This session will explore the technical, clinical and ethical challenges of conducting exome- or genome-scale analyses in both research and patient care. Genome-scale analyses are characterized by a rapidly evolving knowledge base, a broad range and unpredictability of potential findings, a wide spectrum of interpretive uncertainty, and the possibility of results both related and unrelated to the clinical or scientific question that motivated the test. Even when the focus is on somatic variants, as in many oncology settings, genomic analyses may uncover previously unsuspected inherited predispositions to cancer or to non-oncologic conditions. These features create challenges for physicians, investigators, patients and research participants alike.

Dr. Plon will review some of the recently developed projects that involve performing whole exome or genome sequencing of pediatric and adult cancer patients and returning germline results to patients/families as part of the study design. Several trials are well underway through the NHGRI/NCI Clinical Sequencing Exploratory Research Consortium. Issues that investigators need to consider which will be discussed include: 1) the range of pathogenic mutations and variants of uncertain significance related to the patient’s phenotype being returned, 2) approaches to the return of incidental findings and 3) what forms of validation are being used prior to returning results. Dr. Plon will also review the additional analyses required to differentiate somatic mutations within the bone marrow from constitutional or inherited mutations.

Dr. Joffe will address the ethical dilemmas created by genomic results in both research and clinical care. He will describe and critique policy statements from professional societies and scientific consensus panels, and will present recent data on attitudes towards return among investigators, research participants and others. Finally, he will explore the communication and decision-making challenges that arise when returning findings to patients and research participants.

The session will conclude with a dialogue between the audience and panelists using case examples about these and other questions that genomic analyses pose for the clinical and scientific communities.