Synapse - Comprehensive assessment of germline pathogenic variant detection in tumor-only sequencing

Comprehensive assessment of germline pathogenic variant detection in tumor-only sequencing Journal Article

Authors:	Terraf, P.; Pareja, F.; Brown, D. N.; Ceyhan-Birsoy, O.; Misyura, M.; Rana, S.; O'Reilly, E.; Carlo, M. I.; Aghajanian, C.; Liu, Y.; Derakhshan, F.; Jayakumaran, G.; Weigelt, B.; Walsh, M.; Stadler, Z.; Offit, K.; Ladanyi, M.; Robson, M.; Zehir, A.; Reis-Filho, J. S.; Mandelker, D.
Article Title:	Comprehensive assessment of germline pathogenic variant detection in tumor-only sequencing
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 21333 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.
Keywords:	olaparib; mutations; cancer; precision medicine; germline testing; tumor-only sequencing
Journal Title:	Annals of Oncology
Volume:	33
Issue:	4
ISSN:	0923-7534
Publisher:	Oxford University Press
Date Published:	2022-04-01
Start Page:	426
End Page:	433
Language:	English
ACCESSION:	WOS:000820214100009
DOI:	10.1016/j.annonc.2022.01.006
PROVIDER:	wos
PMCID:	PMC9172914
PUBMED:	35074424
Notes:	Article -- Source: Wos