The advent of multi-gene cancer panel testing has dramatically altered the landscape of germline cancer genetic testing. An increasing number of patients are being tested for genes beyond just high-risk, well-established culprits such as BRCA1/2 and the mismatch repair genes associated with Lynch syndrome. While broadening the scope of genetic testing allows for the increased detection of mutations overall, it is important to consider the value this information may or may not offer to individual patients as well as the possible limitations and drawbacks of expanded testing.
Multi-gene expanded cancer panel genetic testing is thought to increase the likelihood of identifying mutations in high-, moderate- and low-risk genes. Moderate risk genes are considered to be fairly well studied genes that are associated with more modest increases in cancer risk. For example, most mutations in the CHEK2 gene lead to a 2-fold increase (~20-25%) in lifetime female breast cancer risk compared to the general population. By comparison, mutations in the BRCA1/2 genes increase lifetime breast cancer risk to ~40-60%. Low risk and more newly discovered genes are even less well understood and, in most cases, the related cancer risk spectrum and lifetime cancer risk estimates are unknown or ill defined.
One argument for cancer panel genetic testing is that identifying a pathogenic mutation in a gene of any risk level may provide additional insight into the underlying genetic cause for a patient’s history; this may alert the patient to increased cancer risks not obvious based on review of the family tree alone. For patients found to carry a mutation in a high-risk and well-understood gene, screening and management guidelines are typically available. For many moderate risk genes however, these guidelines are limited in scope as our understanding about risks associated with these genes is not yet as well established. For low risk and more newly discovered genes, screening and management recommendations are not currently available; alterations to a patient’s care are generally based on their reported personal/family history alone. For many patients, it can be anxiety producing to learn that they carry a genetic risk factor for cancer while also being told that changes to their current care plan are not recommended.
While identifying a gene mutation may provide additional information in regard to the underlying etiology of a patient’s cancer history, broad testing also increases likelihood of identifying a disease-causing mutation in an unexpected gene that does not appear to correlate with a patient’s reported personal and/or family history. For example, a patient presenting with a history of colon cancer may be surprised to learn that their test result indicates a susceptibility to breast cancer. While some patients may feel empowered in knowing this information, other patients may wish that this information had not been evaluated and that a more targeted testing approach had been taken. This may be particularly true for patients found to carry pathogenic alterations in less well understood genes where there are currently no well-established screening and management recommendations. It is important to assess a patient’s goals during the pre-test genetic counseling session to ensure that any genetic testing ordered will satisfy those goals and that the patient is prepared for the spectrum of results and information that they may receive from testing.
In the event that an individual is found to carry a pathogenic mutation in a moderate or low-risk gene, it is also important to be aware that this mutation alone may not provide an explanation for the concerning history. Given that mutations in these genes influence cancer risk to a lesser degree than their high-risk counterparts, it is likely that they serve as a piece of the patient’s larger risk puzzle, but are not the sole driver of their cancer risk. Given this, individuals in this scenario are encouraged to report changes to their personal and/or family histories and possibly reconsider additional genetic testing in the future in an effort to uncover additional puzzle pieces.
It is also important to consider that as the number of genes analyzed on a cancer panel increases, so does the chance of identifying variants of uncertain significance (VUS). During the genetic counseling process, we often hear that patients feel unsettled by the uncertainty of these genetic alterations. In many instances, the risk of an uncertain variant can be decreased by testing a more limited scope of genes directly correlated with the patient’s personal and/or family history. A more targeted approach often allows these patients to marry their two desires:
- To obtain information correlated with their family that will influence future screening and care.
- To decrease the chance of finding an unclear result that could contribute to an increase in anxiety.
For each individual patient, it is important to weigh the clinical value cancer panel genetic testing may provide against the potential for added uncertainty and increased anxiety. As broader ranges of genes are analyzed, the chance for identifying a pathogenic mutation increases, and individual patients will differ on whether they feel this information is of benefit to them and their families. As noted previously, some patients may feel empowered after learning of an increased susceptibility while others may feel unsettled by the uncertainty of a VUS or lack of clarity about cancer risks and screening/management guidelines associated with moderate and low risk genes specifically. Considering the pros, cons and limitations of multi-gene cancer panel testing in the context of individual patients and their goals is paramount to determining the best approach to genetic testing; this is the central focus of genetic counseling sessions at Insight Medical Genetics.