There are over one hundred genes known to be associated with hereditary cancers, and more than fifty hereditary cancer syndromes.¹ One type of cancer may be associated with several genes, and one gene can cause multiple types of cancers. Each gene can have 1 to 1,000+ known mutations that increase the risk for cancer. Given the number of genes, possible mutations, and varying cancer risks, it can be challenging to know what test is appropriate for which patient, as well as how to ensure that a person has done testing that makes the most sense for their personal and family history.

Types of hereditary cancer genetic testing

Since the demand for hereditary cancer genetic testing has increased and technology has evolved, there are different ways testing can be obtained.

Clinical Genetic Testing- With this type of testing, a healthcare provider usually orders the genetic testing based on the patient’s personal and family history. This allows the provider to review the testing options and select the testing most appropriate for the patient. Clinical genetic testing is diagnostic and providers can make management recommendations based on these types of tests. Currently, there are hundreds, if not thousands, of clinical tests on the market for hereditary cancer. These clinical tests analyze different numbers of genes, ranging from 1-2 genes, to over 80+ genes to assess a person’s risk for hereditary cancer. Providers tend to order a test that can evaluate the most likely causes for cancer in that patient and their family. Typically, the labs that perform clinical, diagnostic testing use next generation sequencing (NGS) as the basis for testing and may supplement gaps in NGS with other methodologies (see technology review below for more details).

Direct-to-Consumer Testing- Another type of test option is Direct-to-Consumer (DTC) testing. With this type of testing, a person purchases the test without the involvement of a healthcare provider. This testing can provide different types of information, such as ancestry, traits (is the consumer more likely to have wet ear wax, for example), and even health conditions such as hereditary cancer. These tests may be limited in the number of genes evaluated; the number and types of mutations analyzed, and are not considered diagnostic. Generally, the companies that offer DTC testing utilize array platforms, which is why they may not test all mutations associated with a gene or condition. Most medical guidelines recommend confirming DTC results with a clinical, diagnostic genetic test² or at the very least, reviewing DTC results with a clinical genetics provider.³

Consumer Initiated Testing- This type of testing allows for a consumer to purchase the test, but then funnels the consumer’s history and test result through a third party healthcare provider for review. This means that the consumer may not talk directly to a provider, however, at some point in the testing process, a healthcare provider has compared the clinical history provided by the consumer with the test results for that the consumer. The purpose of this is to have a “checkpoint” that allows for further conversation with the consumer if there is a surprising result, or more testing should be considered. Companies that offer consumer initiated testing may utilize NGS, array technology, or a combination of the two. However, the company may still limit what mutations are tested and what findings are reported. Most companies that offer this model of testing encourage confirmation testing on positive findings, as well as recommend consumers share the results with their own healthcare provider.

Testing methodologies for hereditary cancer

The methodologies for hereditary cancer testing typically fall into one of two categories: next generation sequencing (NGS), and array testing. There are other methodologies employed for specific mutations or to rule out interference of a pseudogene (a nonfunctional segment of DNA that resembles a functional gene, but doesn’t code for a protein), but for purposes of this article, we will focus on sequence analysis and more common variant detection. NGS testing allows multiple genes to be analyzed at once and can detect all types of variants (pathogenic, likely pathogenic, variants of unknown significance, likely benign, and benign). Most clinical genetic testing for hereditary cancer utilizes NGS, but laboratories vary on what type of variants they report. The benefit of NGS testing is that in addition to detecting known, well-established mutations, de novo and rare mutations may also be detected.

Array testing may also be referred to as SNP testing or genotype testing. Array testing evaluates targeted, specific DNA fragments that are defined prior to testing. This means not all variant types can be detected and de novo and rare mutations are unlikely to be detected with this technology. Some direct to consumer (DTC), and consumer initiated genetic testing utilize array methodology for hereditary cancer and may be limited in the number of mutations evaluated. Another way to think of the two methodologies is this: NGS is like reading an entire set of encyclopedias, cover to cover without skipping words, and array testing is like only reading assigned sections or pages from the set of encyclopedias.

