Skip to main content
Premium Trial:

Request an Annual Quote

NHGRI Working Group Says Labs, Clinicians Should Include Germline Variants in Tumor Sequencing Tests

NEW YORK (GenomeWeb) – Most genomic sequencing-based cancer tests currently do not analyze germline DNA, focusing instead on tumor tissue to keep costs down and speed up turnaround time, despite the fact that studies have shown that this practice may lead to missed results. Nevertheless, it is still possible to identify cancer risk variants that originate in the germline solely from cancer tissue, and laboratories should be prepared to deal with such findings, according to a National Human Genome Research Institute and National Cancer Institute working group.

The NHGRI- and NCI-funded Clinical Sequencing Exploratory Research Consortium Tumor Working Group laid out a number of guidelines that it recommends for laboratories performing cancer sequencing tests. The group, which includes researchers from the University of Michigan, Harvard University, Ohio State University, the University of Pennsylvania, Texas Children's Cancer Center, and Baylor College of Medicine, published its recommendations in a recent article in the Journal of the National Cancer Institute.

According to the CSER group, even in cases where laboratories are not actively looking for germline variants, they can be found. In addition, laboratories should look for such variants because they can have implications for a patient's management and his or her family.

Earlier this month, researchers from Memorial Sloan Kettering Cancer Center reported that nearly 16 percent of patients whose tumor DNA was analyzed via a 341-gene panel also had pathogenic germline variants. In addition, a large number of patients had cancer susceptibility variants for a cancer type they did not have. Germline variants included those that could impact treatment as well as affect the patient's family.

In April, researchers from Johns Hopkins University reported that 3 percent of patients whose tumor DNA they analyzed also had germline variants, and not analyzing matched normal samples led to false positive results.

In the CSER group's recent article, the consortium addressed the challenges of considering germline variants from cancer sequencing tests.

"It is important to recognize that germline variants can be identified and/or inferred from tumor sequencing results without direct analysis of germline DNA," the authors wrote. In the commentary, they provided examples of such scenarios and the resulting issues that laboratories should consider.

Cancer panels often include genes with well-known and annotated mutations that are "highly suggestive" of hereditary cancer, including BRCA1 and BRCA2 and the set of genes responsible for Lynch syndrome.

Secondly, there are some mutation patterns that suggest an underlying germline variant. Hypermutated tumors often point to a germline variant in a DNA mismatch repair gene, while large chromosomal rearrangements in pediatric medulloblastoma cases suggest a germline TP53 variant.

In addition, a large number of variants have been seen in both the germline, where they cause susceptibility to cancer, as well as in somatic tissue, including the genes MSH2, ALK, RB1, TP53, and VHL.

"Given the collaboration necessary in variant analysis and clinical interpretation, we believe that both ordering clinicians and laboratories share the responsibility for identifying and managing the potential for germline findings, and clinicians will need to appropriately prepare patients for this possibility," the authors wrote.

The group went on to suggest that laboratories that perform large cancer panels or even exome or whole-genome sequencing for cancer patients should design bioinformatics pipelines that consider the possibility of germline findings. In addition, labs should have a plan in place for how they will confirm potential germline findings, including how they will request a germline sample from the patient and whether they will do testing themselves or partner with a reference diagnostic laboratory. The labs should also develop a standardized approach to the way they report germline findings.

Physicians, too, will have a responsibility to properly inform their patients of the possibility that the sequencing test will uncover inherited mutations that could impact their treatment and the cancer risk of other family members.

"The discussion should include summary information about the types of results that might be found, including both pathogenic variants and variants of uncertain significance, and should address the fact that results may have implications for family members," the authors wrote.

Physicians will also need to figure out a protocol for disclosing germline findings to patients and ask patients about their preferences for disclosing such findings to family members if the patient is unavailable — if he or she is too sick, for instance.

Rather than discourage physicians and laboratories from performing cancer sequencing tests, the authors noted that "the promise of precision oncology is vast," but because genomic testing may reveal actionable germline information, physicians and laboratories should "implement solutions that maximize the clinical utility of this germline information while minimizing patient misunderstanding and harm."