Asbestos, chromosomal deletions, and tumor suppressor gene alterations in human malignant mesothelioma.
Exposure to the carcinogen asbestos is considered to be a major factor contributing to the development of most malignant mesotheliomas (MMs). We highlight the role of asbestos in MM and summarize cytogenetic and molecular genetic findings in this malignancy. The accumulation of numerous clonal chromosomal deletions in most MMs suggests a multistep process of tumorigenesis, characterized by the loss and/or inactivation of multiple tumor suppressor genes (TSGs). Cytogenetic and loss of heterozygosity (LOH) analyses of MMs have demonstrated frequent deletions of specific sites within chromosome arms 1p, 3p, 6q, 9p, 13q, 15q, and 22q. Furthermore, TSGs within two of these regions, i.e., p16/CDKN2A-p14ARF at 9p21 and NF2 at 22q12, are frequently altered in MMs. Homozygous deletion appears to be the major mechanism affecting p16/CDKN2A-p14ARF, whereas inactivating mutations coupled with allelic loss occur at the NF2 locus. Finally, recent studies have demonstrated the presence and expression of simian virus 40 (SV40) in many MMs. SV40 large T antigen has been shown to inactivate the TSG products Rb and p53, suggesting the possibility that asbestos and SV40 could act as cocarcinogens in MM. The frequent occurrence of homozygous deletions of p16/CDKN2A-p14ARF and the ability of SV40 Tag to bind TSG products suggest that perturbations of both Rb- and p53-dependent growth-regulatory pathways are critically involved in the pathogenesis of MM.
Murthy
S S
SS
Program of Molecular Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Testa
J R
JR
D001194:Asbestos / Q000009:adverse effects*; D002273:Carcinogens / Q000009:adverse effects*; D002869:Chromosome Aberrations / Q000139:chemically induced*; D025063:Chromosome Disorders; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor / Q000187:drug effects*; D006801:Humans; D008654:Mesothelioma / Q000139:chemically induced* / Q000235:genetics; D010997:Pleural Neoplasms / Q000139:chemically induced* / Q000235:genetics
D002273:Carcinogens; D019941:Cyclin-Dependent Kinase Inhibitor p16; D001194:Asbestos