate cancer.24-27 The best-described risks for males with DDR genes are in those with BRCA1/2 pathogenic variants. Cohort studies have consistently noted elevated risks of prostate cancer for BRCA2 pathogenic variant carriers, but the results are mixed for BRCA1 pathogenic variant carriers.11,28 In addition, varying lifetime risks of prostate cancers have been noted among these populations; in the EMBRACE cohort study from the United Kingdom and Ireland, BRCA2 pathogenic variant carriers had a cumulative risk of prostate cancer exceeding 50% by age 80 years, whereas analogous carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) had a cumulative risk of 27% by age 80 years.11,28 Ascertainment and selection biases may contribute in part to the differences in relative and absolute risks between these populations.
As well, evidence is emerging that pathogenic variants in ATM,29 CHEK2,30,31 and PALB230 are associated with prostate cancer diagnoses, although the evidence is less robust. Notably, in a case-only study of males with aggressive or nonaggressive prostate cancer, germline pathogenic variants in BRCA2, ATM, and NBN were found to be associated with aggressive prostate cancers in multiple study populations in comparison with nonaggressive prostate cancers.32,33
Among those with pathogenic variants in MMR genes and clinical diagnoses of Lynch syndrome, some evidence has been found for an increased risk of prostate cancer.34,35 A prospective registry of individuals with Lynch syndrome identified a relatively high cumulative incidence of prostate cancer by age 75 years (23.8%; 95% CI, 17.2%-33.2%) among carriers of MSH2 pathogenic variants.36 However, the population-based data linking pathogenic variants in MMR genes to prostate cancer risk are relatively limited.
TP53. Recent work has shown that prostate cancer is associated with TP53 pathogenic variants, although prostate cancer was not initially considered to be part of the spectrum of Li-Fraumeni syndrome (LFS) cancers. The likelihood of a germline pathogenic variant in TP53 is 9-fold higher in individuals with prostate cancer than in population controls.37 One possible reason for a general lack of association between prostate cancer and germline TP53 variants is the fact that up to 70% of the variants identified in the above study showed evidence of being hypomorphic, meaning that the variants amounted to only a partial loss of gene function. In traditional or classic LFS cohorts with more deleterious variants, patients will have competing risks of death from other malignancies before the development of prostate cancer, which may explain the historical lack of an association between LFS and prostate cancer.
8q24. Another genetic risk locus for prostate cancer of note is 8q24. Multiple studies have identified that genetic variation in this region is associated with prostate cancer.9,15,38 This region is a “gene desert,” with a lack of coding genes, although it does contain the oncogene MYC as well as several noncoding RNA transcripts. Further in-depth analyses of this region have uncovered a regulatory role of long, noncoding RNAs such as PVT1 and PCAT1 in prostate cancer, suggesting increased expression of these RNAs as a putative mechanism for the increased risk of prostate cancer.9,39 One risk allele in this region, rs72725854 A>T, is specific to persons of African ancestry. It has an allele frequency of 6% and confers 2-fold higher odds of prostate cancer.40
Polygenic Risk
Rare or less-common pathogenic germline variants in cancer predisposition genes such as HOXB13 or other DDR genes play an important role in prostate cancer, but these variants are present in fewer than 10% of men, pointing toward a significant amount of missing heritability.41 Multiple genome-wide association studies (GWAS) have identified common genetic variants associated with prostate cancer, each with a relatively small effect size and with genome-wide significance. These small individual associations can be combined into a polygenic risk score (PRS) or a genetic risk score (GRS), which can contribute to the evaluation of prostate cancer risk.
