Potentially pathogenic germline CHEK2 c.319+2T>A among multiple early-onset cancer families.
Fam Cancer
; 17(1): 141-153, 2018 01.
Article
in En
| MEDLINE
| ID: mdl-28608266
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Hamartoma Syndrome, Multiple
/
Breast Neoplasms
/
Genetic Testing
/
Li-Fraumeni Syndrome
/
Mitochondrial Diseases
/
Checkpoint Kinase 2
Type of study:
Diagnostic_studies
/
Prognostic_studies
Limits:
Adult
/
Aged
/
Female
/
Humans
/
Middle aged
Country/Region as subject:
Europa
Language:
En
Journal:
Fam Cancer
Journal subject:
NEOPLASIAS
Year:
2018
Document type:
Article
Affiliation country:
Norway