Abnormalities of the p53 MDM2 and DCC genes in human leiomyosarcomas.
In this study we have screened a series of 29 primary leiomyosarcomas for abnormalities of both the p53 gene and the MDM2 gene, which encodes a p53-associated protein. SSCP (single-strand conformation polymorphism) analysis and direct sequencing of polymerase chain reaction (PCR)-amplified DNA were used to establish that 6/29 tumours possessed point mutations of the p53 gene. Using a monoclonal antibody that recognises the p53 protein in immunohistochemical staining experiments, we observed overexpression of the p53 protein in five of the six tumours containing point mutations in the p53 gene. Southern analysis of tumour DNA revealed that 2/29 tumours demonstrated amplification of the MDM2 gene. When considered together, these results indicate that alterations in both the p53 gene and MDM2 gene are important in the development of a significant minority of leiomyosarcomas. In addition, we have demonstrated a significant association between the presence of abnormalities of the p53 gene or MDM2 genes in leiomyosarcomas and a more advanced clinicopathological stage (P = 0.03). We have also examined the role of the DCC tumour-suppressor gene in the development of human soft-tissue tumours in a variety of histological types. Except for evidence of a rearrangement in a single leiomyosarcoma cell line, SK-UT-1, we have found no direct evidence to support a role for mutation of the gene in the development of human soft-tissue tumours.
Patterson
H
H
Section of Molecular Carcinogenesis, Institute of Cancer Research, Belmont, Sutton, Surrey, UK.
Gill
S
S
Fisher
C
C
Law
M G
MG
Jayatilake
H
H
Fletcher
C D
CD
Thomas
M
M
Grimer
R
R
Gusterson
B A
BA
Cooper
C S
CS
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001483:Base Sequence; D004252:DNA Mutational Analysis; D017931:DNA Primers; D004317:Doxorubicin / Q000008:administration & dosage; D005091:Exons; D005500:Follow-Up Studies; D017353:Gene Deletion; D016163:Genes, DCC; D016158:Genes, p53; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007150:Immunohistochemistry; D007890:Leiomyosarcoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D015080:Mesna / Q000008:administration & dosage; D008875:Middle Aged; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics*; D009367:Neoplasm Staging; D009687:Nuclear Proteins; D017354:Point Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000096:biosynthesis
D017931:DNA Primers; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D015080:Mesna; D007069:Ifosfamide