Concise Handbook of Familial Cancer Susceptibility Syndromes - Second Edition

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, the primary site of cancer origin, the degree of relatedness between the respondent and the relative of interest, the vital status of the affected relative, and the recentness of the reported cancer diagnosis (11,12). In general, reported breast and colorectal cancer diagnoses are quite accurate, whereas cancer “sites” that are vaguely defined (eg, organs in the female pelvis) or which represent tissues commonly involved with metastatic disease (eg, brain, liver, bone, and lung) are often incorrect (13). The predictive value of a negative cancer report (eg, “my mother did NOT have cancer”) is very high. The accuracy of reports from first-degree relatives is substantially better than for second-degree relatives; information from more distant relatives is of such poor quality that it is of questionable value in routine practice. Genetic risk assessment in the context of childhood cancer represents another specific setting in which a meticulous clinical evaluation often provides essential information upon which to base a syndromic diagnosis. An elegant and detailed evaluation of the prevalence and patterns of morphological abnormalities in nearly 1100 consecutive pediatric cancer patients resulted in the identification of confirmed cancer susceptibility syndromes in 42 (3.9%) patients and suspected syndromes in an additional 35 (3.3%). Half of the proven disorders had been missed before the study-related physical examination, leading the authors to recommend that with cancer be by a clinical or a in the clinical in this the need for from a essential to the cancer risk assessment enterprise. of the data that the basis of our understanding of hereditary cancer syndromes are from evaluation of The to the from which such are major on to these in cancer that are to the that was as well as being to risk for rare are in of familial as to with specific hereditary cancer and for most patients with a history of these are most relevant in clinical decision hereditary syndromes for only a of familial on a The and the have been in an to the of related to the of familial cancer of the data available from these is in Table which the familial relative risk of cancers first-degree relatives of with a The of by site is between the and the data, with in the of relative and of the cancer first-degree relatives of cancer by primary cancer site [modified from familial relative in of prevalence in for and for relative and of the cancer first-degree relatives of cancer by primary cancer site [modified from familial relative in of prevalence in for and for The data were by at cancer diagnosis in the and they substantially increased relatives of with with the clinical to an inherited cancer susceptibility For example, the for breast cancer is but the relatives of breast cancer was at than (Table The has data regarding the related to familial cancer susceptibility in the in Table The is the of that is to the risk of family history of a and it represents that of that be the risk were These data substantial for the that familial and inherited for a of specific For most the is between and and colorectal cancer have substantially and comment before on to of the specific cancer susceptibility and that is for germline mutations in cancer susceptibility It is commonly that the of clinical testing for mutations in such as and that such testing and be to who has a their familial cancer the of these mutations in the in predictive that are Genetic testing to be most when on an with a of the for which the testing is a report has the when family is The clinical and molecular of the past by the with which our was and have led to this of the of Family The 35 the has been to and the familial and disorders are now The syndromes are in and for a is the number and Diagnosis features risk management We have attempted to the major of the hereditary cancer syndromes in Table to of a diagnosis upon the cancers that are in a For example, a family history of breast cancer be a of several hereditary cancer but the of in the family would guide risk assessment In we have now the (Table and additional clinical (Table that to a familial cancer syndrome diagnosis. with specific familial cancer with specific familial cancer with specific familial cancer with specific familial cancer with specific familial cancer with specific familial cancer the that are now a number of additional that more information these than is for a to be These are in 1. for identification of genetic testing and clinical management information for of these we to the a that has become to with genetic 1. 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