Epigenetics and genetics: The future of cost-effective care?


The purpose of this article is to provide a clear understanding of the basis for the genetic and epigenetic tools that are increasingly used in medicine, highlight some of these tools currently used in urology, and explain the clinical and medicolegal ramifications of direct-to-consumer tests.


Genetics and epigenetics will likely become a valuable asset in urologic care. The central dogma of biology is that DNA can lead to RNA production, which can make proteins, alterations of which can cause disease states. This paradigm has been further revealed by improved understanding of dynamic epigenetic pathways wherein changes and exposures over the course of an individual’s lifetime can cause noncoding changes that alter gene expression and protein production.

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Epigenetic marks may be driven by DNA sequence, alterations in various enzymes, or environmental exposures, such as diet, exercise, and other medical conditions that fluctuate over the course of a lifetime change in the gene expression. Perhaps even more intriguing is that these acquired changes can be passed on to future generations through a man’s sperm (Nature Neuroscience 2014; 17:89–96)(figure 1). The impact of lifestyle and exposure to a man’s spermatogonial stem cells and propagation of these changes to offspring through methylation has now been proven in many studies.

The purpose of this article is to provide a clear understanding of the basis for the genetic and epigenetic tools that are increasingly used in medicine, highlight some of these tools currently used in urology, and explain the clinical and medicolegal ramifications of direct-to-consumer tests.

Next - The genetic revolution: Urologic applications


The genetic revolution: Urologic applications

While the genome-wide association studies (GWAS) have yet to live up to their full potential, whole genome sequencing costs have fallen from about $2.7 billion for the human genome project to $3,000 to $5,000. This has stimulated the growth and development of the Precision Medicine Initiative, whereby genetic data can not only aid in diagnosis, but also improve therapy through a better understanding of the utility of therapeutic options based on genotype.

Currently, many GWAS studies are limited to oncology. While these have led to the development of clinically relevant prognostic tests such as GenomeDx, 4K score, Prolaris, Oncotype DX (Genomic Prostate Score), and ConfirmMDx, they are only the tip of the iceberg. All of these tests rely on genetic, RNA, or epigenetic data to help stratify and prognosticate prostate cancer risk.

Next: How genetic studies are performed


In order to fully understand these tests, one must first examine how genetic studies are performed. Typically, blood, saliva, or tissue undergoes either whole genome or targeted genetic sequencing to identify single nucleotide polymorphisms (SNPs), which are variations in a cytosine, guanine, adenine, or thymine at one specific location in the genome.

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If we think of the genome as a library of books, these are changes of letters on individual pages of a book. To extend the analogy further, we would say that we have two copies of the same book and on page 52, line 8, word 6, one book has “THE” (patient 2), another has “TEH,” and another (patient 3) has “HET.” Each book can be thought of as an individual. When we compare tens of thousands of individual people, these changes can be associated with a phenotype of interest, such as male infertility (figure 2). What makes these studies difficult is that thousands of genes may contribute to a phenotype such as prostate cancer, and the disease state may be the result of one gene or SNP of high penetrance or the combination of multiple SNPs.

Although most of this work has been done in urologic oncology, in large part through access to large registries such as Surveillance, Epidemiology, and End Results (SEER), other investigators are now working on developing applications to benign urologic diseases. Work by the DCCT/EDIC group (funded by the National Institute of Diabetes and Digestive and Kidney Diseases) has identified genetic factors that increase the risk of men with type 1 diabetes developing erectile dysfunction (J Urol 2012; 188:514-20).

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Our hypothesis has been that genetic changes that predispose a man to ED, once identified, will be able to prognosticate treatment response for ED, thus saving millions in wasted clinic visits and phosphodiesterase type-5 inhibitor trials. Work such as this will help to further solidify the role of genetic screening and testing in urologic disease. Ultimately, urologists may be able to rely on the validated results of a genetic test to guide targeted interventions.

Next - Epigenetics: Case study in the sperm methylome


Epigenetics: Case study in the sperm methylome

While genetic analysis evaluates changes to the coding of DNA, epigenetics involves noncoding, heritable changes that affect gene expression. Epigenetic factors include methylation changes to cytosine bases of DNA, chemical modifications to histones that bind DNA in nucleosomes and microRNAs. DNA methylation and certain histone modifications cause structural changes that impede access to transcription factors of a gene, thus inhibiting transcription and protein synthesis, while other histone modifications facilitate access of transcription factors to genes in that region of the genome. Epigenetic regulation can be very specific in “turning on” or “turning off” gene expression and can be inherited through the germline (figure 3).

