Abstract
In the past two decades the human genome has been sequenced, enabling the identification of the genetic variants predisposing to most complex diseases. Moreover, in the not-so-distant future we will be able to sequence the entire genome of any individual at a minimal cost. This new knowledge and powerful genetic tools are now coming to fruition and will be harnessed to enable us to predict disease susceptibility, prognosis, and response to therapy much more accurately. Indeed, for some cancers it is now possible to predict with increased certainty which patients will have the more aggressive variants of their cancer and thereby will be likely to require more complex and sophisticated treatment. An example is the treatment of breast cancer for which it has been known for some time that the response to chemotherapy is influenced by certain genes expressed by the tumor (e.g., estrogen receptor, HER2). In a related area we are starting to be able to predict which patients are likely to experience an adverse reaction to a drug that would otherwise be well tolerated by most of the population. Also important is the information that is developing on the relationship between gene variants and toxic reactions. Thus it is known that variants in the TPMT gene predict bone marrow aplasia in patients receiving azathioprine and 6-mercaptopurine, while variants in the VKORC1 and CYP2C9 genes can predict the response to warfarin.
We are also learning that genetic susceptibility alone cannot explain disease susceptibility, prognosis, response to therapy, or even phenotype. Environmental and epigenetic factors play a major role. These too, are now being unraveled. Undoubtedly environment and genotype are each important not only in their own right, but in how they interact. Genotype is likely important for diseases that develop after exposure to an environmental trigger. It is therefore obvious that personalized medicine offers promise not only for therapy of established disorders but for prevention of disease occurrence.
These rapid developments, which will revolutionize medicine and have a tremendous impact on the way we care for patients, led us to choose Personalized Medicine as the theme for the American Thyroid Association's (ATA) recent spring symposium “Thyroid Disorders in the Era of Personalized Medicine” (1). Personalized medicine (1) is something that practicing physicians will need to implement more and more in their practice. We believe it is imperative that they be updated about its current strengths and pitfalls and continue to learn as new discoveries are being made.
For this issue of Thyroid, a choice was made to publish a special series of articles based on the themes explored at the ATA symposium. Here the reader will find 13 articles, most written by experts who participated in the symposium, that review our current knowledge of the genetic and nongenetic factors contributing to the etiology of thyroid disease, its expression, and the responses to therapy.
The series opens with a comprehensive review of a new field in pharmacology called pharmacogenomics by first author Colin J.D. Ross and senior author Michael R. Hayden, two pioneers in this field, who are joined by distinguished colleagues involved in the Canadian Pharmacogenomics Network for Drug Safety (CPNDS) consortium (2). They review the implementation of the new genomics and genetic tools for developing tests to predict responses to medications, perhaps ultimately those that are beneficial as well as adverse. As beautifully summarized in their article, there are already a handful of pharmacogenomic tests that are approved by the United States Food and Drug Administration or that are in the pipeline.
The next series of articles deal with thyroid cancer. The first, authored by Drs. Tirthia Das and Ross Cagan (3), starts the series with an exceptional review on the use of Drosophila models to design novel therapies for thyroid cancer. Dr. Cagan's group is comprised of world leaders in this exciting new technology, and they have already identified a novel therapeutic compound (ZD6474, Vandetanib) for medullary thyroid cancer, now in phase III clinical trials. This article is followed by two comprehensive reviews on the genetics of familial and nonfamilial thyroid cancer. Dr. Mingzhao Xing (4) reviews the major alterations in the phosphatidylinositol-3 kinase/serine-threonine kinase (PI3K/Akt) pathway and their impact on the diagnosis and treatment of thyroid cancer, while Dr. Melanie L. Richards (5) summarizes the current knowledge of familial syndromes associated with thyroid cancer. Knowledge of these two fast growing fields is essential because genetic testing both of tumor tissue (for somatic mutations) and the patients and their families (for germline mutations), is gradually being integrated into daily practice.