What do these results mean?

It depends on the type of testing done, the methodology used, and the individual’s personal and family history. For example, a positive result does not necessarily mean that person should start considering surgery or other treatments to reduce their risk of cancer. If the person purchased their own test, either through a DTC company or consumer initiated test, then they should talk to a genetic counselor. Confirmation of the test result, via a clinical genetic test, may be indicated. Also, additional genetic testing may be warranted. One study found a false-positive rate of 40% when comparing DTC results with confirmatory diagnostic testing results.⁴ Once a patient has a positive result on clinical genetic testing, the genetic counselor can discuss what cancers are associated with the result, options available for risk reduction and management of cancer, and how family members can be tested for the known mutation.

Typically, DTC and consumer initiated testing do not assess for variants of unknown significance or VUS’s. Regardless of the type of testing or methodology used, genetic counseling is necessary for VUS test results. A genetic counselor can provide insight on the VUS, make recommendations on management and follow up, and contact the laboratory to see if family studies are available. Additionally, it is a good idea to have a patient establish care with a genetic counselor so that over time, if more information is learned about the VUS, the patient and genetic counselor can communicate.

If a person has a negative hereditary cancer test, talking to a genetic counselor is crucial. Given the number of testing options and benefits and limitations of each option, there is a chance that the person may still have an increased risk for cancer. One way this can happen is if the person with the negative result has a mutation in a gene that was not part of the test. For example, a woman with four relatives with breast cancer may have taken a DTC test and felt relieved when it came back negative for BRCA1/2. However, with over 20 genes associated with hereditary breast cancer², she is still at potential risk from 18 other genes that may not have been analyzed by that test. Consumers are often unware of this additional potential risk if they have not spoken with a genetic counselor.

Another real-life scenario that has happened involves a DTC test that looks at the BRCA1/2 gene. Instead of evaluating the thousands of possible mutations on these two genes, this DTC test only assesses three mutations that are more common in individuals of Ashkenazi Jewish (AJ) ancestry. This means that a person can undergo this test, have a negative BRCA result, and still be at risk. A study found that out of 12,846 patients with a mutation in a hereditary cancer syndrome gene, only 6% of non-Ashkenazi Jewish patients had one of the three AJ mutations. This equated to an overall clinical false-negative rate of 88%! Additionally, this study found that among the patients who had a positive DTC result, about 50% were analytic false positives.⁵

Genetic testing is not one size fits all when it comes to hereditary cancer, and there are many nuances to the tests available. Genetic counseling is of great value in helping patients, consumers, and providers navigate testing options, results, and the follow up recommendations for both negative and positive results.

References:

1. National Cancer Institute, The Genetics of Cancer https://www.cancer.gov/, accessed 12.30.20

2. National Comprehensive Cancer Network® Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. V2.2021.

3. National Society of Genetic Counselors, At-home genetic testing position statement. Approved June 2019.

4. Tandy-Connor S, Guiltinan J, Krempely K, et al. False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care. Genet Med 2018;20:1515-1521.

5. Esplin ED, Haverfield E, Yang S, Herrera B, Anderson M, Nussbaum RL. Limitations of direct-to-consumer genetic screening for HBOC: False negatives, false positives and everything in between [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-03-06.

Kate Wilson, MS, CGC

Kate is Senior Product Manager for Quest Diagnostics. She is a board-certified genetic counselor with a passion for genetic education and increasing access to genetic counseling. Kate has worked clinically in both prenatal and oncology settings, establishing new clinics and educating patients and providers about the benefits and limitations of genetic testing. She continues to focus on education in her industry role by working with healthcare providers, health plans, and laboratory professionals about options for oncology and elective genetic testing that empower patients to make informed healthcare decisions.