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BMC Med Genet. 2018 Feb 20;19(1):26. doi: 10.1186/s12881-018-0533-9.

Identification of genetic variants for clinical management of familial colorectal tumors.

Author information

1
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. mev_dv@yahoo.com.
2
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
3
Inserm-U1245, UNIROUEN, Normandie Univ, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.
4
Interactive Biosoftware, Rouen, France.
5
Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Ziemssenstr. 1, Munich, Germany.
6
MGZ-Medizinisch Genetisches Zentrum, Munich, Germany.
7
Department of Human Medicine, Universität Witten, Herdecke, Germany.
8
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
9
Department of Informatics, University of Oslo, Oslo, Norway.
10
Institute of Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway.

Abstract

BACKGROUND:

The genetic mechanisms for families who meet the clinical criteria for Lynch syndrome (LS) but do not carry pathogenic variants in the mismatch repair (MMR) genes are still undetermined. We aimed to study the potential contribution of genes other than MMR genes to the biological and clinical characteristics of Norwegian families fulfilling Amsterdam (AMS) criteria or revised Bethesda guidelines.

METHODS:

The Hereditary Cancer Biobank of the Norwegian Radium Hospital was interrogated to identify individuals with a high risk of developing colorectal cancer (CRC) for whom no pathogenic variants in MMR genes had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by using our in-house designed TruSeq amplicon-based assay for targeted sequencing. RNA splicing- and protein-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as likely to affect splicing were experimentally analyzed by resorting to minigene assays.

RESULTS:

We identified a patient who met the revised Bethesda guidelines and carried a likely pathogenic variant in CHEK2 (c.470 T > C, p.I157T). In addition, 25 unique VUS were identified in 18 individuals, of which 2 exonic variants (MAP3K1 c.764A > G and NOTCH3 c.5854G >A) were analyzed in the minigene splicing assay and found not to have an effect on RNA splicing.

CONCLUSIONS:

Among high-risk CRC patients that fulfill the AMS criteria or revised Bethesda guidelines, targeted gene sequencing identified likely pathogenic variant and VUS in other genes than the MMR genes (CHEK2, NOTCH3 and MAP3K1). Our study suggests that the analysis of genes currently excluded from routine molecular diagnostic screens may confer cancer susceptibility.

KEYWORDS:

CHEK2; Gene panel testing; Lynch syndrome; RNA splicing mutations

PMID:
29458332
PMCID:
PMC5819082
DOI:
10.1186/s12881-018-0533-9
[Indexed for MEDLINE]
Free PMC Article

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