Τίτλος:
Characterization and prevalence of two novel CHEK2 large deletions in Greek breast cancer patients
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Germline CHEK2 mutations confer increased cancer risk, for breast and other types, which is variable depending on the specific mutation. Of these, Large Genomic Rearrangements (LGRs) have been rarely reported; to date only eight LGRs have been published with just the Czech founder mutation, the deletion of exons 9 and 10, being molecularly characterized and studied extensively. The present study aimed to molecularly define and determine the contribution of two rare, apparently novel CHEK2 LGRs, among Greek breast cancer patients. These specifically involve a ~6 kb in-frame deletion of exons 2 & 3 that removes CHEK2’s FHA domain and a ~7.5 kb in-frame deletion of exon 6, which removes an α-helix of CHEK2’s kinase domain. The latter was identified in 5 out of 2355 (0.22%) patients tested, while haplotype analysis revealed a common disease-associated haplotype, suggesting a single common ancestor and a Greek founder. Although in-frame, this LGR is predicted to be damaging by a yeast-based functional assay and structure–function predictions. The present study highlights the existence of rare, population-specific, genomic events in a known breast cancer predisposing gene, which can explain a proportion of hereditary breast cancer. Identification of such mutation carriers is rather important since appropriate clinical actionability will be inferred. © 2018, The Author(s) under exclusive licence to The Japan Society of Human Genetics.
Συγγραφείς:
Apostolou, P.
Fostira, F.
Mollaki, V.
Delimitsou, A.
Vlassi, M.
Pentheroudakis, G.
Faliakou, E.
Kollia, P.
Fountzilas, G.
Yannoukakos, D.
Konstantopoulou, I.
Περιοδικό:
Journal of Human Genetics
Εκδότης:
Nature Publishing Group
Λέξεις-κλειδιά:
checkpoint kinase 2; checkpoint kinase 2; CHEK2 protein, human; microsatellite DNA, adult; aged; alpha helix; Article; breast cancer; cancer patient; cancer susceptibility; computer model; controlled study; exon; female; gene deletion; gene mutation; genetic predisposition; Greece; haplotype; human; major clinical study; middle aged; predictive value; prevalence; breast tumor; computer simulation; dna mutational analysis; gene deletion; gene rearrangement; genetic predisposition; genetics; male; metabolism; pathology; pedigree; Saccharomyces cerevisiae; single nucleotide polymorphism; structure activity relation; young adult, Adult; Aged; Breast Neoplasms; Checkpoint Kinase 2; Computer Simulation; DNA Mutational Analysis; Female; Gene Deletion; Gene Rearrangement; Genetic Predisposition to Disease; Greece; Haplotypes; Humans; Male; Microsatellite Repeats; Middle Aged; Pedigree; Polymorphism, Single Nucleotide; Prevalence; Saccharomyces cerevisiae; Structure-Activity Relationship; Young Adult
DOI:
10.1038/s10038-018-0466-3
