Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in MCPH1 Associating with Hereditary Breast Cancer Susceptibility

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. © 2016 mantere et al.