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. 2021 Jan;15(1):80-90.
doi: 10.1002/1878-0261.12817. Epub 2020 Oct 22.

Tumor and germline next generation sequencing in high grade serous cancer: experience from a large population-based testing program

Melanie Care  1   2 , Jeanna McCuaig  2   3   4 , Blaise Clarke  5 , Sylvie Grenier  1   5 , Raymond H Kim  3   6 , Marjan Rouzbahman  5 , Natalie Stickle  5 , Marcus Bernardini  7 , Tracy L Stockley  1   5
Affiliations

Tumor and germline next generation sequencing in high grade serous cancer: experience from a large population-based testing program

Melanie Care et al. Mol Oncol. 2021 Jan.

Erratum in

Abstract

The aim of this study was to determine the prevalence of somatic and germline pathogenic variants (PVs) in high-grade serous cancer (HGSC) and to demonstrate the technical feasibility and effectiveness of a large-scale, population-based tumor testing program. It involved a retrospective review of genetic test results in 600 consecutive HGSC tumor samples and a subsequent comparison of germline and tumor results in a subset of 200 individuals. Tumor testing was successful in 95% of samples (570/600) with at least one BRCA1/2 PV identified in 16% (93/570) of cases. Among the 200 paired cases, BRCA1/2 PVs were detected in 38 tumors (19%); 58% were somatic (22/38); and 42% were germline (16/38). There was 100% concordance between germline and tumor test results. This is the largest series of BRCA1/2 testing in HGSC (tumor-only and paired cohorts), reported to date, and our data show that an effectively designed and validated population-based tumor testing program can be used to determine both treatment eligibility and hereditary cancer risk.

Keywords: BRCA1/BRCA2; germline variant; high-grade serous cancer; next-generation sequencing; somatic variant; tumor testing.

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Conflict of interest statement

Melanie Care has received speaker honoraria and travel support from AstraZeneca, Inc. Jeanna McCuaig has speaker honoraria and travel support from AstraZeneca, Inc., and speaker honoraria from Pfizer, Inc. Tracy L. Stockley has received funding for test development from AstraZeneca and honoraria for advisory board meetings. All other authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
BRCA1 and BRCA2 variants in tumor samples (n = 570): (A) A total of 158 BRCA1/2 variants were identified: 96 pathogenic variants (PVs) and 62 variants of uncertain significance (VUS); (B) types of pathogenic variants identified in tumor samples, stratified by gene (BRCA1 or BRCA2).
Fig. 2
Fig. 2
Variant allele fraction (VAF) of BRCA1/2 tumor variants. Comparison of VAF of PV versus VUS identified on tumor testing. A higher proportion of PVs were present at a VAF > 40% as compared to VUS (76% vs 56%).
Fig. 3
Fig. 3
Origin of BRCA1/2 pathogenic variants identified in paired cohort (n = 200). Results demonstrating the BRCA1/2 PV profile of paired tumor and germline samples. Negative—refers to samples carrying no variants or VUS; [G]—confirmed germline origin; [S]—confirmed somatic origin.
Fig. 4
Fig. 4
Variants detected in a paired tumor germline cohort. Direct comparison of paired tumor and blood analyses in incident versus prevalent cases. All variants detected through germline testing were identified in tumor samples. To determine somatic versus germline origin, the number of variants identified by germline testing is subtracted from the number of variants identified in tumors.
Fig. 5
Fig. 5
Tumor variant allele fraction (AF) of confirmed germline variants. Distribution of observed VAF in 32 confirmed germline sequence variants. Six germline variants, all VUS, were identified in tumors at VAF < 40%, whereas all germline PVs were present in tumors at VAF > 40%.
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