Multiple risk scores have been developed as new loci associated with prostate cancer are identified, which have been validated in multi-ancestry cohorts.42-44 For instance, with a GRS composed of 451 variants (GRS451), 4.4% of prostate cancers were identified in the bottom quintile of GRS451 while 51.2% of prostate cancers were identified in the top quintile.43 PRS and GRS have also demonstrated an ability to modify the penetrance of rare pathogenic variants in BRCA1/2 and HOXB13.45-47 The ability of risk scores to discriminate between a low and a high risk of prostate cancer is an intriguing avenue for the future study of clinical applications, particularly in identifying high-risk populations to screen with greater or lesser intensity. These scores have not been studied prospectively, impeding their clinical use at this time. It is also important to note that although these scores maintain some predictive power across ancestries, the relatively smaller amount of genetic data available for non-European ancestries can limit the identification of ancestry-specific variants.48
Clinical Implications
Prostate Cancer Screening
As previously discussed, rare pathogenic variants in certain genes and risk loci have a causal effect on the development of prostate cancer. Fewer data are available on how germline genetic information should affect prostate cancer screening practices in males. The international IMPACT study recruited men without prostate cancer between the ages of 40 and 69 years who had rare pathogenic germline variants in BRCA1/2 and mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) as well as known-negative controls; participants were offered prostate biopsy at a prostate-specific antigen (PSA) threshold of 3.0 ng/mL.49,50 After an initial 3 years of screening in the BRCA1/2 cohort, the incidence of cancer was higher in carriers of BRCA2 pathogenic variants but not BRCA1, and the carriers were more likely to have clinically significant prostate cancers (intermediate- or high-risk) than the noncarriers.49 In the Lynch syndrome cohort of the study, MSH6 and MSH2 pathogenic variant carriers had a higher incidence of prostate cancer, as well as a higher incidence of clinically significant prostate cancers.50
Analogous analyses have not been performed for HOXB13 variants, although the Stockholm-3 Model for Prostate Cancer Detection incorporates 232 common genetic variants, the HOXB13 G84E variant, blood biomarkers, and clinical variables.51 This model has been shown to maintain sensitivity vs PSA testing alone, improves specificity for clinically significant prostate cancers, and has been prospectively validated in a diverse, multiethnic cohort.52,53 Ultimately, it is recommended that individuals at higher genetic risk of prostate cancer—whether by strong family history or known genetic lesions such as pathogenic variants in BRCA2 or HOXB13—discuss prostate cancer screening starting at age 40 years according to society guidelines.54,55
Therapeutic Implications
Individuals with pathogenic germline variants in BRCA1/2 and other DDR genes have a later stage at prostate cancer diagnosis and inferior clinical outcomes in the localized and metastatic settings, including overall and cause-specific survival.26,32,56 Notably, however, possession of a germline pathogenic variant in DDR genes can open up additional precision treatment options for patients with metastatic prostate cancer (Table 1).
Poly (ADP-Ribose) Polymerase Inhibitors and Platinum Chemotherapy. Prostate cancers driven by pathogenic germline variants in the HRR pathway (eg, BRCA1/2) are more sensitive to double-stranded DNA breakage. This can be exploited therapeutically through the use of poly(ADP-ribose) polymerase (PARP) inhibitors—that is, olaparib (Lynparza, AstraZeneca), rucaparib (Rubraca, Clovis Oncology), niraparib (Zejula, GSK), and talazoparib (Talzenna, Pfizer)—or platinum-based chemotherapy. Platinum-based chemotherapy induces direct double-stranded DNA damage and has been shown to be effective in males with metastatic castration-resistant prostate cancer (mCRPC) and pathogenic variants in specific HRR genes, particularly in BRCA2.57-59
PARP inhibitors lead to “synthetic lethality” in cells with deficient homologous recombination machinery through multiple putative mechanisms. These include inhibiting the ability of PARP1 to repair single-stranded DNA breaks, PARP trapping (which prevents dissociation between PARP and DNA), and upregulation of the more error-prone nonhomologous end-join repair machinery.60,61 Together, all of these mechanisms lead to further genomic instability in HRR-deficient cells, and ultimately to cell death.
Several trials have established the role of PARP inhibitors in the care of men with mCRPC. For example, PROfound randomized patients to receive olaparib or physician’s choice of abiraterone acetate or enzalutamide (Xtandi, Astellas) in the post-androgen receptor pathway inhibitor (ARPI) setting.62 In cohort A (variants in BRCA1/2 and ATM), overall survival (OS) was 19.1 months in the olaparib arm vs 14.7 months in the control arm (hazard ratio [HR], 0.69; 95% CI, 0.50-0.97; P=.02).63 In cohort B (variants in BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L), no OS benefit was seen, although US Food and Drug Administration (FDA) approval was granted for variants in both cohort A and cohort B genes on the basis of improved progression-free survival (PFS) in the total population (5.8 vs 3.5 months; HR, 0.49; 95% CI, 0.38-0.63; P<.0001).62 In TRITON3, patients with mCRPC and a pathogenic variant in BRCA1/2 or ATM who had progressed on an ARPI were randomized in a 2:1 fashion to receive rucaparib or physician’s choice of control medication (docetaxel or an ARPI).64 This study demonstrated an improvement in PFS in the BRCA1/2 subgroup (11.2 vs 6.4 months; HR, 0.50; 95% CI, 0.36-0.69; P<.001), but no benefit was observed in the ATM subgroup. It is important to note that the eligible pathogenic variants in the trials that led to olaparib and rucaparib approval included germline and/or somatic variants.
