Revealing the incidentalome when targeting the tumor genome

摘要

Personalized (or precision) medicine promises to use genomic information to improve the prevention, diagnosis, and treatment of disease. This promise is particularly anticipated in the arena of cancer treatment. Cancer centers and commercial laboratories are rapidly developing programs to routinely analyze individual cancer genomes to identify therapeutic targets and individualize care. However, the process of decoding the genome of a patient's tumor may incidentally reveal information about inherited predispositions to cancer and otherdiseases (the "incidentalome"). There is a need to establish approaches to decision making with respect to the return of these incidental results. Most of the DNA sequence of a patient's tumor is identical to the DNA sequence of the normal cells of that patient (germline sequence). For this reason, the process of defining the potentially targetable mutations that are related to a cancer requires the delineation and subtraction of the germline sequence from the tumor sequence to identify those variations that are specific to the cancer. Incidental information can be found indirectly (when meaningful germline mutations are identified in the tumor sequence) or directly (in the normal DNA that is sequenced for comparison with the tumor DNA). For example, sequencing a pair of tumor and normal samples from a patient with lung cancer may reveal both an EGFR mutation to target with a specific an-ticancer drug (eg, gefitinib) and the incidental finding of a mutation in RYR1 that would predispose to malignant hyperthermia upon exposure to certain anesthetic agents. However, the medical significance of incidental germline findings in many cases may be unclear. A vigorous ethical debate has unfolded regarding whether laboratories and clinicians have an obligation to inform patients about certain incidental findings, or if such an obligation would constitute a violation of a patient's autonomous right to decide what genetic information he or she wishes to receive. Even though many of the illustrative examples chosen in this debate are drawn from clinical cancer genetics, oncologists have yet to join this discussion.