Detection of biallelic loss of DNA repair genes in formalin-fixed, paraffin-embedded tumor samples using a novel tumor-only sequencing panel Journal Article

   


Authors: Glodzik, D.; Selenica, P.; Rogge, R. A.; Silverman, I. M.; Mandelker, D.; Harris, S.; Zhao, J.; Zinda, M.; Veloso, A.; Malani, N.; Riaz, N.; Koehler, M.; Daber, R. D.; Johnson, V.; Rimkunas, V.; Reis-Filho, J. S.
Article Title: Detection of biallelic loss of DNA repair genes in formalin-fixed, paraffin-embedded tumor samples using a novel tumor-only sequencing panel
Abstract: Patient selection for synthetic lethal–based cancer therapy may be improved by assessment of gene-specific loss of heterozygosity (LOH) and biallelic loss of function (LOF). This report describes SyNthetic lethal Interactions for Precision Diagnostics (SNiPDx), a targeted next-generation sequencing (NGS) panel for detection of LOH and biallelic LOF alterations in 26 target genes focused on DNA damage response pathways, in tumor-only formalin-fixed, paraffin-embedded (FFPE) samples. NGS was performed across all exons of these 26 genes and encompassed a total of 7632 genome-wide single-nucleotide polymorphisms on genomic DNA from 80 FFPE solid tumor samples. The Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing algorithm was optimized to assess tumor purity and copy number based on heterozygous single-nucleotide polymorphisms. SNiPDx demonstrated high sensitivity (95%) and specificity (91%) for LOH detection compared with whole genome sequencing. Positive agreement with local NGS-based testing in the detection of genetic alterations was 95%. SNiPDx detected 93% of biallelic ATM LOF mutations, 100% of ATM single-nucleotide variants and small insertions/deletions, and 100% of all ATM LOH status events identified by orthogonal NGS-based testing. SNiPDx is a novel, clinically feasible test for analysis of allelic status in FFPE tumor samples, which demonstrated high accuracy when compared with other NGS-based approaches in clinical use. © 2023 Association for Molecular Pathology and American Society for Investigative Pathology
Keywords: genetics; mutation; neoplasm; neoplasms; dna repair; formaldehyde; paraffin embedding; high throughput sequencing; high-throughput nucleotide sequencing; humans; human
Journal Title: Journal of Molecular Diagnostics
Volume: 25
Issue: 5
ISSN: 1525-1578
Publisher: Elsevier Science, Inc.  
Date Published: 2023-05-01
Start Page: 295
End Page: 310
Language: English
DOI: 10.1016/j.jmoldx.2023.02.004
PUBMED: 36944408
PROVIDER: scopus
PMCID: PMC10340082
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85158166737&doi=10.1016%2fj.jmoldx.2023.02.004&partnerID=40&md5=168ca8d0006fff0548fa29396d201523
Notes: Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Jorge Reis-Filho -- Export Date: 1 June 2023 -- Source: Scopus
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MSK Authors
  1. Nadeem Riaz
    415 Riaz
  2. Jorge Sergio Reis-Filho
    639 Reis-Filho
  3. Diana Lauren Mandelker
    178 Mandelker
  4. Pier Selenica
    189 Selenica
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