p53 polymorphisms associated with mutations in and loss of heterozygosity of the p53 gene in male oral squamous cell carcinomas in Taiwan (original) (raw)
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Loss of heterozygosity in p53 gene found in oral squamous cell carcinoma patients of Pakistan
Pakistan Journal of Biochemistry and Molecular Biology, 2011
Abstract: Oral squamous cell carcinoma (OSCC) is the leading cause of death in the developing countries like Pakistan. The major risk factor for developing OSCC is the excessive chewing habit of paan (betel quid) chaliya (betel nut), tobacco, niswar (type of dipping tobacco, made from fresh tobacco leaves, calcium oxide, and wood ash) gutka (a preparation of crushed betel nut, tobacco and sweet or savory flavors) and manpuri (the powder of betel nut, tobacco and slaked lime). The p53 gene is the extensively studied tumor suppressor gene involved in the suppression of tumor. The germ line mutation/polymorphism of p53 gene has been reported to be involved in multiple steps of carcinogenesis. It has been reported that exon 4-9 were the hot spots of the mutation in the tumor suppressor gene. Mutagens can damage DNA and generate promutagenic lesions. This study aims to find out the loss of p53 gene functions due to mutation/polymorphism caused by genomic alteration and interaction with tobacco and its related ingredients in Pakistan. A total of 250 OSCC patient’s tissue and blood specimens were collected with informed consent from local hospitals of Karachi. The samples were compared with 250 age and sex matched controls. The OSCC was confirmed by histopathology of the tissue samples. Extraction of DNA from blood and tissue samples was carried out and 10 exons of p53 gene were amplified through polymerase chain reaction (PCR) by using forward and reverse primers. The amplified PCR products were checked by agarose gel electrophoresis, and PCR products were screened for mutation(s) by single stranded conformational polymorphism (SSCP). The PCR-SSCP analyses showing mobility shift bands indicated the single nucleotide mutation/polymorphism in tissue and blood samples of the patients. A single nucleotide change on SSCP gels was observed in the coding region of exon 2, 3, 4, 5, 6, 7, 10 and 11. The change was significantly higher in the tissue samples of the OSCC patients but not in their blood. The change of single nucleotide may be responsible for the substitution of amino acid in the p53 protein. This may result in the germ line mutation(s) of the p53 gene due to chewing habits which are involved in different steps of tumorigenesis and increasing the susceptibility of OSCC in Pakistan.
Journal of Clinical Pathology, 2002
Aims: To identify immunostaining patterns that are predictive for p53 mutations and to investigate whether p53 mutations are associated with established risk factors for oral squamous cell carcinoma (OSCC). Methods: Fifty five OSCCs were investigated for p53 protein expression by immunohistochemistry (IHC). Ten of these cases, including five p53 immunopositive and five p53 immunonegative cases, were subjected to microdissection of representative tumour areas followed by sequence analysis for the detection of TP53 mutations. Results: Paired IHC and sequence analysis revealed that p53 immunoexpression in more than 25% of tumour cells was indicative of TP53 mutations, whereas p53 immunonegativity was not informative. Therefore, for p53 immunohistochemical interpretation, p53 immunonegative cases were excluded from the analysis and the cut off value for p53 immunoexpression was set at 25%. Of the OSCCs showing any p53 immunoexpression, 64% revealed staining in more than 25% of the tumour cells. p53 immunoexpression in more than 25% of the neoplastic cells was significantly associated with smoking but not with alcohol consumption. No significant association with smoking habits was found when OSCCs were dichotomised into p53 immunonegative and p53 immunopositive. Conclusions: In OSCCs the following conclusions can be made: (1) p53 immunonegativity is not informative for TP53 mutations; (2) 25% p53 immunopositive cells appears to be a good cut off value to predict TP53 mutations; (3) p53 immunostaining patterns that appeared to be predictive for TP53 mutations were associated with the smoking habits of the patients.