Combined Androgen Receptor Pathway and PARP Inhibition. Preclinical models of prostate cancer have demonstrated that androgen receptor (AR) activity is necessary for HRR machinery, suggesting that combination AR and PARP inhibition could lead to a synergistic form of synthetic lethality.65 Thus, these combination strategies have recently been investigated in mCRPC. The PROpel trial randomized patients with mCRPC to receive abiraterone and placebo vs abiraterone and olaparib regardless of the presence of a pathogenic variant in the HRR pathway (ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L).66 The primary endpoint of investigator-assessed PFS favored the combination therapy group (24.8 vs 16.6 months; HR, 0.66; 95% CI, 0.54-0.81; P<.001), although the magnitude of benefit was greater in patients with variants in the HRR pathway (HR, 0.50; 95% CI, 0.34-0.73).
TALAPRO-2 randomized patients with mCRPC to receive enzalutamide plus talazoparib or enzalutamide plus placebo in 2 cohorts: an all-comers cohort (irrespective of HRR variants) and an HRR-deficient cohort based on pathogenic variants in the HRR pathway (BRCA1/2, ATM, ATR, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C).67,68 The primary endpoint, radiographic PFS, favored the combination arm (HR, 0.63; 95% CI, 0.51-0.78; P<.0001) among all participants.67 As in PROpel, the PFS benefit of combination therapy with enzalutamide and talazoparib was more pronounced in the HRR-deficient population (HR, 0.45; 95% CI, 0.33-0.61).68
MAGNITUDE randomized patients with mCRPC to receive combination abiraterone plus niraparib or abiraterone plus placebo in 2 cohorts: one with HRR variants (ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2) and one without HRR pathogenic variants.69 The cohort without HRR pathogenic variants was stopped early for futility, but the cohort with HRR variants did show improvement with the combination therapy of abiraterone plus niraparib with respect to the primary endpoint of radiographic PFS (HR, 0.73; 95% CI, 0.56-0.96; P=.022). However, the benefit in the HRR variant group was driven primarily by the patients with variants in BRCA1/2 (HR, 0.53; 95% CI, 0.36-0.79; P=.002), whereas the patients with non-BRCA1/2 HRR variants did not seem to derive benefit.
The FDA has approved the above combination regimens for use in mCRPC, but only in cohorts with HRR pathogenic variants (enzalutamide and talazoparib) or with BRCA1/2 pathogenic variants (abiraterone and niraparib, abiraterone and olaparib). The FDA also performed a pooled analysis of studies with PARP inhibitors for mCRPC.70 Among trials comparing ARPIs with or without PARP inhibitors, the PFS and OS benefits were limited to mostly to patients with BRCA1/2, CDK12, and PALB2 pathogenic variants, whereas no PFS or OS benefit was apparent in those with ATM or CHEK2 variants. In the pooled analysis, PARP inhibitor monotherapy in those with CDK12-variant disease led to overall response rates of only 5% (95% CI, 1%-16%), and previous retrospective studies have shown limited PSA response to PARP inhibitor monotherapy in this population.71 Therefore, it is possible that the benefit of PARP inhibitors is limited to combination therapy with ARPIs among patients harboring CDK12 variants. Because of the heterogeneity of study design, genes included in the HRR cohorts, and outcomes in the above studies, it is important to consider carefully which combination therapy or monotherapy to offer patients. Adverse events are largely similar among the various PARP inhibitors and combinations, with increased risks of anemia, neutropenia/leukopenia, thrombocytopenia, nausea, emesis, fatigue, and poor appetite. Germline genetic testing assays were not used for PROpel or TALAPRO-2 to include participants in the biomarker-positive group, although germline results were used in MAGNITUDE.66,67,69
Lastly, these combination studies may already be outdated; only a small percentage of individuals with mCRPC had received prior ARPI treatment in the above studies, whereas an ARPI is now the standard of care in the frontline setting as part of doublet or triplet therapy combinations. Now, studies are underway of the use of PARP inhibitors in the first-line setting, including AMPLITUDE (NCT04497844), EvoPAR-Prostate01 (NCT06120491), and TALAPRO-3 (NCT04821622). Additionally, the prospective PROMISE registry aims to identify individuals harboring rare germline pathogenic variants and will be able to obtain real-world evidence of therapeutic efficacy in the context of evolving standards of care.72
Immunotherapy. In general, immunotherapy is not effective for treating advanced prostate cancer because the disease is thought to be immunologically cold. However, for those patients who have uncommon tumors with germline pathogenic variants in MMR genes (MSH2, MSH6, MLH1, PMS2, EPCAM) and who have a deficiency of MMR proteins on immunohistochemistry or microsatellite instability, pembrolizumab (Keytruda, Merck) is an option.73 Data regarding the efficacy of immune checkpoint inhibitors (ICIs) in this population are limited, although retrospective data indicate that patients with a higher tumor mutational burden, microsatellite instability, or MMR deficiency have better responses to ICIs.74,75 It is unknown if ICIs are effective in individuals with a germline pathogenic variant in an MMR gene without somatic indicators of genomic instability.
