Validation of CZECANCA (CZEch CAncer paNel for Clinical Application) for targeted NGS-based analysis of hereditary cancer syndromes

PLoS One. 2018 Apr 12;13(4):e0195761. doi: 10.1371/journal.pone.0195761. eCollection 2018.

Abstract

Background: Carriers of mutations in hereditary cancer predisposition genes represent a small but clinically important subgroup of oncology patients. The identification of causal germline mutations determines follow-up management, treatment options and genetic counselling in patients' families. Targeted next-generation sequencing-based analyses using cancer-specific panels in high-risk individuals have been rapidly adopted by diagnostic laboratories. While the use of diagnosis-specific panels is straightforward in typical cases, individuals with unusual phenotypes from families with overlapping criteria require multiple panel testing. Moreover, narrow gene panels are limited by our currently incomplete knowledge about possible genetic dispositions.

Methods: We have designed a multi-gene panel called CZECANCA (CZEch CAncer paNel for Clinical Application) for a sequencing analysis of 219 cancer-susceptibility and candidate predisposition genes associated with frequent hereditary cancers.

Results: The bioanalytical and bioinformatics pipeline was validated on a set of internal and commercially available DNA controls showing high coverage uniformity, sensitivity, specificity and accuracy. The panel demonstrates a reliable detection of both single nucleotide and copy number variants. Inter-laboratory, intra- and inter-run replicates confirmed the robustness of our approach.

Conclusion: The objective of CZECANCA is a nationwide consolidation of cancer-predisposition genetic testing across various clinical indications with savings in costs, human labor and turnaround time. Moreover, the unified diagnostics will enable the integration and analysis of genotypes with associated phenotypes in a national database improving the clinical interpretation of variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor*
  • Computational Biology / methods
  • DNA Copy Number Variations
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic Testing
  • High-Throughput Nucleotide Sequencing* / methods
  • High-Throughput Nucleotide Sequencing* / standards
  • Humans
  • INDEL Mutation
  • Male
  • Mutation
  • Neoplastic Syndromes, Hereditary / genetics*
  • Reproducibility of Results
  • Sensitivity and Specificity

Substances

  • Biomarkers, Tumor

Grant support

This study was supported by the grants of Ministry of Health (www.mzcr.cz) 15-27695A (JS), 15-28830A (ZK), 16-29959A (ZK), and DRO MMCI, 00209805 (LF), grants of Charles University (www.cuni.cz) PROGRES Q28/LF1 (ZK), and SVV2017/260367 (SK) and Ministry of Education, Youth and Sports (www.msmt.cz) project CZ.02.1.01/0.0/0.0/16_013/0001634 (SK).