To understand the role of epigenetics, we will use male infertility as an example to highlight the potential of using epigenetic information in clinical practice. Currently available tests for male reproduction have poor prognostic ability in defining fertility (N Engl J Med 2001; 345:1388-93). Semen analyses have up to 400% inter-test variability, and the only finding that absolutely precludes natural pregnancy is azoospermia.

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Recent work has demonstrated that multiple semen analyses from the same individual do not improve upon the predictive ability of a single semen analysis(Hum Reprod 2014; 29:1360-7). However, recent studies have demonstrated that sperm DNA methylation at specific genes may provide better prognostic value in not only predicting fecundity, but also predicting the probability of normal embryogenesis in couples undergoing in vitro fertilization. A panel of methylation marks was able to classify male fertility status with 82% sensitivity and a positive predictive value of 94% (Fertil Steril 2015; 104:1388-97). Tests such as this will likely make their way into the diagnostic armamentarium of andrology, as well as other areas of urologic care.

Next: "As the costs of these tests continue to decrease, it is very likely that they will become a routine part of clinical care."


Epigenetic marks, unlike an individual’s DNA sequence, are not immutable and change over the course of the lifespan in response to environmental or biological cues. Therefore, they allow a dynamic insight into the response of an intervention, such as starting a medication, as well as the effects of lifestyle factors. For example, it has recently been shown that aging alters the epigenetic marks in sperm at some genes associated with neuropsychiatric disorders, which are well known to increase in offspring of men with advanced paternal age. As the costs of these tests continue to decrease, it is very likely that they will become a routine part of clinical care.

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One scenario where they will likely be used, besides some commercially available prostate cancer tests, is in assessing the risk and speed of disease progression. For example, if a woman with overactive bladder was being seen for an initial clinical workup, she could undergo a methylation-based screening test from a urine sample. This would be able to prognosticate which treatment she would respond to, how her disease would progress, and whether a surgical intervention should be deployed as first-line therapy. Currently, AUA guidelines depict a logical stepwise approach of interventions from least to most invasive. Genetics ad methylation could potentially help inform this progression.

Currently available genetics tests

The Human Genome Project has enabled many companies to perform direct-to-consumer genetic testing. Notable examples are Counsyl, Natera, 23andMe, and Ancestry.com. Counsyl and Natera perform prenatal testing and require a physician’s order to perform. Counsyl screens for a panel of 100 autosomal recessive diseases such as cystic fibrosis in order to determine a couple’s chances of having an affected child. Natera offers cancer screening as well as preimplantation genetic testing: screening of cryopreserved embryos to ensure that they do not carry a genetic disease present in one or both parents with the objective being to transfer only unaffected embryos.

23andMe and Ancestry.com offer direct-to-consumer genetic testing that has no FDA approval for clinical diagnosis beyond determining the carrier status for traits such as cystic fibrosis (23andMe). Ancestry.com uses DNA to determine ethnicity. It is crucial for clinicians to understand the limitations of these tests. Specifically, although Ancestry.com and 23andMe can provide some genetic information, any of their markers must be verified by a clinical diagnostic genetic test.

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Thus, no clinical diagnostic or therapeutic interventions should be undertaken solely on the results of these tests. All of these patients should see a genetic counselor and undergo appropriate genetic testing from a certified laboratory.

Next: The future


The future

Recent studies have clearly shown that single gene and microarray methods of genetic analysis have limited utility in diagnosing the causes of many diseases due to the rarity of many disease-causing SNPs and due to the increased understanding that many SNPs of importance may reside outside of the coding region (exons) of a gene. Concurrently, whole genome analysis has become a realistic option, both in price and the feasibility of analytical and database tools needed for whole genome sequencing and interpretation of the data. The potential of real utility in the clinical decision making suggests that the era of precision medicine has begun and will continue to become more routine and powerful in the next 10 years (Cell Tissue Res 2016; 363:295-312). It is likely that cost-effective medicine will necessitate whole genome sequencing as a routine part of medical care that will facilitate a better understanding of optimal pharmacotherapy and other treatments.

The use of epigenetic analysis in clinical medicine is also advancing and holds great promise in both diagnostics and in monitoring aging, lifestyle, and other risks. It is possible that sperm epigenetic analysis may provide prospective parents with valuable information about the risk of advanced age, prior chemotherapeutic history, lifestyle choices, and other factors on the health of a future child. Such information may also aid in facilitating changes in an individual’s lifestyle.

Recent advances in gene editing using novel methodologies, especially the CRISPR/Cas system, have finally moved forward the realistic possibility of gene therapy to cure certain genetic anomalies. Clinical trials in some limited areas are beginning, and it is likely that this area will rapidly evolve in the near future. While current methodologies are most advanced for genetic therapy, it is likely that epigenetic editing methodologies will evolve in the near future.

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