The molecular mechanisms of
oncogenesis in
mesothelioma involve the loss of negative regulators of cell growth including
p16(INK4a). Absence of expression of the
p16(INK4a) gene product is exhibited in virtually all
mesothelioma tumors and cell lines examined to date. Loss of
p16(INK4a) expression has also been frequently observed in more common
neoplasms such as
lung cancer as well. In a wide variety of these
malignancies, including
lung cancer,
p16(INK4a) expression is known to be inactivated by hypermethylation of the first exon. In a survey of ten
mesothelioma cell lines, one cell line (NCI-H2596) was identified as possessing loss of
p16(INK4a) gene product following gene methylation. This methylation in these
mesothelioma cells could be reversed, resulting in re-expression of
p16(INK4a)
protein, following the treatment of the cells with
cytidine analogs, which are known inhibitors of DNA methylation. In previous clinical trials in
mesothelioma, the
cytidine analog
dihydro-5-azacytidine (DHAC) has been found to induce clinical responses in approximately 17% of patients with
mesothelioma treated with this
drug, including prolonged complete responses. In addition, we identified evidence for methylation of
p16(INK4a) in three of 11 resected
mesothelioma tumor samples. When both cell lines and
tumors are combined, inactivation of
p16(INK4a) gene product expression following
DNA hypermethylation was found in four of 21 samples (19%). We are further exploring the clinical significance of inhibition of methylation in
mesothelioma by
cytidine analogs. This may provide a potential treatment target in some
mesothelioma tumors by inhibition of methylation.