Genetics Cafe2008-08-28T09:39:23ZRonald C. McGlennen, M.D.info@geneticscafe.comCopyright 2008, Ronald C. McGlennen, M.D.SPHPBLOGOncogenic HPV Types: Controversial Characters First, there was the uncovering of the many different HPV types, found with the aid of molecular tools now out of date and by comparison to today techniques, relatively insensitive. Second was the endeavor to understand the social, geographic and coincidental factors that tighten the link between HPV and the “risk” of cellular transformation and cancer. What was then the challenge of research labs worldwide to isolate sequence and catalog the more than 80 HPV types found in the genital tract, soon became the routine mission of the clinical lab who, in turn, would test the validity of the claim that HPV is a cause of cancer.
A recent article revisits one particular controversy concerning HPV type 53, and whether infection by that is high risk for cervical dysplasia or cancer. HPV 53 is curiously uncommon outside of the United States as reported by several studies, but common across North America. The observed difference in prevalence may be accurate and due to geographic isolation of certain peoples, but is equally likely to be explained by differences in testing modalities. Most published studies used probe capture testing methods, which are known to variably detect HPV 53, but are not part of the design of these assays (1).
A recent review of the experience of six independent laboratories using PCR to detect and genotype HPV demonstrates HPV 53 to be the second most frequently detected viral type at 8.64%, behind HPV 16 at 16.07%. The figure below show the distribution of various HPV types detected by this method, and the corresponding variance of that distribution across the six labs using PCR.
The controversy on whether HPV 53 is a low or high-risk viral type does in part involve the discussion as to whether a testing method looks for and reliably detect that genotype, and hence those data will contribute to the debate of the need to test for this virus in routine screening of Pap smears.
From the scientific literature, HPV 53 has been shown to be oncogenic, i.e., a high risk virus, based on in vitro evidence that its DNA sequences can cause cells in culture to become immortalized and in some cases, transform to cells that are tumorigenic in animals. In clinical practice, HPV 53 is presently assigned as high risk lending from the finding of that virus in human cancers (2). This position has been called into question by findings of Brestovac et al., in the article “Human Papillomavirus Genotypes and Their Association With Cervical Neoplasia in a Cohort of Western Australian Women”, Journal of Medical Virology 76:106-110 (2005) (3). This study finds HPV 53 to be among the more commonly detected HPV types, but was not associated with any cases of cervical dysplasia or cancer.
The experience of the same series of six labs using PCR-based methods supports the assignment of HPV 53 as a high-risk vial type. From a database of more than 7131 HPV positive cases, a series of 661 HPV 53 positive Pap samples were diagnosed, and of those, 104 cases were studied in follow-up over 18 months. From that series, six cases demonstrate histological grade CIN III and one case of carcinoma was documented. The primary samples, each tested due to the morphology showing ASCUS were positive for this viral type from the Pap sample as well as in the terminal sample, thereby demonstrating the persistence of this viral infection and role in the development of the disease. Review of the remaining 557 cases from the cumulative database reveals another five cases of HPV 53 associated carcinoma.
This is the largest series of HPV 53 associated cases of cervical carcinoma we are aware of, and, as such, is an illustration of the power of genotypic data for HPV testing in the analysis of this and potential other controversial HPV characters.
What happened in a year’s time that would cause The Dark Report to endorse a “go ahead plan” for molecular diagnostics?
One reason for the change in attitude is that the clinical need for molecular tests is now, more than ever, better defined. Good laboratory practice needs to consider the analytic and clinical validity of tests offered for patient care. Genetic testing provides unparalleled sensitivity and specificity, and therefore serves the question of analytic validity. The clinical validity of a test is the measure of its diagnostic precision and accuracy, i.e., does the test find the disease it is designed to find. Here too, molecular genetic tests have the advantage over other approaches, including biochemical or functional lab assays.
One example is for the laboratory workup of thrombophilia, the set of disorders that result in the increased risk of blood clots. Conventional laboratory tests look at the endpoints of clot production or dissolution. Conventional coagulation assays may isolate a section of the very complex biochemical cascade that leads to clot formation or clearing, but specific causes are often not identified. By contrast, tests such as those for the Factor V Leiden or Prothrombin mutations focus on the changes in genes that make the associated plasma proteins abnormal. The clinical validity of finding these mutations in samples from patients is great because it clearly identifies people who are now, or at sometime in the future, at risk of serious complications do to blood clots and emboli. With the advent of new and safer drugs for anticoagulation, the importance of finding people with the inherited causes of thrombophilia, versus those with an acquired or temporary risk of clotting, is evident.
These facts raise the issue of clinical utility, another advantage of genetic testing for routine patient care. Clinical utility is the measure of a test to be used in various clinical settings. The example of thrombophilia again serves to illustrate that testing for the genetic causes of abnormal blood clot formation may apply to a wide variety of patient care settings, including those who are at increased risk of blood clots independent of their potential genetic risk. These situations include people undergoing surgery, those taking hormones or contraceptives, women with a history of spontaneous abortions, as well as a host of lifestyle risk factors. Clearly, the risk of thrombophilia impacts on a large percentage of patients. Offering tests for the Factor V Leiden or Prothrombin mutations are key to the assessment of patients with these non-genetic risk factors and may, indeed, be the basis of how physicians will choose to treat with anticoagulation.
The clinical utility of these genetic tests has greatly increased the number of potential samples for testing, which is a principal reason for considering bringing molecular diagnostics to your lab.]]>http://www.geneticscafe.com/weblog/index.php?entry=entry050531-1908172005-06-01T00:00:00Z2005-06-01T00:00:00ZWelcome to Genetics CaféGenetics Café has been developed to expand the types of support offered by Access Genetics to its partner labs. Our mission is to increase the awareness and utilization of molecular genetics in the practice of laboratory medicine. We have created Genetics Café as a resource for patients, clinicians and laboratorians, and aspire to expand this site’s content in dimensions as broad and exciting as the field of genetics itself.
Genetics Café has been designed to create a new venue to tell the story of molecular genetics in the practice of medicine. Most importantly, we hope to help demonstrate that genetic testing has a practical place in the care of patients with infections, cancers and inherited genetic disease. We will be posting a variety of content on this site that will be useful to our partner labs as they share the message about genetic testing.
In the next few weeks, we will be posting presentations on the topics such as HPV & Infectious Disease of the Genital Tract, Maternal Screening for Cystic Fibrosis, and The Role of Thrombophilia Testing in Women’s Health. These are exciting, relevant and useful topics to help your clinical colleagues better manage patient care.
We also intend this Weblog as a resource for discussing important and timely topics important to labs offering genetic testing. No topic is irrelevant, but rather, we should be free to discuss technical concerns, selected case reports and observed trends in the activities of your lab. Our Weblog is most successful when you participate, so we encourage you to use the Contact link to send your comments and questions. We are committed to responding to your questions within a week of the posting. To that end, we will provide or find the expertise to help us all to learn.
Again, thank you for visiting Genetics Café. We hope you enjoy the content of the site and return frequently to this blog!]]>http://www.geneticscafe.com/weblog/index.php?entry=entry050502-1729302005-05-02T00:00:00Z2005-05-02T00:00:00Z
