Testing to identify genomic variants related to cancer

Identifying biomarkers present in cancer cells can impact treatment decisions, including whether a patient is eligible for targeted treatment. For most cancer patients, genomic variants that are present only in the cancer cells (somatic) and not in non-cancer cells (germline) are more likely to be driving cancer growth and, therefore, are the best targets for treatment. Less commonly, germline variants drive cancer growth and can be targeted therapeutically, such as germline variants in BRCA1/2. Confirming whether a genomic variant is present in the cancer cells only or also present in the germline can affect management decisions.

There are different types of tests available to assess cancer cells for genomic variants to identify potential treatment targets. It is important to understand the specific test’s strengths and limitations to appropriately interpret the results. The purpose of this resource is to define the current approaches to testing and outline the benefits and limitations to each. Note that multiple commercial testing companies and academic laboratories offer these tests, and each may have different limitations than discussed here.

Testing approaches

Somatic testing assesses genetic material from the tumor and reports the variants present in cancer cells. Labs use existing databases and bioinformatic methods to identify likely germline variants, which they filter out of the results. This approach cannot definitively determine if a variant is germline or somatic. This type of testing requires a tumor sample.

The goal of somatic testing is to identify options for genome-informed treatment.

Paired somatic-germline testing (also called tumor-normal) assesses variants in both cancer cells (somatic) and non-cancer cells (germline) and “subtracts out” the germline variants. This process results in a somatic-specific genomic tumor profile. This type of testing requires both tumor and blood samples.

Like somatic testing, the goal of paired somatic-germline testing is to identify options for genome-informed treatment. Depending on the parameters of the paired somatic-germline test, the lab may report on pathogenic germline results.

Concurrent somatic + germline testing assesses variants in both cancer cells (somatic) and non-cancer cells (germline). In concurrent testing, a comprehensive hereditary cancer panel is performed on the germline sample and reported separately from the somatic results. These results are typically not used to filter the somatic results. Somatic results may be identified using somatic testing or paired somatic-germline testing. The options for concurrent testing include:

  • Somatic testing + hereditary cancer risk assessment
  • Paired somatic-germline testing + hereditary cancer risk assessment

This type of testing requires both tumor and blood samples.

In the future, there may be the option to use results from a comprehensive hereditary cancer risk assessment to subtract out results from somatic testing. This is currently not a commonly available option due to laboratory expertise and resources.

The goals of concurrent somatic + germline testing are to identify options for genome-informed treatment and to assess for hereditary cancer risk.

Liquid biopsy assesses both cancer and non-cancer DNA present in the peripheral blood. This approach relies on having pieces of DNA from cancer cells in the blood. This type of testing requires a blood sample.

While there are multiple uses of liquid biopsy, when used for treatment the goal is to identify options for genome-informed treatment.

Benefits and limitations of testing approaches

Identification of somatic only variants. Genomic variants identified in cancer cells can be acquired during carcinogenesis (somatic) or they could have been present prior to carcinogenesis and seen in all body cells (germline). To identify variants that are present only in cancer cells, it is necessary to remove those that are present in the germline. The definitive identification of germline variants requires testing a non-cancer sample directly.

Somatic testing assesses only cancer cells and uses existing databases and bioinformatics to filter results and is not designed to detect germline variants directly. Paired somatic-germline testing, either alone or as a component of concurrent somatic and germline testing, tests a non-cancer directly and uses those results to identify those variants that are present only in cancer cells. Concurrent somatic + germline testing may include somatic testing and a hereditary cancer panel. In this case, the results of the hereditary cancer panel typically are not used to ‘subtract out’ the variants identified in the cancer cells. Liquid biopsy assesses a single blood sample which may contain variants derived from ctDNA fragments (i.e., somatic variants), non-cancer DNA (i.e., germline), or nontumor somatic variants such as clonal hematopoiesis of indeterminate potential (CHIP). The test is not designed to differentiate among these sources of variation.

Cost. The cost of testing is affected by the amount of testing being performed. Somatic testing and liquid biopsy are less expensive because they assess a single sample, while paired somatic-germline testing assesses cancer cells and non-cancer cells using both tumor and blood samples. Concurrent somatic + germline testing is typically the most expensive because it adds a comprehensive hereditary cancer panel to the test or tests performed to assess for somatic variants. Most insurance companies cover assessment of genomic variants in cancer as well as hereditary risk assessment when clinical criteria are met.

Assessment of hereditary cancer risk. Identifying germline variants provides the opportunity to assess a patient’s risk for hereditary cancer, which can have implications for their treatment for current cancer, future cancer risk and their relatives’ cancer risk. Concurrent somatic + germline testing includes a separate hereditary cancer panel that is designed for that purpose. Such testing can be considered comprehensive, though with the same caveats as any test for germline variants including that there may be a variant in a gene not assessed and there are certain types of variants that may not be detected.

Paired somatic-germline testing uses results from germline testing to help identify variants unique to cancer cells. In this test approach, germline testing should not be considered a comprehensive hereditary cancer risk assessment. There are typically fewer genes assessed, and there are limitations in the detection of certain variant types known to be significant in hereditary cancer syndromes, such as large deletions and duplications. Interpretation of possible germline variants from paired testing depends on the result and patient’s other risk factors:

  • If a germline variant is detected through paired testing, this is a clinically significant result for the patient and family members. Confirmation is typically not needed.
  • If a germline variant is not detected, it reduces risk but does not rule out the presence of a germline variant.
    • The patient does not need to be referred for further hereditary evaluation unless there are additional personal or family history risk factors present.
    • If the patient does meet clinical or family history criteria for hereditary cancer evaluation, further germline testing may be warranted.

Somatic testing and liquid biopsy are not designed to differentiate between somatic and germline variants. As such, separate germline testing may be warranted if there is concern or suspicion for hereditary risk based on somatic results or personal or family history, or if the presence of a germline variant would inform treatment options (e.g., PARP inhibitors). In addition, liquid biopsies typically assess fewer genes and may also identify variants that are due to CHIP.

FOR MORE INFORMATION

  • Liquid Biopsy FAQDescribes the benefits, risks and limitations of liquid biopsy.
  • Indications for Germline Testing in Cancer Patients. Identifies genetic red flags to inform personal and family history risk assessment and genomic tumor test results that are suggestive of a germline variant.
  • Choosing the Best Genomic Tumor Test (CME and CNE versions available). Learn about the benefits and limitations of different genomic tumor test options for patients with cancer and how to determine the best test for each patient.

REFERENCES

Foundation One Liquid CDx FDA label. Accessed 1/22/22

De Mattos-Arruda L, Siravegna G. How to use liquid biopsies to treat patients with cancer. ESMO Open. 2021 Apr;6(2)

This resource was developed as part of Precision Oncology Online Education and the Maine Cancer Genomics Initiative (MCGI) and is supported by The Harold Alfond Foundation, Maine Cancer Foundation and The Jackson Laboratory. 

Updated January 2022 

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