Germline Testing: Indications for Testing
It is currently recommended that all males with high-risk localized or metastatic (regional or distant) prostate cancer be offered germline genetic testing (Table 2).73 Relying on reflex testing following positive results of somatic tumor testing is not recommended because up to 20% of pathogenic germline variants will be missed with tumor-only testing,76 and HOXB13 is not included on all somatic sequencing panels. Other indications for germline testing of males affected with prostate cancer include the following: Ashkenazi Jewish ancestry, a strong family history of prostate cancer (≥2 close relatives with prostate cancer on the same side of the family), and at least one close blood relative with a malignancy suggestive of a genetic syndrome (early-onset breast cancer, triple-negative breast cancer, male breast cancer, ovarian cancer, pancreatic cancer, or high-risk or metastatic prostate cancer).77 We also recommend that confirmatory germline testing be considered for patients with somatic alterations in cancer predisposition genes that are identified on somatic tumor testing. Specific genes that are currently recommended to be included in testing panels include BRCA1, BRCA2, ATM, PALB2, CHEK2, HOXB13, MLH1, MSH2, MSH6, PMS2, and EPCAM.73,78 Note that EPCAM pathogenic germline variants are exceedingly rare in the population and may be omitted because no consensus exists among different guidelines regarding testing of this gene.
Testing is recommended to identify potential personalized therapies in the metastatic setting and also to identify germline pathogenic variants that would put the patient at elevated risk of a second primary cancer or that would put family members at elevated risk of cancer development. For instance, pathogenic variants in BRCA1/2 have strong associations with breast, ovarian, and pancreatic cancers, and risk-reducing interventions are available that can be offered. Increased screening and even risk-reducing surgery have been options for female BRCA2 carriers for several years,79 and pancreatic cancer screening programs have also emerged for individuals at high genetic risk.80,81
Unanswered Questions
Clinical Implementation and Barriers to Germline Genetic Testing
Evidence shows that patients with prostate cancer want germline genetic testing to be offered if it can help inform treatment decisions or inform screening practices for family members.82 Despite these known benefits of germline testing and guideline recommendations, clinically indicated germline testing is lacking. A recent nationwide analysis of Veterans Affairs and administrative claims data demonstrated that fewer than 20% of males with metastatic prostate cancer in a contemporary cohort underwent germline genetic testing.83 In a survey of academic oncologists conducted in 2017 (before guidelines began recommending germline testing in 2019), 62% of responding oncologists considered germline testing for all patients with metastatic prostate cancer, whereas the other 38% considered testing for these patients depending on their family history and/or clinical trial availability.84 Some significant operational barriers were identified in this survey, including clinic workflow, time limitations, insurance coverage/cost, and limited access to genetic counselors. Another qualitative study including medical oncologists, urologists, and radiation oncologists revealed similar barriers to genetic testing.85 Many of these barriers were related to practice/provider factors, with the notable exception of financial cost to the patient. Ongoing research aimed at improving the implementation and acceptance of genetic testing for males with prostate cancer is underway, with interventions such as Web tools for patient education and oncologist-driven pretest counseling.86-88
Gene-Gene and Gene-Environment Interactions
Prostate cancer is a complex disease with a complex inheritance pattern. A significant portion of heritability may be attributable to rare pathogenic variants in cancer predisposition genes, in addition to hundreds of low-penetrant loci identified in GWAS. These genetic variants do not exist in isolation, and many questions remain. Do specific pathways with alteration and/or increased expression exist that can modify the risks of rare pathogenic variants? Or, do combinations of low-penetrant single-nucleotide polymorphisms (SNPs) exist that work in tandem to create multiplicative, rather than additive, risk? The statistical power to study gene-gene or SNP-SNP interactions in an unbiased, systematic fashion is limited by the risk of false discovery (because of the number of statistical tests that would need to be performed). Hypothesis-driven mechanistic and pathway-specific investigations of gene-gene/SNP-SNP interactions may be one way to limit the number of tests performed and improve the statistical power to identify associations.
