Genetic Polymorphisms and Early-onset Prostate Cancer: A Real Potential to Personalize Prostate Cancer Screening?

Lucinda Hughes; Veda N Giri

Disclosures

Future Oncol. 2009;5(7):923-926. 

Abstract and Introduction

Introduction

Prostate cancer is the most common noncutaneous cancer in men in the USA, with 192,280 new cases estimated in 2009.[1] In addition, death from prostate cancer ranks second in US males after lung cancer, with an estimated 27,360 deaths in 2009.[1] While the risk of prostate cancer is higher with increasing age, a subset of men who die from prostate cancer have early-onset disease. A recent report found that the percentage of men aged less than or equal to 55 years and diagnosed with prostate cancer has increased from 2.3% between 1988 and 1991 to 9% between 2000 and 2003.[2] This study also found that men aged 35–44 years had a higher rate of all-cause and prostate cancer-specific death if diagnosed with aggressive disease, raising the question of possible phenotypic differences in prostate cancer between younger and older men. Screening studies in high-risk men (men with familial prostate cancer and African–American men) have found a relatively younger average age of diagnosis in the range of 50–57 years.[3,4] In addition, a subset of these men were diagnosed with disease that was aggressive or at low prostate-specific antigen (PSA) values.[4]

Despite these statistics, significant controversy surrounds prostate cancer screening, with limited understanding of how to optimize early detection. The key issues revolve around diagnosing aggressive prostate cancer at a curable point while not subjecting men to the morbidity of unnecessary diagnostic tests and treatment. In addition, there is little understanding of how to optimally utilize the serum PSA test for screening in younger men. Two recent randomized prostate cancer screening studies found little to no benefit of screening for prostate cancer using serum PSA testing.[5,6] However, these studies did not enroll men of less than 55 years of age, and therefore have limited application regarding prostate cancer screening benefits in younger men. Genetic polymorphisms have the potential to revolutionize prostate cancer screening by allowing for personalized early-detection approaches. Genetic markers associated with prostate cancer are being reported at a rapid pace with the advent of high-throughput DNA sequencing technologies. Once validated and clinically characterized, genetic polymorphisms may be useful for risk counseling younger men. However, several issues remain regarding personalized screening for early-onset prostate cancer. These include the following:

  • What is the definition of early-onset prostate cancer?

  • How can genetic polymorphisms predict who is at risk of developing prostate cancer at a young age?

  • Can prostate cancer screening be individualized for men who are predicted to be at risk of developing early-onset disease?

Currently, there is no national consensus regarding the definition of early-onset prostate cancer. The definition of 'early onset' varies depending on the study. Some studies cite an age of less than 50 years for prostate cancer diagnosis to represent early-onset disease,[7,8] while other studies include age at diagnosis of less than 66 years when evaluating genetic associations to early-onset prostate cancer.[9] Overall, most studies tend to define early-onset prostate cancer as a diagnosis at an age of less than or equal to 55 years, which encompasses a risk of developing prostate cancer of one in 38 men.[10]

The second issue is the ability to predict which man will develop prostate cancer at a young age. This issue is of particular importance since the goal of screening and performing diagnostic tests is to detect aggressive, life-threatening prostate cancer in younger men and not to subject men to unnecessary tests that may lead to the diagnosis of clinically insignificant cancer, physical morbidity from prostate biopsies, psychological stress and impairment of quality of life from potentially unnecessary, treatment-related side effects. Here, genetic polymorphisms may have clinical utility to predict which men develop early-onset prostate cancer. These polymorphisms may reside in known genes or in gene-poor regions. Typically, the mechanism of how polymorphisms impact the onset of prostate cancer is unknown. However, owing to their association with prostate cancer (usually from genome-wide association studies [GWAS]), these polymorphisms warrant further clinical study in order to understand how to utilize them for personalizing prostate cancer screening.

