Retrospective NGS Study in High-risk Hereditary Cancer Patients at Masaryk Memorial Cancer Institute

Czech version

Authors: E. Macháčková; J. Hazova; E. Sťahlová Hrabincová; P. Vašíčková; M. Navratilova; M. Svoboda; L. Foretová
Authors‘ workplace: Oddělení epidemiologie a genetiky nádorů, Masarykův onkologický ústav, Brno
Published in: Klin Onkol 2016; 29(Supplementum 1): 35-45
Category: Original Articles
doi: https://doi.org/10.14735/amko2016S35

Overview

Background:
Currently, more than 200 hereditary cancer syndromes have been described, yet, in most countries genetic testing is restricted to a narrow spectrum of genes within a limited group of people tested.

Methods:
For this retrospective study we used the TruSight cancer panel (Illumina) – NGS panel targeting 94 cancer predisposition genes in order to analyze 50 high-risk cancer patients with significant personal and family history of cancer who did not carry mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6, TP53 or APC genes. All pathogenic and potentially pathogenic mutations detected by NGS technology have been confirmed by Sanger sequencing.

Results:
There were several deleterious (frame-shift/nonsense) mutations detected in ATM, BAP1, FANCC, FANCI, PMS2, SBDS, ERCC2, RECQL4 genes. Various pathogenic or potentially pathogenic (missense, predicted splice site, in-frame insertion/deletion) mutations were detected in ATM, BRIP1, CDH1, CHEK2, ERCC2, ERCC3, ERCC4, FANCA, MC1R, MEN1, MRE11A, MUTYH, PALB2, RAD51C, RET, SDHB, STK11. These mutations affect highly conserved protein domains and affect their function as proved by the available functional assays. They were confirmed to be pathogenic as an „Parent No2 “ in serious recessive diseases such as Ataxia telangiectasia or Fanconi anemia. The clinical significance of the majority of detected missense variants still remains to be identified.

Conclusion:
Moderate or low penetrance variants are of limited clinical importance. Panel genetic testing in high-risk individuals with cancer provides important information concerning the cause of the investigated cancer, and may assist in the risk assesment and optimal management of the cancer, as well as in further preventive care.

Key words:
hereditary cancer syndromes – hereditary breast and ovarian cancer syndrome – hereditary nonpolyposis colorectal cancer – high-throughput DNA sequencing – TruSight cancer panel – MiSeq

This work was supported by MH CZ – DRO (MMCI, 00209805) and by the State budget project of CR (OP VaVpI – RECAMO CZ.1.05/2.1.00/03.0101).

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted:
20. 8. 2015

Accepted:
22. 9. 2015

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