Direct-to-consumer genetic testing, including personal genome analysis, has been available for several years and raises challenging questions of risk and benefit.
Among the potential harms are that clients may not fully understand their results, that abnormal results may lead to undue anxiety and/or inappropriate responses, and that normal results may lead to false reassurance ("Direct-to-consumer genetic analysis," Internal Medicine News, Oct. 1, 2008).
Dr. Howard P. Levy
This is particularly concerning in the context of single-gene disorders such as hereditary breast and ovarian cancer syndrome, in which a mutation in either the BRCA1 or BRCA2 gene confers up to 50%-60% lifetime risk of female breast cancer and up to 40% lifetime risk of ovarian cancer – as well as increasing the risk of female primary papillary serous peritoneal carcinoma, male breast cancer, prostate cancer, and pancreatic cancer ("BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer," GeneReviews 1998 [Updated 2011 Jan. 20]).
The three mutations in these two genes that are most common among Ashkenazi Jews are now included in commercial direct-to-consumer (DTC) personal genome analysis, making it possible for consumers to screen themselves for these mutations.
In February, a DTC genetic testing company published a report suggesting that the potential harms of such testing may be overstated (Peer J. 2013;1:e8). They invited all 136 adult clients who had one of the three common Ashkenazi BRCA gene mutations and had elected to view their BRCA results to participate in an interview about their experience. A total of 32 agreed: 16 men and 16 women.
For 25 of them, this was a newly discovered mutation, while 7 previously knew that they carried a mutation. Thirty-one mutation-negative clients were interviewed as controls. The groups were identical for most demographics, but differed as expected with respect to cancer history.
Four of the 16 women with mutations had a personal history of breast and/or ovarian cancer, but only 1 of 18 mutation-negative women had breast cancer. There was a positive family history of breast/ovarian cancer for 72% of those with mutations and 48% of those without mutations.
Some of those with mutations were surprised at the news, because they had no significant family history of breast/ovarian cancer. But most were not surprised, because they either knew their mutation status or suspected it, based on family history or Ashkenazi ancestry.
However, no one reported feeling extremely upset, and only four people (12.5%) reported moderate upset feelings. Nine (28%) had self-limited disappointment or anxiety, and 17 (53%) had neutral feelings about their result. Even among the 25 for whom this was a new finding, 11 (44%) felt neutral. Only 1 of the 32 participants expressed regret about learning his result, citing the emotional cost of knowing he has a mutation and that he might pass it on to his children.
Overall, these anxiety results are mostly reassuring and are in line with other published studies of patients’ emotional response to receiving adverse test results (both genetic and nongenetic).
Half of the mutation-negative clients felt neutral about their result, and the other half expressed relief. Almost all of those who felt relieved had a positive family history of breast/ovarian cancer.
Fears of false assurance
The question of false reassurance for these individuals remains a concern. The DTC company required all clients to read a brief written passage about the meaning and limitations of these results prior to viewing them, including a statement that this test does not identify all genetic causes of breast and ovarian cancer.
The interview responses are summarized to indicate that the majority of mutation-negative participants understood that their risk of developing breast cancer was unchanged as a result of their negative testing.
However, because the testing did not involve full sequencing of all known genes associated with breast and ovarian cancer, it is quite possible that some of those who were negative in this study might in fact truly have a genetic cancer predisposition syndrome and be at substantially increased (but unrecognized) risk of breast, ovarian, and possibly other cancers.
Actions taken by clients after learning of a BRCA mutation are generally reassuring: 60% discussed their results with a physician (28% with their primary care physician). Most of the women obtained appropriate medical counseling and took steps to reduce their risks (with prophylactic surgery and/or increased cancer screening). Many people shared the information with family members, resulting in identification of additional relatives with the same mutations, who then sought appropriate screening and prevention.
Several of the mutation carriers, both those in the original study and their relatives, do not meet current criteria for BRCA gene testing or intensified screening and prophylaxis. Assuming such identification reduces future morbidity and mortality, these results argue in favor of more widespread screening for such mutations. But many more data need to be considered before implementing such a program.