The main aim of research in this section is to identify the role of genetic variation in causing heritable or familial forms of cancer. It includes research to discover new genes involved in this predisposition, as well as research to unravel the functional impact of genetic variation on protein function and its connection to cancer predisposition. The functional work includes in vitro models (cell lines) as well as mouse models. In terms of cancer types, our research focuses on breast cancer and paragangliomas.
Breast cancer is the most common type of cancer among women in the Netherlands, with a cumulative lifetime risk of around 10%. A number of risk factors for breast cancer have been established, of which family history remains one of the strongest. Known susceptibility genes (e.g., BRCA1, BRCA2, p53, ATM, CHEK2) account for approximately 25% of the familial risk of breast cancer. The residual genetic variance may be due to the combined action of rare variants that confer high- to moderate risks, and common variants that confer low risks. Ultimately, genetic risk profiling may improve the cost-benefit of breast cancer screening by targeting it to those who most urgently need it.
The present research programs in this unit are:
• Genome-wide sequence analyses of familial non-BRCA1/2 breast cancer
• Association studies to reveal the involvement of genetic variants in breast cancer susceptibility
• Search for genes that may modify the cancer risks conferred by BRCA1 and BRCA2
• Analysis of variants of uncertain clinical significance in BRCA1, BRCA2 and other breast cancer susceptibility genes to determine their associated cancer risk
• Development of risk prediction models incorporating genetic and lifestyle risk factors to determine individual breast cancer risk
Head and neck paraganglioma is a rare and generally benign tumor of the parasympathetic nervous system, chiefly affecting the carotid body. Pheochromocytomas are closely related tumors of the sympathetic nervous system, mainly occurring in the adrenal gland.
Interest in these syndromes has led to our focus on the genes encoding succinate dehydrogenase (SDH) and associated proteins. SDH is a mitochondrial enzyme complex with dual functions in the tricarboxylic acid cycle (TCA) and in the respiratory chain, as complex II. All subunits of SDH, including SDHA, SDHB, SDHC, and SDHD, in addition to the accessory factor SDHAF2, are now known to be involved in paraganglioma.
Together with the highly tissue-specific occurrence of these tumors, another remarkable feature of two of these genes, SDHD and SDHAF2, is the inheritance pattern. Genetic mutations in either of these genes can be passed via either parent, but tumors will only occur when a child inherits the mutation from the father.
Our past contributions to paraganglioma research include the first recognition of the ‘imprinted’ pattern of inheritance of the tumor, the identification of the first gene involved in head and neck paraganglioma – SDHD, and establishing the identity and clinical relevance of SDHAF2.
The ongoing research lines in this unit are:
• Understanding the role of SDHD and the tricarboxylic acid cycle in paraganglioma tumor formation
• Searching for new paraganglioma genes
• Understanding the parent-of-origin dependent inheritance of paragangliomas
• Development of novel paraganglioma-related mouse models
• Development of novel paraganglioma-related cell lines
• Maintaining the TCAC Gene Mutation Database, an online database of all mutations involved in paraganglioma