Carcinogenesis, 1998
Inactivation of tumor suppressor genes like p53 and p16 play a key role in tumor progression, with a high incidence of mutations existing for both genes in oral squamous cell carcinomas. Previous studies have demonstrated, (i) a correlation between the prevalence of p53 mutations and tobacco use [Brennan et al. (1995) New Engl. J. Med., 332, 712-717; Lazarus et al. (1996) Carcinogenesis, 17, 733-739], and (ii) a link between genotypes in specific xenobiotic metabolizing enzymes and oral cancer susceptibility [Park et al. (1997) Cancer Epid. Biomarkers Prev., 6, 791-797). In this paper, we present results of our examination of a series of 80 oral squamous cell carcinomas for p53 exons 5-9 and p16 exons 1-2 mutations, and the potential association of these mutations with specific genotyping patterns. p53 mutation prevalence in oral tumors was linked with increased patient tobacco use using several stratification criteria. There was a significantly higher prevalence of p53 mutations in OCSCCs from patients who smoked Ͼ30 pack-years as compared to tumors from patients who smoked ഛ30 pack-years (OR ⍧ 2.8; CI ⍧ 1.1-7.2). No significant association was observed with patient alcohol consumption. There was a significant association between the prevalence of p53 mutations in oral tumors and CYP1A1 genotyping patterns in these oral cancer patients, with the highest p53 mutation prevalence observed in subjects with the CYP1A1 [val]/GSTM1 [⍣] genotype (OR ⍧ 6.0; CI ⍧ 1.2-29.7). A significant association was not observed between the prevalence of p16 mutations in oral tumors and tobacco use, or CYP1A1 [val] or GSTM1 (0/0) genotypes. These data suggest that the induction of mutations in specific tumor suppressor genes or oncogenes in oral tumors may be associated with specific carcinogen exposures, and that this association may be linked to specific polymorphic genotypes in xenobiotic-metabolizing enzyme genes.
A low incidence of p53 mutations in pre-malignant lesions of the oral cavity from non-tobacco users
International Journal of Cancer, 1995
To determine the incidence of pS3 mutations in pre-malignant lesions of the oral cavity from individuals without prior history of tobacco use, we have analyzed the conserved regions of the pS3 gene (exons 5-9) in archival oral cavity lesion specimens obtained from patients with varied tobacco use histories, by polymerase chain reaction/single strand conformational polymorphism (PCR/SSCP) and DNA sequencing analysis. Twenty-six lesions were analyzed from 14 patients, with multiple lesions obtained from 8 patients. Six of these patients used tobacco, (3 being cigarette smokers, 1 ex-cigarette smoker, 1 moderate cigar smoker and 1 snuff chewer). The remaining 8 patients had no prior history of tobacco use. Thirteen of the pre-malignant lesions exhibited severe dysplasia, 9 exhibited moderate dysplasia and 4 exhibited mild dysplasia. Four of the 26 lesions exhibited pS3 mutations, each being from a tobacco user. None of the 13 lesions from never-tobacco users exhibited pS3 mutations. There was a significantly higher p53 mutation incidence in pre-malignant lesions from tobacco users (including ex-smokers) than in non-tobacco users as well as in cigarette smokers plus snuff chewers than in non-tobacco users. Two of the mutations were observed in lesions exhibiting severe dysplasia: I in a lesion exhibiting moderate dysplasia and I in a lesion exhibiting mild dysplasia. These data suggest that pS3 mutation may be a very early event in oral cavity tumor progression and demonstrate that pre-malignant lesions obtained from non-tobacco users do not exhibit pS3 mutations.
Loss of heterozygosity is related to p53 mutations and smoking in lung cancer
British Journal of Cancer, 2001
Carcinogenesis results from an accumulation of several genetic alterations. Mutations in the p53 gene are frequent and occur at an early stage of lung carcinogenesis. Loss of multiple chromosomal regions is another genetic alteration frequently found in lung tumours. We have examined the association between p53 mutations, loss of heterozygosity (LOH) at frequently deleted loci in lung cancer, and tobacco exposure in 165 tumours from non-small cell lung cancer (NSCLC) patients. A highly significant association between p53 mutations and deletions on 3p, 5q, 9p, 11p and 17p was found. There was also a significant correlation between deletions at these loci. 86% of the tumours with concordant deletion in the 4 most involved loci (3p21, 5q11-13, 9p21 and 17p13) had p53 mutations as compared to only 8% of the tumours without deletions at the corresponding loci (P < 0.0001). Data were also examined in relation to smoking status of the patients and histology of the tumours. The frequency of deletions was significantly higher among smokers as compared to non-smokers. This difference was significant for the 3p21.3 (hMLH1 locus), 3p14.2 (FHIT locus), 5q11-13 (hMSH3 locus) and 9p21 (D9S157 locus). Tumours with deletions at the hMLH1 locus had higher levels of hydrophobic DNA adducts. Deletions were more common in squamous cell carcinomas than in adenocarcinomas. Covariate analysis revealed that histological type and p53 mutations were significant and independent parameters for predicting LOH status at several loci. In the pathogenesis of NSCLC exposure to tobacco carcinogens in addition to clonal selection may be the driving force in these alterations.
