Allelic losses from chromosome 17 in human osteosarcomas

Abstract

Genetic alterations of chromosome 17 have been reported to occur frequently both in human sporadic and familial malignancies. The present study was undertaken to explore the possible involvement of chromosome 17 genes including TP53 and the breast cancer susceptibility sarcoma. Fifteen patients were screened by polymerase chain reaction (PCR) for loss of heterozygosity (LOH) using four highly polymorphic markers. Loss of heterozygosity at the TP53 locus was detected in 40% (6/15) of informative cases while it was 14% (2/14) at the locus of thyroid hormone receptor alpha (THRA1), 21% (3/14) at the D17S855 locus intragenic to BRCA1 and 27% (4/15) at the D17S579 locus. In 53% of the cases studied at least one locus on chromosome 17 was affected by LOH. In our panel, the overall LOH frequency on 17p and 17q was observed to be 40% (6/15) and 27% (4/15), respectively. Comparison of LOH frequencies with clinical and prognostic features revealed significant correlation only with tumor recurrence. Our results confirm that the role of the TP53 tumor suppressor gene is important in the pathogenesis of sporadic osteosarcoma and suggest that 17q12-21 region abnormalities may be involved in the development and/or progression of this tumor.

Osteosarcoma Development and Stem Cell Differentiation

“…TP53 encodes a transcription factor and regulates genes involved in cell cycle, DNA damage response, and apoptosis [40,69,87,126]. Alterations in TP53 observed in OS tumors consisted of point mutations (20%-30%, mostly missense mutations), gross gene rearrangements (10%-20%), and allelic loss (75%-80%) [3,20,28,119,152,162,163,169,170,184,186,199,206,214,221,227,236,237,241,249,271]. The association of TP53 with OS is further supported by the high risk of OS in patients with the Li-Fraumeni syndrome, an autosomal dominant disorder characterized by a germline mutation of TP53 [128,144,145,194,223].…”

Cytogenetics and Molecular Biology of Osteosarcoma

“…Point mutations of the p53 gene are predominantly missense mutations, whose products can presumably form heterodimers with, and inactivate, normal p53 molecules (Ladanyi and Gorlick, 2000). Many reports have identified abnormalities of the p53 gene in osteosarcoma, with frequencies of up to 50% of cases (Guo et al, 1996;Lonardo et al, 1997;Masuda et al, 1987;Miller et al, 1996;Sztan et al, 1997). Further evidence of the association of p53 with osteosarcoma is provided by the high risk of bone sarcomas in patients with the Li-Fraumeni syndrome who have a germline mutation of p53 (Li et al, 1988;Srivastava et al, 1990).…”

Monoallelic deletion of the p53 gene through chromosomal translocation in a small cell osteosarcoma

“…BRCA1 is implicated in the transcriptional regulation of DNA damage-inducible genes that function in cell cycle arrest. It is interesting to note that loss of heterozygosity at the BRCA1 gene locus has been demonstrated in 21% of sporadic osteosarcomas, suggesting that inactivation of BRCA1 may play a role in the development and/or progression of sporadic osteosarcoma [24].…”