Mutations of the tumor suppressor gene p53 in hepatocellular carcinomas are not limited to patients from geographic regions where the ingestion of aflatoxin is high.
We searched for possible mutations in the entire coding region of tumor suppressor gene p53 in primary human renal cell carcinomas using polymerase chain reaction and single-strand conformational polymorphism analysis of RNA.
Mutations changing the p53 coding sequence were found in 14 of 30 tumor samples (47%), while G:C to T:A transversions which are uncommon in other cancers such as colon cancer were the most frequently observed mutations, in agreement with an earlier report on non-small cell lung cancer in American patients.
We found no p53 mutations in the corresponding normal tissue from 19 patients whose tumors had p53 lesions, indicating that the mutations were all somatically acquired.
Nuclear p53 protein was observed in 16% of the 31 in situ carcinomas, 22% of the 172 sporadic carcinomas, 34% of the 50 tumors from patients with familial breast cancer, 52% of the 23 tumors from patients with the familial breast and ovarian cancer syndrome, and all three tumors from two patients with the Li-Fraumeni syndrome.
In order to facilitate more objective differential diagnosis of multiple hepatocellular carcinoma, we used the pattern of mutation of the p53 gene as a marker for each tumor nodule.
Although all the tumor cell lines express comparable levels of p53 RNA, only HTB31 and HTB32 contain high or detectable levels respectively of p53 protein.
The mutation frequency (46%) of the p53 gene in tumors carrying mutated ras genes was essentially the same as the overall frequency in lung cancers, suggesting that accumulation of mutations in these two genes in a tumor is a random phenomenon.
None of 19 tumors with a large copy number of HPV DNA sequences detectable by Southern blot analysis (more than 1 copy of HPV/2 to 10 cells) nor any of 7 tumors with undetectable HPV DNA sequences contained p53 gene mutations in the regions examined.(ABSTRACT TRUNCATED AT 400 WORDS)
Direct sequencing of the evolutionarily conserved regions of p53 (exons 5, 6, 7 and 8), where mutations have been commonly found in a variety of tumors, confirmed that only two hepatocellular carcinomas had mutations in p53, one a 6-bp deletion of codons 158 and 159 (exon 5) and the other a G to A transition at codon 286 (exon 8).
The c-myc-positive tumors had a significantly higher level of p53 expression, judged by PAb 1801 and PAb 240, than c-myc-negative tumors.For PAb 421, there was no difference.
Mutations of the p53 gene in tumour cells are associated with a slower turnover and subsequent accumulation of the protein in both nucleus and cytoplasm.
The mutations of the p53 gene in low grade tumors leads to a selective advantage in vivo and seems to be a critical step in the transformation from low grade to high grade gliomas.
Neither constitutional DNA nor DNA extracted from a retinoblastoma of the left eye of the patient contained the TP53 mutation, suggesting that the TP53 mutation in the osteosarcoma cells may represent a tumor-promoting mutation, which confers a selective growth advantage.
Classical examples are the Rb-1 gene associated with the development of retinoblastoma and the p53 gene, which is associated with a wider range of neoplasms, including breast cancer.
Immunoperoxidase studies performed with monoclonal antibodies to the p53 protein product showed focal nuclear expression in one of five of the original tumors while most cells grown in vitro and in the xenograft were positive.(ABSTRACT TRUNCATED AT 250 WORDS)
Loss of heterozygosity (LOH) was determined by Southern transfer analysis of somatic and tumor DNA from these same patients using polymorphic markers for various loci on chromosomes 10 and 17. p53 mutations were found in 7 of 25 glioblastomas (28%), in 5 of 14 anaplastic astrocytomas (36%) but in 0 of 6 low-grade astrocytomas. p53 mutations were found in 62% of patients with LOH on chromosome 17p.
Deletions of the 3p chromosome region and molecular alterations of the tumor suppressor genes RB1 and TP53, located, respectively, at 13q14 and 17p13, are well-documented in small cell lung cancer (SCLC).