ArticleJCO precision oncology2021
Germline Testing Data Validate Inferences of Mutational Status for Variants Detected From Tumor-Only Sequencing.
Article in JCO precision oncology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- Performance and clinical utility of Spanish germ line genetic testing criteria for hematologic neoplasms predisposition.Blood advances · 2026Article
- Evaluating the Use of Tumor Bank DNA to Validate Genetic Factors Impacting Opioid Response in Patients with Advanced Cancer.Current oncology (Toronto, Ont.) · 2026Article
- Detecting likely germline variants during tumor-based molecular profiling.The Journal of clinical investigation · 2025Review
- Clinical integration of germline findings from a tumor testing precision medicine program.BMC cancer · 2025Article
- Germline mechanisms of immunotherapy toxicities in the era of genome-wide association studies.Immunological reviews · 2023Review
- Management of patients with presumed germline pathogenic variant from tumor-only genomic sequencing: A retrospective analysis at a single facility.Journal of human genetics · 2023Article
- Prevalence of BRCA homopolymeric indels in an ION Torrent-based tumour-to-germline testing workflow in high-grade ovarian carcinoma.Scientific reports · 2023Article
- Tumor and Constitutional Sequencing for Neurofibromatosis Type 1.JCO precision oncology · 2022Article
- An integrated somatic and germline approach to aid interpretation of germline variants of uncertain significance in cancer susceptibility genes.Frontiers in oncology · 2022Article
- An optimized protocol for evaluating pathogenicity ofMethodsX · 2022Article
- Management of BRCA Tumour Testing in an Integrated Molecular Tumour Board Multidisciplinary Model.Frontiers in oncology · 2022Article
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10 authors at 4 institutions in 1 country.
Funding
Abstract
Pathogenic germline variants (PGVs) in cancer susceptibility genes are usually identified through germline testing of DNA from blood or saliva: their detection can affect treatment options and potential risk-reduction strategies for patient relatives. PGV can also be identified in tumor sequencing assays, which, when performed without patient-matched normal specimens, render determination of variants' germline or somatic origin critical.
methodsTumor-only sequencing data from 1,608 patients were retrospectively analyzed to infer germline versus somatic status of variants using an information-theoretic, gene-independent approach. Loss of heterozygosity was also determined. Predicted mutational models were compared with clinical germline testing results. Statistical measures were computed to evaluate performance.
resultsTumor-only sequencing detected 3,988 variants across 70 cancer susceptibility genes for which germline testing data were available. We imputed germline versus somatic status for > 75% of all detected variants, with a sensitivity of 65%, specificity of 88%, and overall accuracy of 86% for pathogenic variants. False omission rate was 3%, signifying minimal error in misclassifying true PGV. A higher portion of PGV in known hereditary tumor suppressors were found to be retained with loss of heterozygosity in the tumor specimens (72%) compared with variants of uncertain significance (58%).
conclusionAnalyzing tumor-only data in the context of specimens' tumor cell content allows precise, systematic exclusion of somatic variants and suggests a balance between type 1 and 2 errors for identification of patients with candidate PGV for standard germline testing. Although technical or systematic errors in measuring variant allele frequency could result in incorrect inference, misestimation of specimen purity could result in inferring somatic variants as germline in somatically mutated tumor suppressor genes. A user-friendly bioinformatics application facilitates objective analysis of tumor-only data in clinical settings.
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