Genetic Testing: Guide for Health Pros

Several companies offer direct-to-consumer genetic testing. These tests generally are single nucleotide polymorphism (SNP) tests, in which variations within the DNA that have been associated with different diseases or traits are tested. The association between SNPs and disease risk is investigated by genome-wide association studies, or GWAS.

Using GWAS to find genetic links to disease is different than evaluating a known disease gene for a mutation that affects the gene function. Some SNP tests are tailored to look for a specific risk, such as colon cancer or heart disease. Other tests evaluate dozens of diseases and traits and report them all. The list of conditions that are reported might range from things like cancer and diabetes to HIV susceptibility and earwax production. Typically the test kits are sent to the consumer by mail, and the results are mailed directly to the consumer.

You will likely encounter a patient who will bring you his or her SNP risk test results and ask you to make a health care recommendation. It’s important to know that the accuracy in predicting disease risk from SNP testing generally is not well validated, and these tests have largely not been endorsed by the medical community. While it might be fun for patients to find out if they have a genetic change that causes them to make more earwax, the utility of these tests is somewhat limited.

Often, family history and lifestyle factors are better predictors of diseases such as cancer, diabetes, and heart disease. Because they may explain only a small portion of the heritability of disease, SNP risks need, at a minimum, to be interpreted in light of family history and lifestyle factors.

It’s important for individuals who are considering SNP testing to understand the limitations of these tests, as well as the significance of other factors affecting their risk and how SNP panels might include information about disease risk that is clinically unactionable.

That said, some SNP tests can be medically important. Specific SNPs have been shown to affect drug metabolism, such as for warfarin or 5-FU. For some medications, evaluating the SNP profile affecting drug metabolism is becoming a part of routine care.

Laboratories develop panels of genes to evaluate risk for different types of hereditary cancers. Each laboratory examines different genes on its panels, and there is currently no standard of which genes should be evaluated for a given type of cancer.

Next-Generation Sequencing

Unlike traditional genetic testing, which involves analyzing a single gene with Sanger sequencing and MLPA analysis for deletions and duplications, next-generation sequencing (NGS) allows for the simultaneous sequencing of multiple genes. NGS tests generally target the coding exons of the genes of interest, as well as a small portion of the flanking exons. MLPA analysis is still needed to detect deletions and duplications.

NGS panels can include five to 50 or more genes and can range in price from approximately $1,000 to $5,000. There are a variety of panel-testing options at laboratories throughout the country. These include cancer-site-specific and general cancer panels. Additionally, some laboratories have options of smaller panels with clinically actionable information only. Please contact one of our genetic counselors if you have questions regarding available testing options.

NGS Limitations

One limitation of NGS testing is that a disease-causing alteration could occur outside the region captured by the test. NGS testing is most useful when testing an affected patient who has a history that is suggestive of more than one gene.

Some of the genes evaluated on NGS panels are moderate-risk genes. Currently, consensus guidelines have not been established for clinical management of moderate-risk genes. Clinicians’ understanding of the types of cancers associated with these genes and the level of risk will evolve over time.

At this point, NGS panels have a high yield of uncertain results (variants of uncertain significance).

Because of the limitations, the paucity of clinical management guidelines, and the increased likelihood of uncertain results, patients should be carefully counseled prior to having NGS testing. NCCN guidelines state: “Cancer risk assessment and genetic counseling is highly recommended when genetic testing is offered (i.e., pre-test counseling) and after results are disclosed (i.e., post-test counseling)” (Genetic/Familial High Risk Assessment: Breast and Ovarian Version 2.2015).

If a deleterious (also called pathogenic) gene mutation is identified in a family, the individual family members typically are tested for only the mutation that was found. Testing for the known familial mutation is called single-site testing. Most insurance companies will cover single-site testing, which typically costs $200 to $500.

It’s important to carefully evaluate a person's family history when undertaking single-site testing. Clinicians should consider the possibility that the patient may have a risk for a different mutation from the other side of his or her family.

