Prenatal Diagnosis, Preimplantation Genetic Diagnosis, and Cancer: Was Hamlet Wrong?
Authors: David Malkin
Journal: Journal of Clinical Oncology (2009)

Shakespeare’s Hamlet proclaimed to his friend Horatio that “nature cannot choose his origin....” Who we are is predetermined and beyond our control. It has frequently been said that one cannot choose one’s parents, yet with advances in genetic diagnostic technologies, through prenatal diagnosis (PND) and preimplantation genetic testing (PGD), it is possible to select one’s children. Prenatal diagnosis and preimplantation genetic testing have been established for a wide spectrum of single-gene conditions including congenital disorders, inborn errors of metabolism, and chronic neurodegenerative diseases of childhood, such as Duchenne muscular dystrophy, or progressive conditions such as cystic fibrosis, or aneusomy syndromes such as Down’s syndrome. New tests for single-gene disorders continue to be added to the armamentarium of the prenatal diagnostician, regardless of the choices offered by prospective parents’ physicians. Whether to terminate a pregnancy or carry it to term, the fact remains that this ever-increasing array of tests challenges our medical and moral values. There are now almost 1,500 gene tests available in Clinical Laboratory Improvement Amendments (CLIA)–certified laboratories worldwide. Both PND and PGD offer prospective parents opportunities to select out embryos that would inevitably carry a universally lethal or medically devastating gene. For those families whose pedigrees have been riddled with cancer, these therapeutic options might be seen as a possibility to provide a prospect for a better future for their children. With these opportunities come great challenges. For which conditions should prenatal testing be offered? Should conditions of later age of onset be included? And what is considered later age of onset? Should testing only be available for genetic diseases with 100% penetrance, and when a lethal outcome is inevitable? These questions and many more have been raised in the context of adult-onset cancers including BRCA1/2 testing, where it remains generally accepted that, in light of the exclusively adult-onset nature of the disease, PND is not recommended. However, the work outlined in the study of Julian-Reynier in this issue of Journal of Clinical Oncology brings such recommendations into debate. Genetic testing for cancer susceptibility risk has until recently been primarily undertaken in the purview of geneticists with an interest in oncology, or in familial cancer genetics programs. Much of the activity in this field has been focused on hereditary breast and ovarian cancer and hereditary nonpolyposis colon cancer syndromes, both of which are almost exclusively diseases of adult onset. However, genetic testing for a wide spectrum of cancer predisposition disorders with a high frequency of high-penetrant childhood onset malignancies is attracting more attention from the genetics, pediatric oncology, and bioethics communities. With the advent of high-throughput rapid whole gene (and whole genome) sequencing, clinical molecular diagnostic laboratories will rapidly expand their ability to offer testing of virtually any disease susceptibility gene. With the potential to implement various clinical surveillance strategies for early detection of pediatric and adult cancers, the role for presymptomatic genetic testing becomes a topic that requires thorough evaluation. While presymptomatic testing and accompanying measures of clinical surveillance will not generally prevent cancers from developing outright, at least in the case of multiple endocrine neoplasia type 2A, prophylactic thyroidectomy at an early age ( 6 years) has been demonstrated to eliminate medullary thyroid carcinoma risk. Even in this circumstance, C-cell hyperplasia has been reported. Carrier testing for retinoblastoma susceptibility has led to early postnatal detection and even early delivery to minimize the devastating clinical effect of aggressive tumor formation. The Julian-Reynier study sheds new light on the complex algorithm that is required to effectively clarify the decision-making process for parents at extraordinarily high risk of transmitting a cancercausing gene to their offspring. It is undoubtedly appropriate that this work be published in the mainstream oncology literature, for treatment of individuals/patients at risk of cancer should very much be the concern of both the community and the academic oncologist. Beyond the diagnosis, treatment, and follow-up of patients with cancer, the oncologist and patient develop a unique bond. Based on a strong family history or the documentation of a mutation in a cancer predisposition gene in a practitioner’s patient with cancer, it is most likely that the patient’s oncologist will be the first to be asked about risks to offspring, and what options may be available to minimize or eliminate these risks. While it may be the case that the oncologist is not expert in providing such genetic counseling, it is incumbent on them to appropriately guide the patient to the best resource to address these concerns. Ideally, such discussions should incorporate expertise of comprehensive multidisciplinary teams of oncologists, pediatric or medical geneticists, psychologists, genetic counselors, and bioethicists. In particular, while genetic testing and counseling remain in the framework of the genetics community, oncologists must share the burden of management decisions. In fact, the scenario for genetic testing (preor postnatally) of offspring, or potential offspring, of adult patients with cancer present a somewhat unique dilemma to the practitioner. Generally, adult JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 27 SEPTEMBER 2