Clinically Significant Germline Mutations in Cancer-Causing Genes Identified Through Research Studies Should Be Offered to Research Participants by Genetic Counselors
Authors: Laura E. Forrest, Mary-Anne Young
Journal: Journal of Clinical Oncology (2016)

Genetic sequencing, resulting in the identification of pathogenic germline mutations conferring significantly increased cancer risk, has become de rigueur for research studies with access to populations with and without personal and family histories of cancer. Genetic technology is now more efficient and affordable, and evidence has amassed of the pathogenicity of identified gene mutations. Debate continues about the benefits and harms of returning research results. Benefits include the clinical and personal utility of the genetic information and the potential for treatment or prevention. An example is cancer genetics, where efficacious cancer risk-management strategies known to reduce cancer-related morbidity and mortality are available to individuals who carry a high-risk germline mutation. Harms include psychological distress, perceived patient discrimination and stigmatization, and erroneous results as a result of research laboratories’ not being required to adhere to the Clinical Laboratory Improvement Amendments standards and regulations. The notion of “therapeutic misconception” has also been cited as a risk to participants. This theory describes participants’misunderstanding about the boundaries between research and clinical domains, where participants assume that a research study will provide clinical benefit. Current opinion proposes that researchers have an ethical duty to return individual genetic research results subject to the existence of proof of validity, significance, and benefit. Therefore, attention needs to be focused on how the information should be communicated so participants can make an informed decision about whether they wish to receive their genetic research results. Australia offers a valuable perspective on this issue because of the evolving methods used to return results and the availability of data regarding participants’ experiences and actions. The predominant method of notification in Australia has involved sending consenting participants a letter informing them that genetic information has been identified by the research study. Participants who wished to act upon the letter could contact a familial cancer center (FCC) for genetic counseling and potential confirmation through clinical genetic testing. Australian FCCs are funded by the health system, theoretically making them more readily accessible to research participants. This method was purposefully chosen as a sensitive way to approach participants and breaking to them what was often unexpected news and to optimize their independent decision making about whether to pursue their genetic information. Furthermore, participants’ privacy was maintained by not being contacted directly by the research team, and this lack of contact also reduced the capacity for therapeutic misconception. The content of the notification letters tended to be fairly uniform across different studies, with each study contextualizing the letter according to the inherited cancer syndrome under examination. However, as exploratory qualitative research findings emerged that demonstrated chiefly that participants did not understand or value the letter, the strength and clarity of the wording in the letter has increased. The wording has changed from “the research has identified information that may have relevance for you and your family” to “our research has identified information relevant to your family. This means a genetic change has been found in your family which may account for the family’s experience of cancer” (Australian Ovarian Cancer Study [AOCS] notification letter, October 2007). The uptake rate of confirmatory genetic testing postnotification offers one perspective of examining outcomes resulting from sending these notification letters to participants. Four Australian studies have published uptake rates of confirmatory genetic testing by participants who have received a notification letter. In three of these studies—the Australian Breast Cancer Family Study, the Kathleen Cuningham Foundation Consortium for Research into Familial Aspects of Breast Cancer, and the AOCS—the percentage of participants who received a notification letter and had confirmatory genetic testing ranged from 8% to 49%. Slightly more participants (56%) enrolled in the Australian site of the multinational Colon Cancer Family Registry (CFR) confirmed their mismatch-repair-gene mutation status through confirmatory genetic testing. A consistent outcome of notifying participants by letter of the availability of genetic information, regardless of the wording, is that, in most Australian studies, more than half of the participants did not act upon the letter. It was unknown whether these