Somewhat limited data on gene-environment interactions are also available. Common environmental or comorbid exposures, such as smoking, alcohol intake, diabetes, and body mass index and weight, do not seem to modify the genetic risks of prostate cancer–risk SNPs identified in GWAS.89,90 Studies have identified lead exposure as modifying the risk of prostate cancer associated with SNPs juxtaposed with another zinc finger protein 1 (JAZF1) and delta-aminolevulinate dehydratase (ALAD) in Black or African American males.91,92 The results from these studies again highlight the need to focus on pathway-specific, hypothesis-directed interactions between gene and environment. The genes JAZF1 and ALAD were chosen because of their interactions with lead at the biochemical level, so the authors were able to uncover an association between genes and environment in modifying the risk of prostate cancer.
Disparities
In the United States, the incidence of prostate cancer is 1.8-fold higher in Black or African American males than in White males, and the risk of prostate cancer mortality is 2.2-fold higher in Black than in White males.93 The genetics of prostate cancer is another area in which racial disparities exist. Throughout much of the history of cancer genetics research, individuals of European ancestry have been the dominant ancestral population studied. Because of the way these data have been discovered and generated—uniquely in European ancestry–dominant populations—the associations for these variants may not always be applicable or valid in individuals of other ancestries. This phenomenon can be seen in multi-ethnic validations of polygenic scores, in which the discriminating performance of polygenic scores is worse in non-European ancestry populations than in European ancestry populations across multiple disease phenotypes.94,95 The implementation of clinical genetic testing is another area of racial disparities. Research has demonstrated that Black or African American males are typically less likely to undergo recommended germline genetic testing for prostate cancer, although the number of representative studies since testing has been formally recommended in guidelines is limited.83 Fortunately, efforts are being made to increase the study of non-European populations, but much work is needed to improve the pipeline of gene/SNP discovery to risk score development to clinical implementation among populations with non-European ancestry.
Conclusion
Prostate cancer is a highly heritable disease with contributions from both rare and common variants across the genome. Although both rare and common variants contribute to heritable prostate cancer risk, moderate- to high-penetrant rare pathogenic variants in cancer predisposition genes—primarily in the HRR pathway—contribute significantly to prostate cancer biology, aggressiveness, and clinical outcomes. Targeted therapeutic approaches have shown clinical benefit for those with pathogenic variants in several HRR pathway genes. Thus, it is imperative to offer and confirm equitable access to germline testing completion for men with prostate cancer who meet the indications for clinical testing on the basis of personal cancer history (high-risk or metastatic disease) or family cancer history. As research continues in this field, it is important to ensure adequate representation from populations of all ancestries to provide the power to identify ancestry-specific risk loci and to uncover further gene-gene and gene-environment interactions that may affect prostate cancer risk.
Disclosures
Dr Shevach has received research funding from AstraZeneca and Merck; owns stock in Pfizer; has received travel funds from AstraZeneca and Dava Oncology; and has received honoraria from MJH Life Sciences. Dr Cooney has received book royalties from Elsevier and Springer and holds a patent based on the discovery of HOXB13 and its relationship to prostate cancer (U.S. Patent No. US 9,593,380 B2).
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