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Germline Genetic Testing After Tumor-Only Sequencing Finds Additional Targets, Study Says


The researchers, from a medical genetics firm, said the findings illustrate the usefulness of germline analysis for the right patient.

While germline testing after tumor DNA sequencing is recommended for some cancers, it isn’t yet current practice for most. A retrospective study published this week found that additional testing picked up an additional 20% of potentially dangerous variants that otherwise would have been missed.

The researchers, writing in JAMA Network Open, said the findings illustrate the usefulness of germline analysis for the right patient with cancer, even after tumor sequencing or independent of tumor sequencing, and suggested the possibility that germline testing is underused.

The study of 2023 patients found that nearly one-third (30.5%) harbored a pathogenic germline variant, most of which were potentially actionable, said the authors, most of whom work for the genetic company Invitae.

“Potentially actionable” was defined by current management guidelines, published expert opinion, approved precision therapy labels, and/or clinical trial eligibility criteria, the study said.

Eight percent of the variants, which were prevalent across diverse cancer types and genes, were missed by tumor sequencing results reviewed for the study and 11% of these variants were found in patients diagnosed with a second cancer that could have possibly been prevented.

Had current conventional guidelines been followed, about 20% of the patients with the pathogenic germline variants would not have qualified for follow-up germline testing, meaning the disease would have been missed, the authors said.

In this study, the patients received germline testing between January 5, 2015, and January 31, 2020, although the majority (81.0%) received testing between January 2, 2018, and January 31, 2020. The median age at diagnosis was 56 (0-92); 53.6% were female.

Pathogenic germline variants (PGVs) were detected in 617 patients (30.5%; 95% CI, 28.5%-32.6%) and were prevalent across the lifespan (1-85 years) and cancer types. Cancer types included those known to be strongly associated with germline variance (eg, breast, colorectal) as well as others (eg, renal, lung, bladder).

Of those with germline-positive results, 69 patients (95% CI, 8.9%-14.0%) had PGVs identified only after presenting with a second primary cancer that possibly could have been detected earlier. Many patients (78%-82%) with PGVs met criteria for germline follow-up testing by current guidelines.

The researchers contrasted their results with what would have occurred against the recommendations released last year by the European Society for Medical Oncology; they said using ESMO criteria was effective but also conservative, because it would have recommended follow-up testing for 82% of patients who had PGVs. That would have been somewhat more than the 73% recommended for follow-up using MSK-IMPACT.

The role of both somatic and germline testing has become more important in guiding treatment. The 2019 annual conference of the National Comprehensive Cancer Network (NCCN) featured guideline updates calling for more comprehensive testing in multiple cancers, including a recommendation that all patients with ovarian cancer have germline testing to determine if poly ADP ribose polymerase (PARP) inhibitors should be used.

In prostate cancer, NCCN calls for tumor testing as well as germline testing in cases where family history indicates mutations. A new guideline issued for January 2020 includes major updates for testing in breast, ovarian, and pancreatic cancer.


Lincoln SE, Nussbaum RL, Kurian AW, et al. Yield and utility of germline testing following tumor sequencing in patients with cancer. JAMA Netw Open. Published online October 7, 2020. doi:10.1001/jamanetworkopen.2020.19452

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