Analysis of p73 and p53 gene deletions in multiple myeloma

Abstract

Recently, p73, a protein with structural and functional similarities to p53, an extensively studied tumor suppressor gene, has been cloned. After being mapped to the chromosomal region 1p35-1p36, it has been postulated to act as a tumor suppressor gene, too, as this region is altered in several human malignancies. Deletions of the short arm of chromosome 1 have frequently been described in multiple myeloma (MM) whereas structural abnormalities of the 17p13 region including p53 are rare events in this disease. Since it has been proposed that especially neoplasias lacking p53 alterations might show a loss of heterozygosity at 1p35-1p36, we studied the frequency of p53 and p73 deletions in bone marrow mononuclear cells of 68 patients with MM, two patients with monoclonal gammopathy of undetermined significance and four patients with plasma cell leukemia. Dual-color fluorescence in situ hybridization (FISH) for p53 and p73 was performed using commercially available DNA probes for 17p13.3 and the microsatellite marker D1Z2, respectively. Centromeric DNA probes served to distinguish gene deletions from whole chromosome losses. In contrast to recently published FISH results, we only detected heterozygous p53 deletions in eight out of the 74 patients, three of them showing a monosomy 17. Heterozygous deletions of the D1Z2 region at 1p36 were found in six cases with one patient having a monosomy 1. Neither homozygous deletions of either chromosomal region nor nullisomies 1 or 17 could be detected. These results argue against a major role of p73 deletions in MM. As MM patients with 1p structural abnormalities have a significantly poorer survival rate than those with normal karyotypes, the role of other putative tumor suppressor genes located at the chromosomal region 1p36 in the pathogenesis of MM has to be determined.

Selective Pharmacologic Activation of the p53-Dependent Pathway as a Therapeutic Strategy for Hematologic Malignancies

“…These analyses are in good agreement with genetic and cytogenetic studies, that generally imply p53 defects in about 10% of medullary myeloma cases, but report higher incidences for patients with plasma cell leukemia. [17][18][19][20] Our observations confirm the target specificity of nutlin-3a and clearly demonstrate the p53 dependence of the observed biological effects. These experiments suggest that the downstream components of the p53 pathway appear to be at least partially intact in more than 90% of primary medullary MM cases.…”

Comparison between Conventional Cytogenetics and Interphase Fluorescence in situ Hybridization (FISH) for Patients with Multiple Myeloma

“…7,15) In most of the previous FISH series, the incidence of p53 deletion among the newly diagnosed patients was in the range of 5% to 10%. 5,21,22) However, functional loss of the gene is present in up to 40% of patients with advanced MM and also in more than 60% of the human myeloma cell lines, which points to this abnormality as a marker of tumor progression. 23) Deletion of the p53 gene locus was identified by FISH is a predictor of shorter survival in several previous studies, and this was independent of the mode of treatment (conventional chemotherapy or high-dose chemotherapy).…”

Genetics and Cytogenetics of Multiple Myeloma

“…p53 inactivation by either deletion or mutation seems to be a rare event in MM, and is restricted mostly to the late stages of disease progression (136,137). Deletions of 17p13 are detectable in 10% of patients and are associated with a shorter survival (53,136).…”