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Potentially pathogenic germline CHEK2 c.319+2T>A among multiple early-onset cancer families

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Abstract

To study the potential contribution of genes other than BRCA1/2, PTEN, and TP53 to the biological and clinical characteristics of multiple early-onset cancers in Norwegian families, including early-onset breast cancer, Cowden-like and Li-Fraumeni-like syndromes (BC, CSL and LFL, respectively). The Hereditary Cancer Biobank from the Norwegian Radium Hospital was used to identify early-onset BC, CSL or LFL for whom no pathogenic variants in BRCA1/2, PTEN, or TP53 had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by our in-house designed TruSeq amplicon-based assay for targeted sequencing. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the more likely to affect splicing were experimentally analyzed by minigene assay. We identified a CSL individual carrying a variant in CHEK2 (c.319+2T>A, IVS2), here considered as likely pathogenic. Out of the five VUS (BRCA2, CDH1, CHEK2, MAP3K1, NOTCH3) tested in the minigene splicing assay, only NOTCH3 c.14090C>T (p.Ser497Leu) showed a significant effect on RNA splicing, notably by inducing partial skipping of exon 9. Among 13 early-onset BC, CSL and LFL patients, gene panel sequencing identified a potentially pathogenic variant in CHEK2 that affects a canonical RNA splicing signal. Our study provides new information on genetic loci that may affect the risk of developing cancer in these patients and their families, demonstrating that genes presently not routinely tested in molecular diagnostic settings may be important for capturing cancer predisposition in these families.

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Abbreviations

ACMG:

American College of Medical Genetics and Genomics

BC:

Breast cancer

CS:

Cowden syndrome

CRC:

Colorectal cancer

CSL:

Cowden syndrome like

LF:

Li-Fraumeni syndrome

LFL:

Li-Fraumeni like syndrome

MMR:

Mismatch repair genes

NGS:

Next generation sequencing

SNP:

Single nucleotide polymorphism

SNVs:

Single-nucleotide variants

VUS:

Variants of unclassified significance

WT:

Wild type

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Acknowledgements

We thank the included families for their participation and contribution to this study.

Funding

This work was supported by the Radium Hospital Foundation (Oslo, Norway), Helse Sør-Øst (Norway), the French Association Recherche contre le Cancer (ARC), the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (Gefluc), the Association Nationale de la Recherche et de la Technologie (ANRT, CIFRE PhD fellowship to H.T.) and by the OpenHealth Institute.

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Authors and Affiliations

  1. Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

    Mev Dominguez-Valentin, Sigve Nakken, Daniel Vodak, Per Olaf Ekstrøm, Pål Møller & Eivind Hovig

  2. Normandy Centre for Genomic and Personalized Medicine, Inserm-U1245, UNIROUEN, Normandie Univ, Rouen, France

    Hélène Tubeuf & Alexandra Martins

  3. Interactive Biosoftware, Rouen, France

    Hélène Tubeuf

  4. Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Ziemssenstr. 1, Munich, Germany

    Anke M. Nissen, Monika Morak & Elke Holinski-Feder

  5. MGZ—Medizinisch Genetisches Zentrum, Munich, Germany

    Anke M. Nissen, Monika Morak & Elke Holinski-Feder

  6. Department of Human Medicine, Universität Witten/Herdecke, Witten, Germany

    Pål Møller

  7. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

    Pål Møller

  8. Department of Informatics, University of Oslo, Oslo, Norway

    Eivind Hovig

  9. Instituteof Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway

    Eivind Hovig

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  1. Mev Dominguez-Valentin
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  2. Sigve Nakken
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  3. Hélène Tubeuf
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Correspondence to Mev Dominguez-Valentin.

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Dominguez-Valentin, M., Nakken, S., Tubeuf, H. et al. Potentially pathogenic germline CHEK2 c.319+2T>A among multiple early-onset cancer families. Familial Cancer 17, 141–153 (2018). https://doi.org/10.1007/s10689-017-0011-0

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