Asian Cardiovasc Thorac Ann 2007;15:35-38
© 2007 Asia Publishing EXchange Ltd
Clinical Significance of p53 Gene Mutation in T1-2N0 Non-Small Cell Lung Cancer
Cengiz Gebitekin, MD,
Ahmet S Bayram, MD,
Berrin Tunca1,
adiman A Balaban2
Department of Thoracic Surgery
1 Department of Medical Biology and Genetics
2 Department of Pathology, Uludag University, School of Medicine Bursa, Turkey
For reprint information contact: Ahmet S Bayram, MD, Tel: 90 224 442 9166, Fax: 90 224 442 8698, Email: asbayram2{at}yahoo.com, Uludag University, School of Medicine, GKDC-ABD Bursa 16059, Turkey.
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ABSTRACT
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In the early stage, long-term survival with non-small cell lung carcinoma has never been ideal. The aim of this study was to compare pathologically proven N0 lymph nodes obtained during mediastinoscopy with p53 gene mutation, and to correlate these with postoperative recurrence. Thirty patients undergoing mediastinoscopy for staging of non-small cell lung carcinoma were studied prospectively. Standard cervical mediastinoscopy was performed in all cases, and the specimens were divided into two pieces for histopathological and genetic investigations. All but one of the patients were male, and the mean age was 61.2 years (range, 42–74 years). Although the histopathology was negative in all cases, p53 gene mutation was observed in 6 (20%) patients. Recurrence was detected in 3 patients who had negative histopathology but were positive for p53 mutation, and in one who had negative histopathology and no p53 mutation. Patients with pathologically N0 disease and p53 gene mutation must be carefully monitored for local recurrence or distant metastasis. Neoadjuvant and/or adjuvant therapies may be considered in this group of patients.
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INTRODUCTION
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Lung cancer is the leading cause of cancer death worldwide, and early diagnosis and treatment are essential.1 Non-small cell lung carcinoma (NSCLC) accounts for 75%–85% of lung cancers, and its staging is critical to the planning of treatment strategies and prognosis. Surgical intervention remains the gold standard of treatment for locoregional disease; however, even after complete resection for stage I disease, 5-year survival varies between 43% and 80%.2 Despite undergoing radical surgery, at least one quarter of patients with stage I NSCLC die of disease recurrence. This poor prognosis suggests the occurrence of micrometastases, which often takes place before the primary operation and thus cannot be assessed by routine clinical examinations and conventional clinicopathologic methods of staging. Currently, micrometastases can be detected by immunohistochemical staining or genetic methods.3 Alterations in p53 tumor suppressor gene are the most common acquired genetic lesion observed in lung cancer.4 The p53 protein expression in NSCLC has been researched much more than point mutation on exons 3–9, because of the cost and availability on paraffin sections. A p53 point mutation on exons 5–8 is observed in 40%–50% of NSCLC, mainly in squamous cell carcinoma.5 Although mutation or expression of p53 in the pathogenesis of lung cancer is evident, it is not clear whether the presence or absence of these abnormalities adversely affects long-term survival. The aim of this study was to seek the clinical significance of p53 gene mutation in pathologically proven N0 lymph nodes obtained during mediastinoscopy in patients with NSCLC who subsequently underwent major lung resection.
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PATIENTS AND METHODS
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After obtaining the University Ethical Committee approval, 30 highly selected patients with pathologically proven stage IA–B NSCLC were prospectively recruited for this study between August 1999 and January 2001. Only those with negative mediastinal lymph nodes or a maximum diameter of 8 mm on computed tomography were chosen for the study in order to increase the value of the study and to exclude fewer patients due to lymph node metastases following surgery. Routine cervical video-mediastinoscopy was performed in all patients prior to major lung resection. According to tumor localization, lymph nodes in stations 2R/L, 4R/L, and 7 were biopsied, if feasible. The sentinel lymph node according to the tumor location was particularly biopsied in all patients. The biopsy specimen was divided into two equal pieces and sent for histopathological examination with hematoxylineosin staining and genetic studies. For the detection of p53 gene mutation, the samples were freshly prepared and stored for the final examination. Mutation was detected by polymerase chain reaction in exons 5–8, as described previously.6 All patients with N0 disease underwent lung resection, and those who had N1/N2 disease or adjuvant treatment were excluded from the study.
