Pathogenesis and precision medicine in breast and ovarian cancers
In the last decade, large-scale next-generation sequencing of DNA and RNA allowed for a new comprehension of cancer. Each tumor is characterized by specific genomic alterations that include multiple gene mutations, amplifications and/or deletions. These cancer cells interact with different components of the tumor microenvironment. Our lab is focused on the correlation between these genomic alterations, the immune infiltrate and response to therapies in breast and ovarian cancers. We are committed to precision medicine by combining our knowledge about the genomic alterations of cancer cells and the immune composition of the tumor microenvironment in order to develop new therapies. We use digital pathology, laser capture microdissection, next-generation sequencing and multispectral immunohistochemistry to reach our goal. Currently, our main research focus is on BRCA1 and BRCA2 mutations.
Another major goal of our lab is the pathogenesis of ovarian cancer. We are investigating the cell of origin of different ovarian cancer histotypes in order to develop new screening tools of the “silent killer”.
The lab’s research is strongly oriented toward real world translation of these findings into diagnostic and therapeutic tools to improve the lives of cancer patients.
BRCA1/BRCA2 mutations in breast and ovarian cancer
Germline mutations of BRCA1/BRCA2 genes occur in up to 5% of breast cancer patients and 15% of ovarian cancers. These genes are major players in the repair of DNA double strand breaks. BRCA carriers have therefore increased sensitivity to DNA-damaging agents, such as platinum or PARP inhibitors. We recently showed a correlation between the BRCA2 genotype and response to platinum in ovarian cancer patients. Only BRCA2 carriers, harboring mutations located in the RAD51-binding domain (RAD51-BD), have prolonged treatment-free intervals and longer survival, whereas the other BRCA2 carriers did not show a survival benefit. We are currently investigating the impact of BRCA mutations on toxicity and response to chemotherapy in breast cancer patients.
Pathogenesis of high grade serous ovarian carcinoma
High-grade serous ovarian carcinoma (HGSOC) is the most frequent and most lethal subtype of ovarian cancer. It is mainly diagnosed at advanced stages. In the last decade, compelling data suggested that the cell origin of HGSOC is the fallopian tube rather than the ovarian surface epithelium. Recently, we conducted extensive genomic analyses (whole-exome sequencing and copy number variation) of early tubal lesions of HGSOC (p53 signatures), serous tubal intraepithelial carcinomas (STICs), and invasive carcinomas of the fallopian tubes, ovaries and peritoneum. On average, the timing of progression from STICs to ovarian cancer was 6.5 years, with the cancer spreading to other areas quickly thereafter. Our work has provided important information about the development of HGSOC and has implications for prevention, early detection and therapeutic intervention of this disease.