Chest
Volume 120, Issue 2, August 2001, Pages 589-594
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Laboratory and Animal Investigations
Association of p53 Gene Mutation and Telomerase Activity in Resectable Non-Small Cell Lung Cancer

https://doi.org/10.1378/chest.120.2.589Get rights and content

Purpose

Mutation of the p53 gene and deregulation of telomerase may be essential for canceration in some malignant diseases. However, relationships between these occurrences have not yet been clarified. We examined the roles of p53 gene mutation and telomerase activity relative to the clinical and pathologic features of non-small cell lung carcinoma (NSCLC).

Methods

Frozen sections of 40 surgically resected NSCLC specimens were used. DNA extracted from fresh tumor specimens was analyzed with polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP) method, to screen alterations in the p53 gene. Exons showing aberrant band shifts on SSCP were reamplified, and the PCR products were directly sequenced. In addition, the telomerase activity of the same specimens was analyzed quantitatively with the fluorescence-based telomeric repeat amplification protocol assay, and the total product generated (TPG) method. Clinical and pathologic parameters were evaluated using a statistical analysis system.

Results

Mutations of the p53 gene relevant to an altered protein were confirmed in 19 of 40 specimens (47.5%). The TPG of 40 specimens was 75.24 ± 15.55 (mean ± SE). The TPG of the 19 specimens positive for p53 gene mutation was significantly higher than that of the 21 specimens negative for p53 gene mutation. Furthermore, the degree of cell differentiation was significantly correlated with both p53 gene mutation and high telomerase activity.

Conclusions

p53 gene mutation and high telomerase activity cooperate to induce tumorigenesis and low-grade differentiation in NSCLC. Simultaneous occurrence of p53 gene mutation and high telomerase activity may be relevant to the grade of malignancy in NSCLC.

Section snippets

Materials and Methods

Forty specimens were sampled from 40 surgical cases of NSCLC between May 1997 and May 1999 (squamous cell carcinoma[n = 21], adenocarcinoma [n = 17], large cell carcinoma[n = 2]). These samples were histologically confirmed to be a part of tumor masses. Samples were frozen in liquid nitrogen immediately after surgical resection and stored at − 80°C until use.

Results

Mutations of the p53 gene were confirmed in 19 of 40 specimens (47.5%), 15 missense mutations, and 4 frameshift mutations. One case, in which the mutation did not cause the alteration of the amino acid, was excluded. The TPG of 40 specimens was 75.24 ± 15.55 (mean ± SE; Tables 1 and 2). TPG of the 19 specimens positive for p53 gene mutation was significantly higher than that of the 21 specimens negative for p53 gene mutation (Fig 2, left, a). The examination of each histologic type showed the

Discussion

The p53 tumor suppressor gene plays two important roles in genomic stability: blocking cell proliferation after DNA damage until it has been repaired,14 and starting apoptosis if the damage is too extensive.15 p53 mutations inactivate the tumor suppressor function of wild-type p53, elevating tumor incidences,16 and mutations are most frequently detected in human cancer.1718 Activation of telomerase extends the telomere length and makes repeated cell divisions possible.91920 Elevation of

References (36)

  • WS el-Deiry et al.

    WAF1, a potential mediator of p53 tumor suppression

    Cell

    (1993)
  • C Deng et al.

    Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control

    Cell

    (1995)
  • CK Chung et al.

    Carcinoma of the lung: evaluation of histologic grade and factors influencing prognosis

    Ann Thorac Surg

    (1982)
  • Y Ichinose et al.

    Prognostic factors obtained by a pathologic examination in completely resected non-small cell lung cancer

    Thorac Cardiovasc Surg

    (1995)
  • LS Gollahon et al.

    Immortalization of human mammary epithelial cells transfected with mutant p53 (273his)

    Oncogene

    (1996)
  • AJ Klingelhutz et al.

    Telomerase activation by the E6 gene product of human papillomavirus type 16

    Nature

    (1996)
  • Y Cao et al.

    Abrogation of wild-type p53-mediated transactivation is insufficient for mutant p53-induced immortalization of normal human mammary epithelial cells

    Cancer Res

    (1997)
  • Y Kishimoto et al.

    Aberrations of the p53 tumor suppressor gene in human non-small cell carcinomas of the lung

    Cancer Res

    (1992)
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