A recent study identifies a novel breast cancer predisposing mutation in the MCPH1 gene. This mutation was significantly more frequent among familial breast cancer cases (3,4%) than in the geographically matched healthy controls (0,4%).
The same mutation was also present in 1,4% (16/1150) of breast cancer cases not selected for or against family history of cancer or age at disease onset, and many of these cases turned out to have a family history of cancer as well. Besides breast cancer, one-third of the families with MCPH1 mutation exhibited also brain tumors and/or sarcomas.
Further studies showed that heterozygous MCPH1 mutation carriers exhibited a significant increase in genomic instability, and that the breast tumors of the mutation carriers had often lost the normal functional copy of MCPH1. These findings collectively establish MCPH1 as a novel breast cancer susceptibility gene.
The identified MCPH1 defect turned out to be a Finnish founder mutation, and based on its prevalence in the analyzed cohorts mutation carriers have at least moderate (3-fold), but potentially even high (up to eight-fold) risk for developing breast cancer.
The research, led by Adjunct Professor Katri Pylkäs and Professor Robert Winqvist at the University of Oulu, Finland, took advantage of recent technical and methodological advances by performing a massive parallel sequencing of hundreds of DNA damage response genes in Northern Finnish breast cancer cases with indication of hereditary disease susceptibility. The new mutation was discovered by PhD student Tuomo Mantere.
Breast cancer is the most common malignancy among women, and in at least 10% of all cases a strong inherited predisposition seems to be involved. The majority of the breast cancer predisposing genes identified to date are involved in the DNA damage response, indicating that specific pathways of DNA repair and checkpoint control are necessary for preventing malignancy in breast epithelial cells. The major susceptibility genes worldwide are BRCA1 and BRCA2 along with their interacting partner PALB2. Of these, PALB2 has also been identified by the researchers at the University of Oulu.
As the currently known moderate-to-high risk genes explain only about 30% of the familial and 5% of the total breast cancer incidence, the identification of new genetic susceptibility factors and understanding of their contribution to disease onset is imperative.
The identification of novel breast cancer susceptibility genes provides further tools for the clinical risk assessment of individuals with family burden of this disease, and could ultimately lead to improved prevention efforts and treatment.
This research was published in PLOS Genetics, January 28th 2016.
Last updated: 29.1.2016