Exon 8 mutation of p53 gene associated with nodal metastasis in non-small-cell lung cancer.

Lee, L N; Shew, Jin‐Yuh; Sheu, J C; Lee, Y C; Lee, W C; Fang, Ming; Chang, Hee-Kyung; Yu, Chong‐Jen; Yang, Po-Jen; Luh, Kwen‐Tay

doi:10.1164/ajrccm.150.6.7952630

Cited by 21 publications

(10 citation statements)

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“…In this study, however, only 18% of the smokers had G-T transversions. Findings similar to our own were reported in NSCLC patients from Taiwan, in whom G-.T mutations constituted only 6% of p53 mutations detected in a population sample comprising 61% smokers (Lee et al, 1994). GC-TA transversions have been attributed to the action of benzo [a]pyrene, a member of the polycyclic aromatic hydrocarbons, which represent the major carcinogens found in tobacco smoke.…”

Section: Discussionsupporting

confidence: 87%

p53 gene aberrations in non-small-cell lung carcinomas from a smoking population

Liloglou

Ross²,

Prime³

et al. 1997

Br J Cancer

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Summary We examined 46 non-small-cell lung carcinomas (NSCLCs) for the presence of p53 mutations in exons 4-9, positive p53 immunostaining and loss of heterozygosity (LOH) in the TP53 locus. p53 mutations were detected in 13 tumour samples (28.3%), whereas overexpression of the p53 protein was found in 30 of 45 (67%) samples. Allelic loss was found in 9 of 38 (23.6%) informative cases. The statistical analysis revealed no significant correlation between p53 mutations and clinicopathological data, although mutations appear to occur more frequently in squamous cell carcinomas (7 of 18) than in adenocarcinomas (2 of 15). All but three individuals in this study group smoked. In contrast to previous reports, we found a higher prevalence of GC-AT transitions than of GC-TA transversions, as expected in a smoking population. A trend was found between p53-positive immunostaining and a history of heavy smoking (76-126 pack-years) and was inversely correlated with allelic deletion (LOH) at the TP53 locus. Eight of the 12 NSCLCs containing p53 mutations also had concomitant p53 overexpression, and it is of specific note that three of the four tumours containing p53 'mutations' with no overexpression of the p53 protein had either insertions or deletions in the p53 gene. No correlation was found between p53 mutations and fractional allele loss or ras mutations. p53 mutations in this Merseyside population in the UK do not appear to be as common as in other reports for NSCLC and exhibit predominance of GC-AT transitions preferentially at non-CpG sites, suggesting that other carcinogens in addition to those in tobacco smoke may be involved in NSCLC in the Merseyside area of the UK.

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Section: Discussionsupporting

confidence: 87%

p53 gene aberrations in non-small-cell lung carcinomas from a smoking population

Liloglou

Ross²,

Prime³

et al. 1997

Br J Cancer

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“…In particular, in tunours from smoking subjects, FHIT gene alterations may be pimarily related to carinogens present im tobacco smoke and not a consequence of p53 inactivation. In the series of smoking patients p53 mutations were significantly associated with metastatic involvement of hilar/mediastinal lymph nodes and advanced stages of disease, in agreement with previous results (Marchetti et al, 1993;Lee et al, 1994). In nonsmoking subjects a trend towards these associations was observed.…”

Section: P53supporting

confidence: 92%

Genetic analysis of lung tumours of non-smoking subjects: p53 gene mutations are constantly associated with loss of heterozygosity in the FHIT locus

Marchetti

Pellegrini²,

Sozzi³

et al. 1998

Br J Cancer

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Summary 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.

