Abstract
Background:Tumor-only sequencing, implemented for the identification of somatic variants, is oftentimes used for the detection of actionable germline variants. We sought to determine whether tumor-only sequencing assays are suitable for detection of actionable germline variants, given their importance for the delivery of targeted therapies and risk-reducing measures.Patients and methods:The detection of germline variants affecting moderate- and high-penetrance cancer susceptibility genes (CSGs) by tumor-only sequencing was compared to clinical germline testing in 21 333 cancer patients who underwent tumor and germline testing using the Food and Drug Administration (FDA)-authorized Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay. Seven homologous recombination deficiency (HRD), two DNA damage response (DDR) and four mismatch repair (MMR) genes, as well as NF1, RB1 and TP53 were included in the analysis. FDA-authorized and New York State Department of Health-approved sequencing methods for germline, tumor/normal and tumor-only sequencing assays and analytical pipelines were employed.Results:In patients who underwent tumor and germline sequencing, as compared to clinical genetic testing, tumor-only sequencing failed to detect 10.5% of clinically actionable pathogenic germline variants in CSGs, including 18.8%, 12.8% and 7.3% of germline variants in MMR, DDR and HRD genes, respectively. The sensitivity for detection of pathogenic germline variants by tumor-only sequencing was 89.5%. Whilst the vast majority of pathogenic germline exonic single-nucleotide variants (SNVs) and small indels were detected by tumor-only sequencing, large percentages of germline copy number variants, intronic variants and repetitive element insertions were not detected.Conclusions:Tumor-only sequencing is adequate for the detection of clinically actionable germline variants, particularly for SNVs and small indels; however, a small subset of alterations affecting HRD, DDR and MMR genes may not be detected optimally. Therefore, for high-risk patients with negative tumor-only sequencing results, clinical genetic testing could be considered given the impact of these variants on therapy and genetic counseling.
Highlights
The detection of pathogenic germline variants in cancer patients enables genetic counseling, riskreducing measures, and familial screening, as well as impacts on the eligibility for genomically stratified clinical trials and the clinical use of targeted therapies.[1, 2] Deficiencies in DNA repair, including homologous recombination (HR), DNA damage response (DDR) and mismatch repair (MMR), have emerged as therapeutic targets,[3] and the detection of actionable germline variants in genes pertaining to these biological processes is crucial to guide therapeutic decision-making
We identified 1,306 pathogenic/likely pathogenic (P/LP) germline variants in blood or saliva samples affecting 16 moderate and high penetrance cancer susceptibility genes (CSGs) in 1,282 cancer patients. 8.9% (95CI=7.510.6%; 116/1,306) of the P/LP germline variants were technically not detected by tumor-only sequencing
When the identical criteria were applied to 20 additional cancer susceptibility genes on the MSK-IMPACT panel with moderate penetrance and/or
Summary
The detection of pathogenic germline variants in cancer patients enables genetic counseling, riskreducing measures, and familial screening, as well as impacts on the eligibility for genomically stratified clinical trials and the clinical use of targeted therapies.[1, 2] Deficiencies in DNA repair, including homologous recombination (HR), DNA damage response (DDR) and mismatch repair (MMR), have emerged as therapeutic targets,[3] and the detection of actionable germline variants in genes pertaining to these biological processes is crucial to guide therapeutic decision-making. Tumor-only sequencing has been proposed as an assay to detect germline variants alongside somatic variants.[4] Whilst guidelines have been proposed to differentiate germline from somatic. Journal Pre-proof variants in tumor-only sequencing,[5] this distinction in the absence of a matched normal sample remains challenging,[4] based on technical and interpretational limitations inherent to this methodology.[6] Here, we sought to assess the suitability of tumor-only sequencing for the detection of pathogenic/likely pathogenic (P/LP) germline variants affecting cancer susceptibility genes (CSGs), as compared to clinical germline testing in a cohort of over 21,000 cancer patients, utilizing an FDA-authorized and New York State Department of Health-approved tumor/normal sequencing assay and analytical pipeline
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
