Abstract

The integration of germline genetic testing into cancer care has been a gradual process. It has taken years to construct the evidence base to define the optimal management of individuals who carry mutations in cancer susceptibility genes. Although this evidence remains imperfect, it would be less robust if it were not for the role of the American Society of Clinical Oncology and other organizations, which have firmly and consistently endorsed the principle that genetic susceptibility testing should, if at all possible, be offered in the context of clinical trials with appropriate informed consent and follow-up. Substantial investment in research by individual centers and large international collaborations, including PROSE, the Hereditary Breast-Ovarian Cancer Study Group, and the Breast Cancer Family Registry, has generated data to guide clinical interventions, such as preventive salpingooophorectomy in BRCA mutation carriers. It is clear that the genetic architecture of cancer predisposition can be quite complex. Researchers have identified numerous cancer susceptibility syndromes and their causative genes. The risk of cancer at a given site may be elevated by mutations in one of a number of different genes, and a mutation in a particular gene often increases risk for more than one type of cancer. There are high-penetrance genes that result in autosomal-dominant predispositions recognizable by pedigree analysis, and moderate-penetrance genes, in which mutations are associated with lower relative risks (usually 2 to 5) and in which mutations may not cosegregate with implicated cancers in individual families. In the traditional model of clinical cancer genetics, patients are evaluated on the basis of family history or patient-specific factors such as age at diagnosis or disease histology. After appropriate evaluation and consent, testing is performed, usually serially, for the most likely genetic causes. The advantage of this approach is that testing is more specific, because genes that are unlikely to be mutated are not analyzed. Importantly, the process of pretest counseling for each gene allows the patient to participate in the decision of whether to pursue a particular test after considering the clinical and personal utility of the result. However, the standard approach of serial testing is time consuming and expensive. In contrast, next-generation sequencing (NGS) technologies now allow simultaneous analysis of multiple susceptibility genes (multiplex testing) at a cost that is modestly greater than single-gene testing (currently $3,855 to $5,466 at one commercial laboratory). Multiplex testing employs the same technologies as whole-exome and whole-genome sequencing but generates a more limited amount of information about predefined target genes. Multiplex test panels that evaluate highand moderatepenetrance genes are now available and are being marketed as a means of quickly assessing cancer susceptibility, either generically or for a specific disease site (Table 1). The multiplex approach has evident advantages, especially the potential for greater time and cost efficiency. It may be particularly useful in situations where: there is significant genetic heterogeneity; the prevalence of actionable mutations in one of several genes is significant; and it is difficult to predict which gene may be mutated on the basis of phenotype or family history. Examples of such situations include early-onset pheochromocytoma/paraganglioma and Lynch syndrome. However, there are nontechnical challenges that must be met to ensure the most responsible and effective implementation of these new technologies.