Germline Genetic Testing Raises Thorny Ethical Questions

OncologyLiveVol. 17/No. 10
Volume 17
Issue 10

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If germline testing for a cancer-associated purpose reveals the risk of an unrelated illness like Alzheimer disease, should patients routinely be told—even if there’s nothing that can be done about that “incidental” finding?

Maurie Markman, MD

The simply stunning advances in our understanding of the molecular basis of human disease are providing revolutionary changes in the management of multiple illnesses. It is well recognized that cancer has been at the leading edge of this paradigm change through the demonstration of the clinical utility associated with knowledge of the unique genomic profile present within an individual patient’s malignancy.

Not surprisingly, the past and current major focus of using molecular testing has been in the treatment of an established malignancy, and in examining for the presence of particular mutations, rearrangements, or amplifications of specific genes that may suggest the delivery of a particular antineoplastic agent targeted to that abnormality. Patients with cancer and their oncology teams are witness to increasingly relevant advances in this arena in multiple clinical settings.

Another critically important and highly clinically relevant issue—one that is less frequently discussed among oncologists—concerns the implications of knowing the germline genetic background for individuals with known cancer or who are at a higher risk for developing a malignancy.

Normal Versus Cancer Genome

Cancers of the colon, breast, and ovary are excellent examples where germline testing has been shown to be of value and where prophylactic interventions in specific clinical settings have been documented to be of substantial utility.However, there is a particular issue when a search is undertaken to discover unique normal polymorphisms or actual mutations that may be present in the germline—versus a sole focus on molecular abnormalities within the cancer itself—that requires particularly careful consideration and discussion. When cancer is present, what is specifically being explored are differences between the individual’s germline versus the cancer, with the goal of finding a target for therapy. In essence, the germline itself is purposefully ignored since there is no intent to target the normal genome.

What Should Patients Be Told?

But when the normal germline is examined to define cancer risk, evaluate genetically influenced probability of treatment-related toxicity, or for other purposes such as assisting in the determination of prognosis, there is the realistic potential that what might be found would include incidental genetically relevant markers associated with illnesses completely unrelated to the intent of the specific search.For example, it has been reported that the presence of unique normal polymorphisms of apolipoprotein E suggest an increased risk for the development of Alzheimer disease. Should such “incidental” information simply be routinely provided to individuals if it is found? Should individuals undergoing genomic testing be asked if they would like to receive this information if it is discovered? This request could be made prior to obtaining the testing or after the results are available and a laboratory reports the presence of such incidental information.

This is a complex and controversial issue, with considerable ongoing debate. Included in the discussion are questions of whether the individual or her/his family would be able to take any action following notification of the results that may lead to a decreased risk of a suggested negative outcome, or conversely whether the information would solely be anxiety-provoking with no current potential to be actionable.

Unfortunately, for example, knowledge of a heightened risk of Alzheimer disease would currently fall into the second category of the impact associated with providing genetically based information.

Alzheimer Study Offers Clues

A related question is the impact of specific germline information being obtained for one indication which may have direct relevance (pleomorphic effect) for a second, unrelated indication. And, for one indication the genomic information may be actionable while that is not currently the case in the second condition.An interesting report outside the cancer arena begins to address this question. Asymptomatic individuals (N = 257) undergoing testing to determine their genetic risk for Alzheimer disease were randomized to either receive this information alone or the Alzheimer disease risk data plus that associated with coronary artery disease risk.1

Previous research had revealed similar genetic data could influence risk in both disease settings. Of considerable interest, among the individuals found to be carriers of the apolipoprotein allele associated with a heightened risk of Alzheimer disease, there was a lower incidence of distress and more changes in health behavior associated with providing genomic for both conditions versus Alzheimer disease risk alone.

Although this highly provocative study does not directly address the issue of malignancy-associated incidental genetic data or pleomorphic germline effects, there are important lessons here that might easily be applied in the cancer domain. The clinical utility associated with the discovery of a statistically significant heightened risk of cancer in a setting where there is no evidence this information is actionable such as with Alzheimer disease may lead to heightened distress in the absence of an individual being able to take any action known to favorably impact that outcome. This conclusion may have relevance for an individual undergoing germline testing for cancer or as an incidental finding for an unrelated condition or a pleomorphic effect of a single gene.

Hopefully, as the cancer research community develops effective screening strategies to discover early-stage cancers such as CT scanning for lung cancer and prophylactic approaches to prevent the development of malignant disease as is the case with bilateral salpingo-oophorectomy for ovarian cancer in the presence of a BRCA mutation, the conclusion that nothing actionable is possible will become an increasingly rare statement.

Maurie Markman, MD, editor-in-chief, is president of Medicine & Science at Cancer Treatment Centers of America, and clinical professor of Medicine, Drexel University College of Medicine. maurie.


  1. Christensen KD, Roberts JS, Whitehouse PJ, et al. Disclosing pleiotropic effects during genetic risk assessment for Alzheimer disease: a randomized trial. Ann Intern Med. 2016; 164(3):155-163.

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