Determination of p53 genotypes in oral cancer patients from India
British journal of cancer, 2001
The p53 tumour suppressor gene is inactivated in various types of human cancers, and has been implicated as an early event in several cancers. A p53 Pro/Arg polymorphism at exon 4 codon 72, has been suggested to be involved in susceptibility to cancers as well. Hence, in the current study, we investigated p53 exon 4 codon 72 polymorphism using Proline or Arginine specific primers from the peripheral blood cells (PBC) representing constitutional DNA from 72 oral cancer patients. PBC from 153 normal healthy individuals were used to determine the frequency of the p53 genotypes, Pro/Pro, Arg/Arg and Pro/Arg, in the Indian population. The frequency of distribution of genotypes in the normal healthy individuals was, Pro/Pro - 0.20 (31/153), Arg/Arg -- 0.14 (22/153) and Pro/Arg -- 0.65 (100/153); and in the oral cancer patients was, Pro/Pro -- 0.19 (14/72), Arg/Arg -- 0.08 (6/72) and Pro/Arg -- 0.72 (52/72). Thus, we observed an equidistribution of the genotypes in normal control and oral ...
British Journal of Cancer, 1998
Lung cancer is strictly associated with tobacco smoking. Tumours developed in non-smoking subjects account for less than 10% of all lung cancers and show peculiar histopathlIogical features, being prevalentty adenocarcinomas. A number of genetic data suggest that their biological behaviour may be different from that of lung tumours caused by smoking, however the number of cases investigated to date is too low to draw definitive conclusions. We have examined the status of p53 and K-ras genes and the presence of loss of heterozygosity (LOH) at the FHIT locus in a series of 35 lung adenocarcinomas that developed in subjects who had never smoked. Results were compared with those obtained in a series of 35 lung adenocarcinromas from heavy-smoking subjects. In the group of non-smoking subjects p53 mutations and LOH at the FHIT locus were present in seven (20%) cases, and the two alterations were constantly associated (P < 0.0001), whereas they were not related in the series of carcinomas caused by smoking. In tumours developed in heavy-smoking subjects, the frequency of LOH at the FHIT locus was significantly higher (P = 0.006) than in tumours from non-smoking subjects. The frequency of p53 mutations in adenocarcinomas caused by smoking was not different from that seen in non-smoking subjects. However, in the group of smoking subjects we observed mostly G:C-* T:A transversions, whereas frameshift mutations and G:C-* A:T transitions were more frequently found in tumours from non-smoking subjects. No point mutations of the K-ras gene at codon 12 were seen in subjects who had never smoked, whereas they were present (mostly G:C-* T:A transversions) in 34% of tumours caused by smoking (P = 0.002). Our data suggest that lung adenocarcinomas developed in subjects who had never smoked represent a distinct biological entity invoMng a co-alteration of the p53 gene and the FHIT locus in 20% of cases.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2003
DNA repair gene polymorphisms have been implicated as susceptibility factors in cancer development. It is possible that DNA repair polymorphisms may also influence the risk of gene mutation. The 399Gln polymorphism in the DNA repair gene XRCC1 has been indicated to have a contributive role in DNA adduct formation, sister chromatid exchange, and an increased risk of cancer development. Two hundred thirty-seven male oral squamous cell carcinomas (OSCCs) were included in a study to investigate the role of the XRCC1 194Trp, 280His, and 399Gln polymorphisms on p53 gene mutation. PCR-single-strand conformation polymorphism and DNA sequencing were used to analyze the conserved regions of the p53 gene (exons 5-9). The XRCC1 genotype was determined by PCR-RFLP. Nineteen (8.02%) of the 237 OSCCs had a Gln/Gln genotype. One hundred six (43.88%) of the 237 OSCCs showed p53 gene mutations at exons 5-9. The OSCC patients with a Gln/Gln genotype exhibited a significantly higher frequency of p53 mu...
British journal of cancer, 1998
Lung cancer is strictly associated with tobacco smoking. Tumours developed in non-smoking subjects account for less than 10% of all lung cancers and show peculiar histopathological features, being prevalently adenocarcinomas. A number of genetic data suggest that their biological behaviour may be different from that of lung tumours caused by smoking, however the number of cases investigated to date is too low to draw definitive conclusions. We have examined the status of p53 and K-ras genes and the presence of loss of heterozygosity (LOH) at the FHIT locus in a series of 35 lung adenocarcinomas that developed in subjects who had never smoked. Results were compared with those obtained in a series of 35 lung adenocarcinomas from heavy-smoking subjects. In the group of non-smoking subjects p53 mutations and LOH at the FHIT locus were present in seven (20%) cases, and the two alterations were constantly associated (P < 0.0001), whereas they were not related in the series of carcinoma...