Gallbladder carcinoma; The identification of the molecular and genetic mechanisms.
Gallbladder carcinoma is a rare, complex form of cancer. The prognosis of patients with gallbladder carcinoma is poor due to late diagnosis and limited treatment options. Little is known about the cause, risk factors and possible treatments for gallbladder carcinoma. Better understanding of the histological and molecular background of gallbladder cancer can lead to the development of new biomarkers for timely diagnostics and grasping points for treatment with targeted therapies.
Figure 1: HER2 Signaling. Human epidermal growth factor receptors, EGFR (HER1), HER2, HER3, and HER4, are receptor tyrosine kinases that play a role in cell growth,-survival, and differentiation. Dimerization and subsequent phosphorylation of the receptors ensures the activation of two main pathways ( PI3K/AKT and RAF/MEK/MAPK pathways). Activation of these two pathways ensures cancer cell survival, proliferation and progression of the cell cycle. Also displayed are available targeted inhibitors of specific parts of the pathway.
This research aims to map the molecular and histological characteristics of gallbladder carcinoma. In addition, we aim to identify specific molecular changes that may be potential targets for personalized therapies or that can be used as diagnostic or prognostic biomarkers. In a small part of gallbladder carcinomas, changes are found in genes for which targeted therapies are currently available (for example, HER2, Figure 1). This knowledge can contribute to both diagnostics and the development of effective (neo)adjuvant systemic therapy.
A link of databases of PALGA (the nationwide network and registry of histo- and cytopathology in the Netherlands) and of INKL (Netherlands Cancer Registry) will be used for the selection of a nationwide cohort of patients with gallbladder carcinoma. Anonymous patient and tumour characteristics will be collected in a new database and archival material is requested through the Dutch National Tissue Portal. Available resection specimens will be systematically reviewed and used for immunohistochemical and molecular experiments. Some histological characteristics that will be analyzed include growth pattern, differentiation rate, inflammation and desmoplastic reaction, (peri)neural, vascular and lymphatic invasion. In addition, using immunohistochemistry the expression of proteins that may play a role in the development of gallbladder cancer will be analyzed. Finally, the molecular background of a subset of specimens will be studied by means of whole exome sequencing, a technique by which all protein-coding areas of the genome of a tumour can be analyzed (Figure 2). These results will be validated by targeted resequencing of specific genomic abberations in a larger cohort of gallbladder carcinoma resection specimens.
Figure 2: The principle of Whole Exome Sequencing. Genomic (tumor) DNA is isolated and cut into small fragments. By means of specific hybridization, only the protein-coding areas (i.e. the exome) are isolated from the DNA pool. These regions are amplified and sequenced after which analysis takes place to identify tumor-specific changes in the DNA sequence.
This study will provide more insight into the complex molecular background of gallbladder carcinoma. This knowledge will contribute to the identification of biomarkers and new treatment options involving targeted therapies. Ultimately, these efforts will contribute to an improved prognosis for patients with this rare form of cancer, for which therapeutic options are currently limited.