Mutations of the p53 Gene as a Predictor of Poor Prognosis in Patients With Non-Small-Cell Lung Cancer

Mitsudomi, Tetsuya; Oyama, Tsunehiro; Kusano, Takuo; Osaki, Toshihiro; Nakanishi, Ryoichi; Shirakusa, Takayuki

doi:10.1093/jnci/85.24.2018

Cited by 186 publications

(88 citation statements)

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“…Mutations in the p53 tumour-suppressor gene were reported in 32%-52% NSCLC (Chiba et al, 1990;Horio et al, 1993;Kishimoto et al, 1992;Mitsudomi et al, 1993;Carbone et al, 1994;Ryberg et al, 1994;Sauter et al, 1995) and reported results are within the range of the 45% detected in our series. We did not find a significant prognostic impact on survival for all NSCLC if p53 mutations were present by both univariate or multivariate analysis.…”

Section: Discussionsupporting

confidence: 80%

“…We therefore started a prospectice study in patients with curatively (RO category) resected NSCLC to conclusively evaluate the prognostic importance of increased expression of c-erbB-2 protein. In addition, the prognostic impact of mutations in the p53 tumor-suppressor gene (Chiba et al, 1990;Kishimoto et al, 1992;Mitsudomi et al, 1993;Carbone et al, 1994;Ryberg et al, 1994;Sauter et al, 1995) and cKi-ras gene (Rodenhuis and Slebos, 1992;Keohavong et al, 1996;Rosell et al, 1996) were evaluated since contradictory results were reported in the literature. The major purpose of this study was to evaluate if multiple molecular marker (c-Ki-ras, p53 and c-erbB-2) testing results in a better definition of low and high risk NSCLC patients for failure of standardized treatment.…”

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confidence: 99%

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Multiple molecular marker testing (p53, C-Ki-ras, c-erbB-2) improves estimation of prognosis in potentially curative resected non-small cell lung cancer

et al. 2000

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Summary A prospective study was performed in patients with non-small cell lung cancer (NSCLC) to evaluate the prognostic importance of multiple molecular marker (p53, c-Ki-ras, c-erbB-2) testing. 103 patients with potentially curative resections (RO resection) for NSCLC in histopathological stages I-IIIA were included. SSCP analysis and DNA sequencing for p53 and c-Ki-ras genes were performed on paired tumour and normal lung tissue samples and immunohistochemistry (c-erbB-2) was done on frozen tissue sections with a specific anti-c-erbB-2 monoclonal antibody. 46/103 (44.6%) NSCLC showed p53 mutations and 17/103 (16.5%) c-Ki-ras mutations including 12/37 (32.4%) adenocarcinomas. Overexpression of c-erbB-2 (p185) was detected in 56/103 (54.4%) tumours. 24/103 (23.3%) NSCLC were negative for alterations in all 3 parameters (c-Ki-ras, p53 and p185) whereas 79/103 (76.7%) were positive for at least one of the 3 parameters. In a regression model including a multiple molecular marker parameter (negative for all 3 markers versus positive for at least one marker), histopathological stage (P < 0.00001), respectively the pT (P < 0.01) and pN (P < 0.00001) categories and the multiple molecular marker parameter (P < 0.01) were of significant prognostic importance. This study demonstrates that testing 3 molecular markers (c-Ki-ras, p53 and c-erbB-2) improves estimation of prognosis compared to single marker testing and appears to define low (82.6% ± 7.9% 5-year survival) and high risk (40.2% ± 5.5% 5-year survival) groups for treatment failure in potentially curative (RO) resected NSCLC.

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

Multiple molecular marker testing (p53, C-Ki-ras, c-erbB-2) improves estimation of prognosis in potentially curative resected non-small cell lung cancer

et al. 2000

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“…Similarly, the potential role of TP53 mutations is also debatable. Carbone et al (1994) did not associate these perturbations with major aggressiveness in NSCLC patients, while other investigators observed the opposite e ect (Horio et al, 1993;Mitsudomi et al, 1993). However, these investigations did not analyse the TP53 mutational pattern, and the interpretation of the single use of screening methods without DNA sequencing in these studies is di cult.…”

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confidence: 82%

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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“…Several genetic alterations, such as the activation of oncogenes or the inactivation of tumor suppressor genes are frequently observed in NSCLC (Masters et al, 1996;Sundaresan et al, 1995). These genetic alterations are considered to be essential for the process of carcinogenesis and a few have been reported to be associated with a poor prognosis for NSCLC (Slebos et al, 1990;Rosell et al, 1993;Mitsudomi et al, 1993;Greenblatt et al, 1994). Mutations in the K-ras and p53 genes have been suggested to indicate a poor prognosis for NSCLS patients (Slebos et al, 1990;Rosell et al, 1993;Mitsudomi et al, 1993;Greenblatt et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

A novel molecular staging protocol for non-small cell lung cancer

et al. 1999

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A molecular staging protocol using reliable markers is of importance in predicting the prognosis of patients with non-small cell lung cancer (NSCLC) and for instituting their appropriate post-surgical treatment. We analysed tumor tissues from 187 NSCLC patients. The DNA and mRNA were extracted from frozen specimens, and then polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct sequencing were performed to investigate mutations of p53 from exons 5 ± 8, and mutations of K-ras at exon 1. To determine MRP-1/CD9 gene and KA11/CD82 gene expression, which have been postulated to be metastasis suppressor genes, we have applied quantitative RT ± PCR. A Cox multivariate regression analysis showed that nodal status, MRP-1/CD9 and K-ras status were signi®cant factors for prognosis (P50.0001, P=0.0083 and P=0.0004, respectively). Based on these results, we classi®ed the patients into three groups according to their MRP-1/ CD9 and K-ras status. Patients with both MRP-1/CD9 positive and wild K-ras tumors were de®ned as group A, patients with either reduced MRP-1/CD9 or mutant Kras tumors were de®ned as group B and patients with both reduced MRP-1/CD9 and mutant K-ras tumors were designated as group C. This new classi®cation was signi®cantly correlated with the tumor status and pathological stage (P=0.0098 and P=0.0017, respectively). The overall survival rate of the group A patients was signi®cantly better than the group B patients (59.6% vs 27.9%, P=0.0001) and also that of group B patients was better than the group C patients (27.9% vs 20.0%, P=0.0378). This tendency was also found in patients with 110 node-negative NSCLCs (A vs B vs C=75.8% vs 34.9% vs 0.0%, P50.0001). A Cox multivariate regression analysis in NSCLC patients demonstrated that an evaluation for both MRP-1/CD9 expression and K-ras mutations had a signi®cant prognostic e ect as well as nodal status (P50.0001).

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Mutations of the p53 Gene as a Predictor of Poor Prognosis in Patients With Non-Small-Cell Lung Cancer

Abstract: Detection of p53 mutations may help in the selection of NSCLC patients suitable for appropriate investigational therapeutic strategies in view of improving their survival and quality of life.

Cited by 186 publications

References 0 publications

Multiple molecular marker testing (p53, C-Ki-ras, c-erbB-2) improves estimation of prognosis in potentially curative resected non-small cell lung cancer

Multiple molecular marker testing (p53, C-Ki-ras, c-erbB-2) improves estimation of prognosis in potentially curative resected non-small cell lung cancer

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

A novel molecular staging protocol for non-small cell lung cancer

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