Different laboratories may use different primers for sequencing. It is possible that a family may have a unique sequence variation that may occur near the location where a specific primer binds. This could potentially cause a laboratory to not be able to detect a mutation that is present in that family, even if the laboratory has detected the same mutation in other families. For this reason, it’s important to perform single-site testing at the same laboratory where the mutation was found in a family member. If this is not possible, a sample from a family member who is known to have the familial mutation should be sent in with the patient's specimen to confirm that the laboratory is able to detect the mutation in that family.

Single-site testing for moderate penetrance gene mutations may not be the only appropriate testing for family members. Given the lack of data on potential multiple germline gene mutations in families with hereditary cancers, full gene or further panel testing may still be recommended, particularly for affected family members.

Many companies now provide genetic testing of tumors, looking for somatic mutations with the aim of providing clinicians with information on their patient’s prognosis, alternative therapeutic agents, or potential clinical trials, particularly if all other options for treatment of the tumor have been explored. These tests usually involve sending a sample of the patient’s tumor and sometimes also a blood sample to assess the patient’s germline genetics, as well.

If the testing lab does ask for a blood sample, it is important to know if this information will be used only as a filter to assess for true somatic variants or if the lab will also report underlying hereditary cancer predisposition syndromes identified.

When considering or reviewing somatic testing results, it’s important to keep the following things in mind:

• Somatic testing, while it is a form of genetic testing, is different from traditional germline testing assessing for underlying hereditary cancer predisposition syndromes.
  
• These tests are not designed to report out these kinds of germline genetic changes.
  
• Just because there is a BRCA1 gene mutation found on a somatic test mutation report does not mean that the patient has Hereditary Breast and Ovarian Cancer syndrome (HBOC).
  
• Conversely, in a patient with a strong personal and family history of breast and ovarian cancer, a clinician should not assume that the patient is “negative” for a BRCA gene mutation just because one is not reported on a somatic test report.
  
• All individuals undergoing somatic tumor testing should be assessed for likelihood for an underlying hereditary cancer predisposition syndrome and be referred for separate appropriate germline genetic testing, if indicated.
  
• Lab quality is very important. The quality of the data returned depends highly on the quality of tumor sample provided and the quality of the assays the lab uses.
  

It can be challenging to determine which “actionable” variants reported on a somatic test report may be most beneficial for the patient. The American College of Medical Genetics (ACMG), American Society of Clinical Oncology (ASCO), and Association for Molecular Pathology (AMP) all recommend a multidisciplinary approach to review of somatic test reports with the ordering clinician, bioinformaticists, molecular pathologists, and genetic counselors to “bridge the inevitable gap in knowledge between those closely involved with genomic data interpretation and health care providers who would be hard pressed to keep up with new developments but who need to integrate this information into their medical practice” (AMP, 2012).

UT Southwestern has developed a Molecular Tumor Board that meets monthly so that these cases and somatic test reports can be presented and reviewed with a multidisciplinary approach. For the date, time, and location of the next meeting, or for other questions, please contact TumorGenomics@utsouthwestern.edu.

Multiple cancer syndromes are associated with one or two genes. Broad cancer panels are not the most appropriate type of testing for evaluation. Single-gene testing may cost up to $2,000.

Continuous research on hereditary cancer genes has expanded the spectrum of many cancer syndromes. It’s important to keep in mind that additional genes may be considered for analysis in individuals that previously had single-gene testing. For example, an individual with 10 to 100 polyps may have a less severe form of FAP(called attenuated FAP or AFAP), MYH-associated polyposis (MAP), or other emerging genes becoming more associated with polyposis (PTEN, POLE, POLD1).

Research is ongoing to identify targeted treatment options for individuals with cancer. Progress in understanding the genetic pathway of tumor development has already led to advancements in targeted therapy. The genetic targets could be based on sporadic mutations detected in the tumor, such as EGFR mutations in lung cancer, or inherited germline mutations.

Lynparza (olaparib) is a new treatment option for women with ovarian cancer, and a BRCA1 or BRCA2 Lynparza is a PARP inhibitor that blocks the DNA damage repair pathway associated with these genes. FDA approval for Lynparza is accompanied by specific criteria. A woman must undergo three lines of chemotherapy prior to receiving the drug and have a BRCA1 or BRCA2 mutation.

As research continues to move forward, new clinical trials and ultimately recommendations will become available to improve the treatment of our oncology patients.