Amber Johns with pancreatic cancer surgeon David Chang
20 June 2014
Whole genome sequencing is rapidly becoming affordable for research and diagnostic purposes, yet there is still much debate surrounding the return of personal genetic information to patients or family members – which factors should be taken into account, what should be revealed or concealed, who should make that decision, and how it should be imparted.
A team of Australian researchers has made a valuable contribution to the debate by developing a ‘framework’, or standard set of considerations and principles, to help guide the process in a research context. Their recommendations have been published in Genome Medicine and are now online.
The authors gained their experience and insight from undertaking a large research project known as the Australian Pancreatic Genome Initiative (APGI)1 that involved gathering tumour samples from nearly 300 pancreatic cancer patients, then sequencing their tumour and normal DNA to identify genetic aberrations. All participants provided written informed consent upon entry to the study, which included their preference concerning return of results.
While some members of the international research community argue that no research findings should be made available to individuals in a research study, others perceive it as unethical not to provide individuals with findings that have clinical relevance to them or their family members.
The Australian National Statement on Ethical Conduct in Human Research (2007) states: “Where research may discover or generate information of potential importance to the future health of participants, or their blood relatives, researchers must prepare and follow an ethically defensible plan to disclose or withhold that information”.
Unfortunately, this guideline neither assumes an obligation to return results, nor defines what constitutes an “ethically defensible plan”.
Amber Johns, project manager of the APGI at the Garvan Institute of Medical Research and lead author of the Genome Medicine paper, was the person who had most contact with patients and family members. Senior Author, Nikolajs Zeps, Research Network Director at Perth’s St. John of God Hospital and principal investigator for the APGI’s Western Australia hub, regularly dealt with the ethical and policy issues surrounding findings disclosure.
The APGI experienced real value in returning information to patients. “Our study demonstrated the actual benefits involved in disclosing information, as well as the practical and ethical dilemmas that accompanied each case. Unfortunately, the real life risks and benefits are rarely, if ever, presented as part of the debate,” said Amber Johns.
“In the course of a research project, researchers may find changes in the genetic sequence that do not directly relate to the research question asked. These ‘secondary’ or ‘incidental’ findings may have a significant impact on the future health of the individual or their families.”
“While each situation is unique, there are common factors that you must always address. These include consent, significance of results, how and to whom results should be communicated, and how to proceed in a clinical sense. These factors determined our ‘ethically defensible plan’ or framework.”
From 285 recruited patients to the APGI project, results were returned to 25. These included 4 that were classified as ‘medically actionable’, 9 as ‘clinically significant’ and 8 that were returned at the request of the treating clinician.
The three case studies2 detailed in the Genome Medicine paper reveal how the circumstances of each case tend to guide and constrain the disclosure process simultaneously.
Nikolajs Zeps said “Our national guidelines issued by the NHMRC require us to have an ethically defensible plan to deal with incidental findings. There is nothing in the literature to help guide ethics committees or researchers create one of these plans, and we believe this paper will provide invaluable help in doing so. Importantly it will also help policy makers refine their guidelines in the future”.
1. The Australian Pancreatic Cancer Genome Initiative (APGI) is the Australian arm of the International Cancer Genome Consortium (ICGC), and aims to catalogue all the genetic changes in pancreatic cancer by analysing the biological material from patients diagnosed with pancreatic cancer. The APGI brings together the expertise of pancreatic cancer scientists and healthcare professionals across Australia, and is dedicated to improving outcomes for pancreatic cancer patients and their families.
This work is supported by the National Health and Medical Research Council of Australia (NHMRC), Cancer Council NSW, the Cancer Institute NSW, Queensland Government (NIRAP); Institute of Molecular Bioscience at the University of Queensland; the Avner Nahmani Pancreatic Cancer Foundation, and Jane Hemstritch in memory of Philip Hemstritch.
2. Case Studies included in the Genome Medicine paper
Case Study 1
This concerned a patient who passed away from disease before the results became available. Sequencing pinpointed a mutation in the BRCA2 gene, which confers a heritable (49%) risk of breast cancer and (18%) risk of ovarian cancer. Affected family members have undergone further testing and have joined Pancreatic, breast and prostate screening programs.
Case Study 2
This case also involved a patient who also had a mutation in the BRCA2 gene. The patient was still alive and receiving treatment for metastatic disease. Results were communicated directly to the treating medical oncologist, who suggested switching to a therapy used for other cancers with the BRCA2 mutation.
Case Study 3
This case concerned a patient who had undergone a biopsy for presumed pancreatic cancer and was receiving treatment for metastatic disease. The tumour genome revealed a mutation pattern consistent with a colonic rather than a pancreatic cancer, and this was communicated directly to the treating medical oncologist and surgeon. Upon further investigation, and a primary colonic tumour was identified.