Lung resection with mediastinal dissection was performed via a full muscle-sparing posterior minithoracotomy in all patients. The patients were followed up at 3-month intervals by chest radiography, and by computed tomography scan every year, for the detection of local or distant metastases.
Fisher’s exact test was used to compare the association between the incidences among groups. A value of p < 0.05 was considered to be statistically significant.
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RESULTS
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Patient characteristics are listed in Table 1
. All but one of the patients were male, and the mean age was 61.2 years (range, 42–74 years). Preoperative clinical staging was T1N0 in 12 (40%) patients and T2N0 in 18 (60%). The predominant cell type was squamous cell carcinoma (70%), and the location of the tumor was the right upper lobe in the majority (53%). Although the histopathologic examination after mediastinoscopy was negative in all patients, p53 gene mutation was observed in 6 (20%). The mutation was positive in 2 of 12 (17%) patients with a T1 tumor, and in 4 of 8 (22%) with a T2 tumor. Although mutation was seen more often in patients with T2 tumors, the difference was not significant. According to tumor differentiation, p53 mutation was positive in 14% of highly differentiated, 60% of moderately differentiated, and 20% of poorly differentiated tumors (Table 2).
Lobectomy was performed in all but two patients (93%). Six patients were excluded from the study because of N1 disease in 2, N2 disease in 2, and adjuvant chemotherapy in 2 with N0 disease. The posterior subcarinal lymph node was involved in both patients with N2 disease. No major morbidity or mortality was observed in this series. The median follow-up was 31 months (range, 22–43 months), and median survival was 27 months (range, 4–45 months). There was only one recurrence (1/18; 5.5%) in patients with no p53 mutation; however, 3 (50%) recurrences were observed in those who were positive for p53 mutation. Although the numbers are very small, the difference was statistically significant ( p = 0.036). The distant recurrences in patients with p53 mutation were in the brain in 2 (at 3 and 7 months postoperatively) and in the pleural space (at 11 months). Pelvic bone metastasis was observed after 26 months in one patient without p53 mutation.
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DISCUSSION
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Although the aim is to achieve a curative resection in patients with stage I NSCLC, recurrence of the disease is observed in at least 20% of cases, but it varies between 20% and 50%. Therefore, the detection of systemic occult micrometastases using biologic markers has become a rapidly growing area to assess recurrence risk and to identify patients who may benefit from adjuvant or neoadjuvant treatment. Dysfunction of the p53 gene allows the inappropriate survival of genetically damaged cells, setting the stage for the accumulation of multiple mutations and subsequent evolution of a cancer cell, and it plays a critical role in lung cancer.7,8
Alteration of the p53 tumor suppressor gene is one of the most frequent genetic changes in NSCLC, and it has been shown that this mutation can be detected in extremely small clinical samples, such as cytopathology or biopsy specimens, using the polymerase chain reaction.6 Mutation of the p53 gene has been studied in stage I NSCLC by several investigators and found to be positive in 33% to 50% of patients.5,9–12 The overall incidence was 46% in the meta-analysis by Tammemagi and colleagues.9
Although the incidence in our series was only 20%, this low rate could be explained by the selection of cases and the high percentage of well-differentiated tumors (58%). Alterations of p53 have been found significantly less often in adenocarcinoma than squamous cell carcinoma (34% vs 54%, 22% vs 47%), and in well-differentiated tumors compared to moderately/poorly differentiated tumors.5,9,13 Although a similar finding was observed in our series in terms of differentiation, the difference was not significant according to the cell type (19% vs 22%). In the meta-analyses by Tammemagi and colleagues,9 the incidence of p53 mutation was 42.1% in NSCLC, and protein expression was noted in 49.1%; the proportion of p53 alterations detected by protein immunohistochemical staining was significantly greater than that detected by p53 mutation. They also observed that p53 alterations (gene and/or protein) in squamous cell carcinoma were significantly more frequent than in adenocarcinoma (51.2% vs 38.8%).