Several genetic polymorphisms have been identified by GWAS as being associated with prostate cancer and have been further characterized for an association with early-onset prostate cancer. While these studies lend insight into genetic markers associated with early-onset disease, none of them include significant numbers of early-onset cases and the findings are from subset analyses, which highlights the importance of further large-scale studies of genetic markers and early-onset disease. A chromosomal region of great interest in prostate cancer genetics research is 8q24.[11–14] One study found that carrying the minor allele of one polymorphism (rs6983561) at 8q24 was associated with a fivefold risk of prostate cancer in men less than 50 years of age.[15] Another chromosomal region of interest for potentially harboring prostate cancer susceptibility variants is 17q12.[16] One study found that the A allele of a polymorphism (rs4430796) at 17q12 increased the risk of prostate cancer in men of less than 50 years of age.[8] New genomic regions of interest for prostate cancer risk are continuing to be identified and reported. Some of these regions are on chromosomes 3, 6, 7, 10, 11, 19 and X.[17] One polymorphism (rs266849) on chromosome 19 was found to be associated with a higher risk of prostate cancer in men less than 60 years of age.[17] Another study examining genetic variants at 10q11 and Xp11 found that one polymorphism (rs10993994) had a twofold increased risk of prostate cancer in men less than or equal to 65 years of age.[18]

A subset of men in families with potential hereditary prostate cancer may be at an increased risk of developing early-onset disease. Hereditary prostate cancer studies have begun to report the rates of transmission of genetic polymorphisms that may increase the risk of early-onset prostate cancer. One study found that a common variant in BRCA1 (rs1799950) was overtransmitted in younger men (aged < 50 years) affected with prostate cancer from hereditary and early-onset prostate cancer families.[19] Another report found that the minor allele of a polymorphism in CYP19 (rs11636639) was overtransmitted in men less than 50 years of age from hereditary and early-onset prostate cancer families.[20]

Other polymorphisms that reside in known genes are being characterized for an association with early-onset prostate cancer. As mentioned above, polymorphisms in CYP19 (involved in testosterone conversion to estradiol) and BRCA1(involved in the DNA repair process) have been studied for information regarding early-onset prostate cancer.[19,20] A study from 2003 found that 2% of men less than or equal to 55 years of age diagnosed with prostate cancer harbor mutations in BRCA2(also involved in the DNA repair process).[21] Another study found a polymorphism (rs2171492) in carboxypeptidase 4 (which may affect the growth and differentiation of prostate epithelial cells) to be associated with increased risk of aggressive prostate cancer in men less than 66 years of age.[9] Other genes studied for polymorphisms associated with early-onset prostate cancer include the vitamin D receptor gene and the androgen receptor gene, although findings have been inconclusive.

A key issue to consider is how to incorporate genetic polymorphisms associated with early-onset disease into clinical practice for personalized prostate cancer screening. While polymorphisms may be associated with early-onset prostate cancer from controlled studies, real-life application involves issues such as how to appropriately risk-counsel men regarding their individual risk of developing early-onset disease, deciding whether the polymorphisms are useful in conjunction with known prostate cancer screening tests (such as the PSA) to more accurately recommend diagnostic testing, and whether the polymorphisms add any additional value to known risk factors for prostate cancer such as family history, race and elevated age-adjusted PSA. Some approaches to studying the clinical application of early-onset polymorphisms include:

  • The incorporation of variants into existing prostate cancer risk calculators to assess for an improvement in the predictive ability of prostate cancer;

  • Study of combinations of polymorphisms for clinical utility in prostate cancer screening;

  • Characterizing the risk-stratifying ability of polymorphisms in men enrolled in screening studies.

One study from a screening population found that four genetic polymorphisms added predictive value to an existing risk prediction nomogram that included PSA, family history of prostate cancer, ethnicity, urinary symptoms and digital rectal examination findings.[22] However, a population-based study found that five specific polymorphisms found to be associated with prostate cancer[23] did not improve upon the predictive ability for prostate cancer over age, PSA and family history.[24] Therefore, clinical studies of genetic polymorphisms need validation.

In summary, genetic polymorphisms provide significant promise for personalizing prostate cancer risk assessment, particularly for men at risk of early-onset disease. These men stand to gain great benefits from these efforts as younger men at increased genetic risk for prostate cancer may be recommended for prostate cancer screening after appropriate risk counseling, while other men who are found not to carry risk polymorphisms can be spared unnecessary physical and psychological morbidity. The main caution is to not prematurely promote the clinical use of genetic polymorphisms prior to appropriate further study regarding their true prostate cancer predictive value and how these markers may be informative for personalized screening strategies. Finally, further study is needed into the way in which genetic polymorphisms inform about prostate cancer risk in younger men of various racial and ethnic backgrounds.

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