Thymoma: Biology

The biology of thymic malignancies is poorly understood. Studies investigating one or a small number of genes, that are involved in cancer development of other tumors, are available, to date. These studies have established EGFR and c-Kit mutations in a small subset of tumors. Clinical observations have confirmed that activating mutations in these genes are rare and this is responsible for the lack of activity of EGFR TKIs such as geftinib and c-Kit inhibitors such as imatinib. Mutations in p53 and methylation of p16 have also been described in a varying percentage of tumors, as well as upregulation of anti-apoptotic genes. However, all these descriptive studies have in common the relatively small number of samples that were investigated and the limited insight on the biology that they provide. Genome-wide studies have also been performed. Genetic alterations involving changes of large parts of chromosome 1 (1q copy number gains) and deletions of chromosome 6 have been established by traditional CGH over a decade ago. Use of array CGH has allowed us to narrow down areas of the genome that may be important for prognosis and potentially be involved in the progression of the disease. Overall type A thymomas according to the WHO classification, have very few changes in copy number, whereas thymic carcinoma and type B3 have common and recurrent copy number losses and gains in several areas of the genome. Gene expression arrays cluster thymomas according to WHO classification. A major limitation in these studies is the necessity to select areas in the tumor that have a significant epithelial tumoral component, and this leaves out a large proportion of thymomas that have large lymphocytic infiltration (WHO B1 and B2). We have recently started a large effort of RNA sequencing, exome sequencing and whole genome sequencing, and some of those results will be presented at this meeting. Functional studies in thymomas are severely hampered by the very limited number of cell lines and the absence of specific tumor models for the disease. Efforts should be made to develop tumor models that allow investigation of this tumor in more detail in the future.