The four articles that follow deal with the current knowledge on the genetics of autoimmune thyroid diseases (AITD). Dr. Yaron Tomer (6) summarizes the familial nature of AITD and the significant progress made in recent years towards understanding the genetic mechanisms for predisposition to AITD. Drs. Terry Davies, Xiaoming Yin, and Rauf Latif (7) give a comprehensive review of the role of the gene for the TSH receptor (TSHR) in the genetic susceptibility to Graves' disease. TSHR is one of the most important genes predisposing to Graves' disease, and significant progress has been made in dissecting the role of its intron 1 variants in the pathogenesis of this disorder. Two reviews discuss the association between thyroid autoimmunity and other autoimmune disorders. Drs. Manuela Dittmar and George Kahaly (8) provide an in-depth discussion of the association between type 1 diabetes mellitus and AITD. This well-recognized association has important clinical and etiological implications because close to 30% of type 1 diabetics develop thyroid autoimmunity. This association is considered a variant of the autoimmune polyglandular syndrome type 3 (APS3 variant or APS3v). Finally, Dr. Richard A. Spritz (9), a pioneer in the study of the genetics of vitiligo, provides a very comprehensive review of the state of the art regarding the genetics of vitiligo and its association with AITD.
The next two reviews deal with environmental effects in precipitating and aggravating thyroid disorders. It is increasingly recognized that, while genetic susceptibility is extremely important to the etiology of complex disorders, environmental effects are also critical because their interaction with susceptibility genes often trigger disease. Dr. Gregory Brent (10) has written a very comprehensive and thought-provoking review on the major environmental factors that cause thyroid disease, including radiation, iodine, and environmental toxins. His review provides a balanced perspective on the contribution of nature vs. nurture in the pathogenesis of thyroid diseases. Next, Dr. Giuseppe Barbesino (11) summarizes the major associations between medications and thyroid dysfunction. Some medications, such as amiodarone and lithium, have long been noted to affect thyroid function. Recently, a new generation of medications, such as the tyrosine kinase inhibitors and immunomodulators frequently used in cancer therapy, have been noted to be associated with thyroid abnormalities. Dr. Barbesino's comprehensive review discusses both the classically recognized medications and this next generation of novel therapies.
The next article discusses individualizing therapy for thyroid cancer. Drs. Ralph Tufano and Emad Kandil (12) provide an extremely important perspective on the surgical care of thyroid cancer patients. The treatment of thyroid cancer requires a multidisciplinary approach involving endocrinologists, thyroid surgeons, nuclear medicine specialists, and oncologists. Their article presents in-depth discussions on the state of the art of individualized surgical management for papillary thyroid carcinoma (PTC), including the unresolved and controversial issues centering around the ideal initial surgery for these tumors. As they note, “The preceding controversies (i.e., those that are the focus of guidelines groups) could all be rendered moot if we had a way to reliably predict the biological behavior of PTC.” This is the promise of personalized medicine.
The final two articles of the Personalized Medicine issue deal with Graves' ophthalmopathy (GO). Drs. Marius Stan and Rebecca Bahn (13) provide a comprehensive and critical review of the risk factors for GO, both those that have been confirmed and those that remain under active investigation. Identifying risk factors for GO is essential for individualizing therapy of the established disease and for predicting which patients with Graves' disease are most at risk for GO. The treatment used for Graves' disease itself may alter the risk for GO. Therefore identifying the environmental and genotypic features that enhance or protect will be critical for designing individualized treatment algorithms for Graves' disease. Drs. Katharina Ponto, Stephanie Zang, and George Kahaly (14) present a detailed discussion on the association between radioactive iodine therapy and GO. While there is little doubt concerning this association, the best approach to preventing GO in patients receiving radioiodine therapy is still controversial. Dr. Kahaly and colleagues provide a solid framework for choosing the best therapeutic options for patients receiving radioiodine therapy for Graves' disease.
It is not too farfetched to imagine that one day, perhaps not many years away, genetic and epigenetic testing will be widely available and relatively inexpensive; at that point medicine will have had to shift to the full-time practice of personalized preventive medicine. As scientists continue to acquire an extensive knowledge of genetic, epigenetic, and molecular biomarkers of common diseases, societies such as the ATA will need to revise their guidelines to incorporate a personalized approach to the care of diseases such as thyroid cancer and AITD. In this process, practicing endocrinologists, including those with a bent towards thyroidology, will need to be informed on how to utilize this new information in the care of their patients.
Footnotes
Acknowledgments
We would like to thank Dr. Charles Emerson for sharing our enthusiasm for this emerging topic, for supporting a special series of articles in Thyroid, and for engaging in helpful discussions. We also would like to thank Ms. Symone Rivera, our administrative assistant, for her assistance in developing this series of articles on personalized medicine.