Recent advances in both technology and research around hereditary cancer has resulted in significant changes in genetic testing options for hereditary cancer. Testing has moved from single gene analysis done in sequence (such as BRCA1 and BRCA2 followed by TP53 testing) to panels of genes available in a single test. Today these panels may incorporate testing as few as 6 genes or as many as 61 genes. The option of choosing which genes to test and custom ordering a panel is also available. This means that individuals and providers have several approaches to genetic testing. Oncology providers must determine the best test for their patients (single site or panel testing and which panel) based on the setting and family history. Oncologists may choose from the following approaches:
- Syndrome-specific gene panel: This approach would include BRCA1 and BRCA2 for hereditary breast and ovarian cancer or testing of mismatch repair genes for Lynch syndrome (MLH1, MSH2, MSH6, PMS2 and EPCAM).
- High-penetrance gene panel: These type of panels include genes with high penetrance and known to be involved in a specific cancer. One example is high risk breast cancer panel testing for mutations in BRCA1, BRCA2, TP53, PTEN, CDH1 and STK11.
- Cancer-specific gene panel: This panel would include testing of between 17-23 genes. Tested genes include both highly and moderately penetrant genes related to a specific cancer type such as breast cancer or ovarian cancer.
- Comprehensive cancer risk panel: Several companies offer these panels, which include testing of between 25 and 61 highly and moderately penetrant genes known to be associated with risk for many different cancers.
Determining if a Panel Test is Appropriate for your Patient
The expansion to panel testing has many advantages, such as decreased cost (one charge for multiple genetic tests) and decreased need for sequential testing. However, panel testing has increased the complexity of genetic testing for hereditary cancer. A provider ordering these tests must consider several issues and understand which approach is best for their patient. Important issues to consider include:
- What will the test be used for? Tests being done to guide cancer treatment are often time sensitive and should only include those tests that guide therapy (for example BRCA1 and BRCA2 testing for surgical decision making or use of PARP therapy).
- The use of panel tests can result in unexpected or unanticipated results. For example, using a panel for testing a colon cancer family may results in identification of a BRCA or TP53 mutation. Additionally, mutations in more than one cancer-causing gene can be identified, especially when there is cancer on both sides of a family.
- Cancer risks associated with moderately penetrant genes are less clear. Our understanding of cancer risks associated with many of the moderately penetrant genes offered in panels is growing. However, there is still great uncertainty about the actual cancer risk. This uncertainty can be difficult to explain to patients and difficult for patients to accept. Management of individuals/families with mutations in moderately penetrant genes must include a review of the literature so that family can determine the most appropriate screening/prevention plan.
- Identification of variants of uncertain significance (VUS). Panel testing has greatly increased the identification of VUS results. A VUS in any given gene has an unknown influence on the gene function and therefore cannot be used to predict cancer risk or for testing of other family members (other than in a research setting). Educating patients about these results is time-consuming and can be difficult.
It is imperative that patients undergoing panel genetic testing have proper counseling, as the results of panel testing may not always be straight-forward. Panel testing can be associated with significant challenges and risks as well as benefits; these should be explained to patients prior to initiation of testing. Patient preferences should be included in decision making regarding the most appropriate test.
ClinVar is a freely accessible, public archive of reports detailing the associations between human variations and phenotypes, with supporting evidence.
NIH Genetic Testing Registry
The Genetic Testing Registry (GTR) provides a central location where providers can voluntary submit genetic test information. The site is designed to assist health care providers and researchers who are navigating the landscape of genetic tests. Tests are searchable by condition or specific laboratory. The site includes a voluntary listing of US and international laboratories offering in-house molecular genetic testing, specialized cytogenetic testing, and biochemical testing for inherited disorders. Listings are divided into clinical laboratories (which require CLIA certification in the US) and research laboratories.
- Clinical Evaluation of a Multiple-Gene Sequencing Panel for Hereditary Cancer Risk Assessment (Kurian et al. JCO. 2014)
- Counseling Framework for Moderate-Penetrance Cancer-Susceptibility Mutations (Tung et al, Nature Reviews Clinical Oncology 2016)
- Frequency of Mutations in Individuals With Breast Cancer Referred for BRCA1 and BRCA2 Testing Using Next‐Generation Sequencing With a 25‐Gene Panel (Tung et al, 2014)
- Multiplex Genetic Testing for Cancer Susceptibility: Out on the High Wire Without a Net? (Domchek et al, JCO. 2013)
- Multigene Panel Testing: Planning the Next Generation of Research Studies in Clinical Cancer Genetics (Robson, JCO. 2014)
- Mutations in 12 Genes for Inherited Ovarian, Fallopian Tube, and Peritoneal Carcinoma Identified by Massively Parallel Sequencing (Walsh et al, 2011)
- SGO Clinical Practice Statement: Next Generation Cancer Gene Panels Versus Gene by Gene Testing (SGO, March 2014)