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.
Highlights
Breast cancer is the most common malignancy among women, and the contribution of hereditary susceptibility to its development has been well recognized
We show here that this recurrent mutation significantly associates with breast cancer susceptibility, and that MCPH1 has an integral role in the maintenance of genomic instability and acts as a tumor suppressor in breast cancer
The targeted next-generation sequencing revealed a recurrent deletion in the MCPH1 gene in 3/189 of the analyzed patients, these carriers being negative for any other known breast cancer associated gene mutations
Summary
Breast cancer is the most common malignancy among women, and the contribution of hereditary susceptibility to its development has been well recognized. As the currently known moderate-to-high risk genes explain only 30% of the familial and 5% of the total breast cancer incidence [1,2,3], the identification of new genetic susceptibility factors and understanding of their contribution to disease onset is imperative For this purpose we have performed a targeted next-generation sequencing of altogether 796 genes involved in diverse DNA repair signaling pathways in individuals with indication of hereditary disease susceptibility, originating from the genetically isolated Northern Finnish population. Based on their strong prior evidence for breast cancer association, the analysis was focused on protein truncating mutations, which were evaluated for cancer association by case-control comparisons. We show here that this recurrent mutation significantly associates with breast cancer susceptibility, and that MCPH1 has an integral role in the maintenance of genomic instability and acts as a tumor suppressor in breast cancer
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