Somatic genetic alterations in human malignant mesothelioma (Review)

A review of cytogenetic and molecular genetic findings in human malignant m esotheliomas (MMs) is presented. The complex profile of somatic genetic cha nges characteristic of MMs implicates a multistep process of tumorigenesis in this malignancy. In particular, the occurrence of multiple, recurrent cy togenetic deletions in MMs suggests that loss and/or inactivation of tumor suppressor genes (TSGs) are critical to the development and progression of such tumors. Karyotypic and comparative genomic hybridization analyses of M Ms have demonstrated frequent deletions of specific regions within chromoso me arms 1p, 3p, 6q, 9p, 15q and 22q, and subsequent loss of heterozygosity (LOH) studies have documented high frequencies of allelic loss from each of these chromosomal sites. Positional candidate gene approaches have identif ied TSGs within two of these regions, i.e., p16/CDKN2A at 9p21 and NF2 at 2 2q12, which are frequently altered in MMs. Homozygous deletions appear to b e the major mechanism affecting p16/CDKN2A, whereas inactivating mutations coupled with allelic loss occur at the NF2 locus. High density LOH analyses have pinpointed minimal regions of deletion in Ip, 3p, 6q, and 15q and are expected to facilitate efforts to identify putative TSGs at these location s which contribute to the pathogenesis of MMs.