It is well known that long-term survival is mainly affected by lymph node metastases in the early as well as advanced stages of NSCLC. Similarly, in almost all series, survival has been adversely affected by p53 gene mutation or protein expression. In a series of 102 patients, p53 mutation was the only adverse prognostic factor for long-term survival.5,14 However, Passlick and colleagues15 found that p53 protein expression was favorable to increased disease-free survival, which was explained by the inheritance of the wild-type tumor suppressor function. This has also been observed in patients with advanced NSCLC and p53 gene mutation.6 However, p53 mutation was negative in 4 patients who were excluded from our series due to lymph node metastases. In advanced NSCLC, p53 protein expression was observed in 67% of patients with stage III disease by Lee and colleagues16 who also found that this mutation was the only prognostic factor for long-term survival in stage I disease. A similar observation was made by Cheng and colleagues.12
Although many studies have concluded that p53 protein expression or mutation was the only adverse prognostic factor in patients with stage I NSCLC, the results have not altered the management of these patients. Surgical resection is the best option in such cases. We believe that this is the first series in which p53 gene mutation has been studied in mediastinoscopy specimens in order to change the management of these patients by giving neoadjuvant chemotherapy on the basis of the p53 mutation results.
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REFERENCES
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- Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin 2002;52:23–47.[Abstract/Free Full Text]
- Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:1710–7.[Medline]
- Harris CC, Hollstein M. Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 1993;329:1318–27.[Free Full Text]
- Moldvay J, Scheid P, Wild P, Nabil K, Siat J, Borrelly J, et al. Predictive survival markers in patients with surgically resected non-small cell lung carcinoma. Clin Cancer Res 2000;6:1125–34.[Abstract/Free Full Text]
- Laudanski J, Niklinska W, Burzykowski T, Chyczewski L, Niklinski J. Prognostic significance of p53 and bcl-2 abnormalities in operable nonsmall cell lung cancer. Eur Respir J 2001;17:660–6.[Abstract/Free Full Text]
- Murakami I, Fujiwara Y, Yamaoka N, Hiyama K, Ishioka S, Yamakido M. Detection of p53 gene mutations in cytopathology and biopsy specimens from patients with lung cancer. Am J Respir Crit Care Med 1996;154(4 Pt 1):1117–23.[Abstract]
- Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 1994;54:4855–78.[Free Full Text]
- Bennett WP, Hussain SP, Vahakangas KH, Khan MA, Shields PG, Harris CC. Molecular epidemiology of human cancer risk: gene-environment interactions and p53 mutation spectrum in human lung cancer. J Pathol 1999;187:8–18.[Medline]
- Tammemagi MC, McLaughlin JR, Bull SB. Meta-analyses of p53 tumor suppressor gene alterations and clinicopathological features in resected lung cancers. Cancer Epidemiol Biomarkers Prev 1999;8:625–34.[Abstract/Free Full Text]
- D’Amico TA, Massey M, Herndon JE 2nd, Moore MB, Harpole DH Jr. A biologic risk model for stage I lung cancer: immunohistochemical analysis of 408 patients with the use of ten molecular markers. J Thorac Cardiovasc Surg 1999;117:736–43.[Abstract/Free Full Text]
- Tanaka F, Yanagihara K, Otake Y, Li M, Miyahara R, Wada H, et al. Biological features and preoperative evaluation of mediastinal nodal status in non-small cell lung cancer. Ann Thorac Surg 2000;70:1832–8.[Abstract/Free Full Text]
- Cheng YL, Lee SC, Harn HJ, Chen CJ, Chang YC, Chen JC, et al. Prognostic prediction of the immunohistochemical expression of p53 and p16 in resected non-small cell lung cancer. Eur J Cardiothorac Surg 2003;23:221–8.[Abstract/Free Full Text]
- Gu CD, Osaki T, Oyama T, Inoue M, Kodate M, Dobashi K, et al. Detection of micrometastatic tumor cells in pN0 lymph nodes of patients with completely resected nonsmall cell lung cancer: impact on recurrence and survival. Ann Surg 2002;235:133–9.[Medline]
- Greatens TM, Niehans GA, Rubins JB, Jessurun J, Kratzke RA, Maddaus MA, et al. Do molecular markers predict survival in non-small-cell lung cancer? Am J Respir Crit Care Med 1998;157(4 Pt 1):1093–7.[Abstract/Free Full Text]
- Passlick B, Izbicki JR, Haussinger K, Thetter O, Pantel K. Immunohistochemical detection of P53 protein is not associated with a poor prognosis in non-small cell lung cancer. J Thorac Cardiovasc Surg 1995;109:1205–11.[Abstract/Free Full Text]
- Lee YC, Chang YL, Luh SP, Lee JM, Chen JS. Significance of P53 and Rb protein expression in surgically treated non-small cell lung cancers. Ann Thorac Surg 1999;68:343–8.[Abstract/Free Full Text]
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ABSTRACT
INTRODUCTION
