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Somatic Tumor Variant Filtration Strategies to Optimize Tumor-Only Molecular Profiling Using Targeted Next-Generation Sequencing Panels
- Source :
- The Journal of Molecular Diagnostics. 21:261-273
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- A common approach in clinical diagnostic laboratories to variant assessment from tumor molecular profiling is sequencing of genomic DNA extracted from both tumor (somatic) and normal (germline) tissue, with subsequent variant comparison to identify true somatic variants with potential impact on patient treatment or prognosis. However, challenges exist in paired tumor-normal testing, including increased cost of dual sample testing and identification of germline cancer predisposing variants. Alternatively, somatic variants can be identified by in silico tumor-only variant filtration precluding the need for matched normal testing. The barrier to tumor-only variant filtration is defining a reliable approach, with high sensitivity and specificity to identify somatic variants. In this study, we used retrospective data sets from paired tumor-normal samples tested on small (48 gene) and large (555 gene) targeted next-generation sequencing panels, to model algorithms for tumor-only variants classification. The optimal algorithm required an ordinal filtering approach using information from variant population databases (1000 Genomes Phase 3, ESP6500, ExAC), clinical mutation databases (ClinVar), and information on recurring clinically relevant somatic variants. Overall the tumor-only variant filtration strategy described in this study can define clinically relevant somatic variants from tumor-only analysis with sensitivity of 97% to 99% and specificity of 87% to 94%, and with significant potential utility for clinical laboratories implementing tumor-only molecular profiling.
- Subjects :
- 0301 basic medicine
Somatic cell
In silico
Population
Computational biology
Biology
DNA sequencing
Germline
Pathology and Forensic Medicine
03 medical and health sciences
0302 clinical medicine
Neoplasms
Humans
1000 Genomes Project
education
Gene
Retrospective Studies
education.field_of_study
Computational Biology
High-Throughput Nucleotide Sequencing
genomic DNA
030104 developmental biology
030220 oncology & carcinogenesis
Mutation
Molecular Medicine
Algorithms
Subjects
Details
- ISSN :
- 15251578
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- The Journal of Molecular Diagnostics
- Accession number :
- edsair.doi.dedup.....d3e88f5e4e8b4b5564393c333677cde4