Concise Handbook of Familial Cancer Susceptibility Syndromes - Second Edition

Abstract

More than 10 years have passed since we first attempted to develop a clinically accessible catalog of recognizable family cancer syndromes (1). Our sense at that time was that we were on the brink of an avalanche of information regarding the inherited basis of human neoplasia and that the clinical consequences of these novel molecular insights threatened to overwhelm both health-care providers and their patients. We attempted to distill currently available data related to the most common genetically determined cancer susceptibility syndromes into a format that would make this arcane knowledge more readily accessible to busy clinicians who only occasionally needed this information. It seemed inevitable that, as the number of disorders for which germline mutation testing for cancer susceptibility increased, the need for a better understanding of how to approach these challenging clinical problems would follow. And so it has. It is now increasingly routine to undertake a cancer genetics risk assessment, which includes the option of germline mutation testing for one or more relevant genes, for an astonishing array of disorders. Experience over the past several decades has demonstrated, unequivocally, that the study of rare familial clusters is a remarkably productive scientific and clinical enterprise. These data have identified multiple new susceptibility genes, defined the clinical phenotype of specific disorders more precisely, and have informed our understanding of the pathogenesis of hereditary and nonhereditary cancers at the individual, population, and laboratory levels. For example, recognition of the Li–Fraumeni syndrome provides a vivid illustration of how the identification of familial clusters of childhood sarcomas and breast cancer ultimately led to the identification of germline mutations in the p53 tumor suppressor gene as the genetic basis for this disorder, thereby providing seminal insights from clinical cancer genetics to the molecular biology of both inherited and sporadic cancers (2–6). Progress begets new challenges. Previously unfamiliar concepts related to clinical genetics are now being integrated into the information base used by diverse health-care providers, most of whom have no formal training in genetics. The need has never been greater for clinicians to be well grounded in the biological and molecular bases of the diseases which they encounter and to become familiar with related new clinical issues, including predictive risk assessment, genetic counseling, germline mutation testing for clinical decision making, the duty to warn at-risk relatives vs their high-risk patients’ right to privacy and confidentiality and, most importantly, the need for evidence-based, safe, and effective management recommendations for high-risk individuals. Proposed elements of informed consent related to testing for inherited cancer susceptibility are set forth in Table 1. Basic elements of informed consent for cancer susceptibility testing (7) Basic elements of informed consent for cancer susceptibility testing (7) The advent of syndrome-specific germline mutation testing represents a major advance in the care of cancer-prone individuals. But, in the process of focusing on the molecular biology of human cancer susceptibility, the importance of taking a thoughtful family history cannot be emphasized sufficiently. Because the pace, complexity, and sophistication of medical practice have accelerated, the decidedly low-tech but nonetheless invaluable family history often receives short shrift, depriving both the patient and the health-care provider of information that might have a substantial impact on clinical decisions and patient outcome. In one survey of 100 unselected colorectal cancer patients, the medical record contained a family history in only 46% of subjects and, of those, only 80% were accurate (8). Taking an appropriately focused family history must receive increased emphasis in the course of daily practice. The Family History Public Health Initiative of the US Center for Disease Control and Prevention (http://www.cdc.gov/genomics/activities/famhx.htm) recognizes and promotes this need (9). Learning the clinical features that suggest the possibility of an underlying genetic predisposition to cancer is another, easily mastered diagnostic tool (Table 2). These guidelines are not infallible but, when used to guide the collection of family history data, they have been proven to be clinically useful. Features that suggest the presence of a hereditary cancer predisposition [modified from Weber et al. (10)] Features that suggest the presence of a hereditary cancer predisposition [modified from Weber et al. (10)] Because much of our risk assessment and clinical decision making rests on empirical studies of self-reported, unverified family history, a brief comment regarding these data is warranted. Diagnosis accuracy varies considerably, depending on the age, gender, and cancer status of the respondent