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“…However, when the Polish population was observed, there was a scarcity of perturbations that lead to p53 ablation, since only one sample contained a nonsense mutation (1%). Nevertheless, null mutations made up 33% of the total number of mutations in the Spanish NSCLC tumors in contrast to lower frequencies documented by other investigators (Kishimoto et al, 1992;Lee et al, 1994;Ryberg et al, 1994;Takagi et al, 1995;Casey et al, 1996).…”

Section: Discussionmentioning

confidence: 54%

“…Inactivation of TP53 tumor suppressor gene emerge as the most frequent molecular disturbance in human neoplasms, although frequency and type of mutation di er substantially among cancers. Particularly in NSCLC, the TP53 mutational frequency is considerably variable among di erent populations and studies, ranging from 20 ± 60% (Kishimoto et al, 1992;Lee et al, 1994;Ryberg et al, 1994;Takagi et al, 1995).…”

mentioning

confidence: 99%

TP53 mutational pattern in Spanish and Polish non-small cell lung cancer patients: null mutations are associated with poor prognosis

Anta

Jassem²,

Rosell

et al. 1997

Oncogene

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Inactivation of TP53 tumor suppressor gene is the most frequent molecular alteration in NSCLC, involving up to 60% of cases. Furthermore, TP53 mutational spectrum is related to the type of mutagen exposure, as well as racial and/or diet di erences. Nearly 95% of TP53 perturbations a ect codons included within exons 5 ± 8 which encode for almost the entire DNA-binding domain. In this study we addressed the possible prognostic value of the molecular alterations identi®ed in exons 5 ± 8 of the TP53 gene in DNAs from 151 para n-embedded NSCLC sections corresponding to 59 Spanish and 92 Polish stage I-IIIA resected patients. PCR/single-strand conformation polymorphism (SSCP) analysis revealed that the occurrence of TP53 exon 5 ± 8 mutations was 17/59 (29%) in the Spanish cohort and 17/92 (18%) in the Polish group. However, when DNA sequencing analysis was performed, these frequencies were reduced because of the presence of SSCP-false positive, intronic and silent mutations and polymorphisms. Fifteen of the 59 Spanish NSCLC tumors (25%) harbored TP53 mutations a ecting exons 5 ± 8 coding sequences, whereas only 12 of 92 Polish neoplasms (13%) contained alterations in the central hydrophobic region of p53. Our results indicate that the occurrence of TP53 mutations a ecting exon 5 ± 8 coding sequences in some European NSCLC populations may be lower than previously reported, and that the TP53 mutational patterns of these cohorts di er somewhat. The Spanish NSCLC patients contained missense mutations (9/59, 15%) and a relatively high percentage of null mutations (5/59, 8%) while the Polish patients mostly harbored missense mutations (9/92, 10%) and only one tumor contained a null type (1/92, 1%). Moreover, most TP53 missense mutations in the Spanish group were located outside the conserved regions, whereas the same mutations in the Polish group a ected conserved amino acids. Furthermore, the Polish patients harbored a high percentage of G?A transitions (most of them at non-CpG sites), while G?T transversions were predominant in the Spanish group. Our ®ndings suggest that there may be di erent racial or exogenous factors in these two populations which may help to explain both the distinct TP53 mutational pattern and the lower frequency obtained in the Polish group. The presence of missense mutations did not confer a worse clinical outcome in these subsets of NSCLC patients. However, patients whose tumors contained null TP53 gene mutations had a 5 month median disease-free survival time in contrast with 42 months in those patients without mutations (P=0.008). These ®ndings suggest that loss of p53 function may enhance tumor progression in NSCLC patients independently of whether dominant negative TP53 missense mutations are present.

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Exon 8 mutation of p53 gene associated with nodal metastasis in non-small-cell lung cancer.

Cited by 21 publications

References 0 publications

p53 gene aberrations in non-small-cell lung carcinomas from a smoking population

p53 gene aberrations in non-small-cell lung carcinomas from a smoking population

Genetic analysis of lung tumours of non-smoking subjects: p53 gene mutations are constantly associated with loss of heterozygosity in the FHIT locus

TP53 mutational pattern in Spanish and Polish non-small cell lung cancer patients: null mutations are associated with poor prognosis

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