Other frequent abnormalities include structural rearrangement of 1p, 3p, 9p and 6q chromosome arms.Common gene abnormalities in mesothelioma cell lines include deletion of the tumor suppressor genes:
Neurofibromatosis type 2 at 22q12
P16INK4A
P14ARFAsbestos has also been shown to mediate the entry of foreign DNA into target cells. Incorporation of this foreign DNA may lead to mutations and oncogenesis by several possible mechanisms:
Inactivation of tumor suppressor genes
Activation of oncogenes In tumor cells, these genes are often mutated, or expressed at high levels. Activation of proto-oncogenes due to incorporation of foreign DNA containing a promoter region
Activation of DNA repair enzymes, which may be prone to error
Activation of telomerase
Prevention of apoptosisSeveral genes are commonly mutated in mesothelioma, and may be prognostic factors. These include epidermal growth factor receptor (EGFR) and C-Met, receptor tyrosine kinases which are overexpressed in many mesotheliomas. Some association has been found with EGFR and epithelioid histology but no clear association has been found between EGFR overexpression and overall survival. Expression of AXL receptor tyrosine kinase is a negative prognostic factor. Expression of PDGFRB is a positive prognostic factor. In general, mesothelioma is characterized by loss of function in tumor suppressor genes, rather than by an overexpression or gain of function in oncogenes.As an environmentally triggered malignancy, mesothelioma tumors have been found to be polyclonal in origin, by performing an X-inactivation based assay on epitheloid and biphasic tumors obtained from female patients.
Deposition of asbestos fibers in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fiber can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques. The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibers from the lung are transported to the abdomen and associated organs via the lymphatic system. Additionally, asbestos fibers may be deposited in the gut after ingestion of sputum contaminated with asbestos fibers.Pleural contamination with asbestos or other mineral fibers has been shown to cause cancer. Long thin asbestos fibers (blue asbestos, amphibole fibers) are more potent carcinogens than "feathery fibers" (chrysotile or white asbestos fibers). However, there is now evidence that smaller particles may be more dangerous than the larger fibers. They remain suspended in the air where they can be inhaled, and may penetrate more easily and deeper into the lungs. "We probably will find out a lot more about the health aspects of asbestos from [the World Trade Center attack], unfortunately," said Dr. Alan Fein, chief of pulmonary and critical-care medicine at North Shore-Long Island Jewish Health System.Mesothelioma development in rats has been demonstrated following intra-pleural inoculation of phosphorylated chrysotile fibers. It has been suggested that in humans, transport of fibers to the pleura is critical to the pathogenesis of mesothelioma.