title: Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in MCPH1 Associating with Hereditary Breast Cancer Susceptibility.
abstract: Breast cancer is strongly influenced by hereditary risk factors, a majority of which still remain unknown. Here, we performed a targeted next-generation sequencing of 796 genes implicated in DNA repair in 189 Finnish breast cancer cases with indication of hereditary disease susceptibility and focused the analysis on protein truncating mutations. A recurrent heterozygous mutation (c.904_916del, p.Arg304ValfsTer3) was identified in early DNA damage response gene, MCPH1, significantly associating with breast cancer susceptibility both in familial (5/145, 3.4%, P = 0.003, OR 8.3) and unselected cases (16/1150, 1.4%, P = 0.016, OR 3.3). A total of 21 mutation positive families were identified, of which one-third exhibited also brain tumors and/or sarcomas (P = 0.0007). Mutation carriers exhibited significant increase in genomic instability assessed by cytogenetic analysis for spontaneous chromosomal rearrangements in peripheral blood lymphocytes (P = 0.0007), suggesting an effect for MCPH1 haploinsufficiency on cancer susceptibility. Furthermore, 40% of the mutation carrier tumors exhibited loss of the wild-type allele. These findings collectively provide strong evidence for MCHP1 being a novel breast cancer susceptibility gene, which warrants further investigations in other populations.
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, Northern Finland Laboratory Centre NordLab Oulu, University of Oulu, Oulu, Finland.
authors.forename: Tuomo
authors.initials: T
authors.lastname: Mantere
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, Northern Finland Laboratory Centre NordLab Oulu, University of Oulu, Oulu, Finland.
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
authors.affiliation: Department of Pathology, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Saila
authors.initials: S
authors.lastname: Kauppila
authors.affiliation: Department of Surgery, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Mervi
authors.initials: M
authors.lastname: Grip
authors.affiliation: Department of Oncology, Oulu University Hospital and University of Oulu, Oulu, Finland.
authors.forename: Arja
authors.initials: A
authors.lastname: Jukkola-Vuorinen
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, Northern Finland Laboratory Centre NordLab Oulu, University of Oulu, Oulu, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Tervasmäki
authors.affiliation: Laboratory of Genetics, Northern Finland Laboratory Centre NordLab Oulu, Oulu, Finland.
authors.forename: Katrin
authors.initials: K
authors.lastname: Rapakko
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, Northern Finland Laboratory Centre NordLab Oulu, University of Oulu, Oulu, Finland.
authors.forename: Katri
authors.initials: K
authors.lastname: Pylkäs
mesh_terms: D000328:Adult; D017668:Age of Onset; D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree
chemical_list: D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins
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