dr. Mattias Van Heetvelde (PhD)
Research staff – Lab for cancer predisposition and precision oncology, Center for Medical Genetics Ghent (Faculty of Medicine and Health Sciences, UGent)
Principal investigator: prof. Kathleen Claes (PhD)
BRCA1 and BRCA2 are the most important breast and ovarian cancer predisposition genes. These two tumor suppressor genes are involved in several core pathways influencing genome stability and cell cycle progression. Both genes have long been presumed to follow the second hit hypothesis of Alfred Knudson; pathway functionality is lost when both gene alleles become inactivated. Individuals with a germline mutation in BRCA1 or BRCA2, already carry one inactivated allele in all cells of their body. During their life, inactivation of the second allele, or second hit, can occur. Conventionally, this inactivation happens through loss of heterozygosity in favor of the mutant allele, a point mutation in the remaining functional allele or hypermethylation of the promoter region of the remaining functional allele.
Research has shown that the occurrence of BRCA1 or BRCA2 inactivation through second hits is much more complex. There have been reports of tumors from germline carriers that did not show loss of gene functionality. Other tumors showed regions both with and without inactivation by second hits or with several second hit mechanisms occurring in the same tumor. The purpose of my work the last few years has been to unravel the complexity of BRCA1/BRCA2 inactivation in breast and ovarian cancer. Furthermore, I investigate the possibility of post-transcriptional regulation by microRNA of BRCA1 or BRCA2 in tumors from germline carriers. These non-coding RNA molecules could theoretically contribute to the spectrum of BRCA1/BRCA2 inactivation in combination with conventional second hit mechanisms. Such mechanisms are potential targets for future therapeutics. By destabilizing regulatory networks that occur in tumor cells, but are absent in healthy cells, it is possible to target tumor cell populations specifically. Understanding DNA repair and genomic stability more clearly could also contribute to our understanding of therapy sensitivity/resistance (e.g. PARP-inhibitors).
For my research I use PCR-based techniques, second generation sequencing, long-read sequencing (Oxford Nanopore), immunohistochemistry, cell cultures, transient and stable ectopic expression protocols, etc. Furthermore, over the years I’ve gained a lot of expertise in data and statistical analyses and bioinformatics.
- PhD Fellowship – IWT scholarship; Center for Medical Genetics Ghent; Defended June 2019
- Master Bioscience engineering: Cell and gene biotechnology; Ghent University; Graduated with distinction in September 2013
- Bachelor Bioscience engineering; Ghent University; Graduated with distinction in June 2011
- Latin and Mathematics; Xaveriuscollege, Borgerhout; Graduated in June 2007
- ‘Accurate detection and quantification of (epi-)genetic second hits in BRCA1/2- associated hereditary breast and ovarian cancer reveals multiple co-acting second hits.’ Cancer Letters, 2018 (PMID: 29580810)
- ‘Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores. Journal of Clinical Oncology, 2017 (PMID: 28448241)
- ‘Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.’ Human Mutation, 2018 (PMID: 29446198)
- ‘Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.’ Nat. Genetics, 2017 (PMID: 28346442)