Alcohol consumption and cigarette smoking increase the frequency of p53 mutations in non-small cell lung cancer

Epidemiological studies have demonstrated a strong association between tobacco use and lung cancer; however, the genetic targets of these carcinogens and the role of other environmental agents in this process have yet to be defined. We examined the contribution of alcohol use and cigarette smoking top53 gene mutations in patients with non-small cell lung cancer. Mutations of the p53 gene were detected by sequence analysis in 105 patients with non-small cell lung cancer. Patient characteristics significantly associated with p53 gene mutations were determined using logistic regression. Mutations in the p53 gene were present in 53% of the patients (56 of 105). p53 mutations were more common in patients who used alcohol than in patients who consumed less than one drink per day (72 versus 39%; P = 0.003), and were detected more often smokers than nonsmokers (58% versus 10%, P = 0.02). Mutations in the p53 gene were present more often (P = 0.01) in alcohol drinkers who smoked cigarettes [76% (31 of 41)], than in nondrinkers (<1 drink per day) who smoked cigarettes [42% (20 of 48)] or in nondrinkers who did not smoke [14% (1 of 7)]. In conclusion, alcohol consumption and tobacco use are both associated with p53 mutations in non-small cell lung cancer. The link between exposure to both alcohol and tobacco and p53 mutations raises the possibility that alcohol may enhance the mutagenic effects of cigarette smoke in the lung.     

p53和PCNA与非小细胞肺癌

p53基因和增殖细胞核抗原(PCNA)均与非小细胞肺癌(NSCIE)的放疗有密切关系.两者同时高表达的NSCLC患者的生存期低于同时阴性者.研究p53基因和PCNA在NSCLC中的表达,及其与NSCLC放射敏感性和预后的关系,可以对临床制定个体化治疗方案和提高疗效起到积极作用.     

非小细胞肺癌p53、FHIT、K-RAS基因突变与吸烟相关性Meta分析

目的:从循证医学的角度对非小细胞肺癌患者p53、FHIT、K-RAS基因突变异常表达与吸烟相关性进行Meta分析。方法:检索中国学术期刊网全文数据库(CNKI)、中国科技期刊数据库(维普资讯网)、美国国立图书馆PubMed数据库,美国临床肿瘤学会(ASCO)论文集,辅以手工检索;检索时间段为1990年-2010年。检索出p53、FHIT、K-RAS基因突变与吸烟关系研究的文献197篇,最终符合纳入标准的文献26篇。对纳入文献进行方法学质量评价,采用Meta分析专用软件Review Manager 5.0进行统计分析。结果:共纳入26个研究,分别对有相同统计内容且可以合并统计的p53、FHIT、K-RAS基因突变与吸烟关系合并OR值并计算95%CI。分别为:吸烟人群p53基因突变率较高,表现为低表达,[OR=3.50,95%CI(2.45-5.00),总体效应检验Z=6.88,P<0.0001];吸烟人群K-RAS基因突变率明显偏高,表现为高表达,[OR=4.50,95%CI(3.00-6.75),总体效应检验Z=7.26,P<0.0001];吸烟人群FHIT基因突变率较高,表现为低表达,[OR=2.99,95%CI(1.01-8.88),总体效应检验Z=1.98,P=0.005]。结论:吸烟与p53、FHIT、K-RAS基因突变率呈正相关,其中p53、FHIT基因高表达为保护性因素,K-RAS基因高表达为危险因素。     

The p53 codon 72 proline allele is associated with p53 gene mutations in non-small cell lung cancer.

The p53 gene plays a critical role in cell cycle control, the initiation of apoptosis, and in DNA repair. An Arg/Pro polymorphism at codon 72 of the p53 gene alters the ability of the p53 protein to induce apoptosis, influences the behavior of mutant p53, decreases DNA repair capacity, and may be linked with an increased risk of lung cancer. To further define the role of the p53 codon 72 polymorphism on DNA repair, lung cancer risk, and mutant p53 function, we examined the effect of this polymorphism on mutation of the p53 gene and patient survival in non-small cell lung cancer (NSCLC). Tumor and nonneoplastic (lung or lymphocyte) samples were collected from 182 patients with NSCLC. p53 mutations were detected by direct sequencing and/or the Gene Chip p53 assay in 93 of 182 (51%) tumors. p53 codon 72 polymorphisms were identified by PCR/RFLP analysis. p53 mutations were significantly (P = 0.01) associated with the number of codon 72 Pro alleles: Pro/Pro homozygotes, 17 of 26 (65%); Arg/Pro heterozygotes, 45 of 79 (57%); and Arg/Arg homozygotes, 31 of 77 (40%). The number of codon 72 Pro alleles was independently associated with p53 mutations (odds ratio, 1.97; 95% confidence interval, 1.14-3.40; P = 0.01) in a multiple logistic regression model. The codon 72 polymorphism did not influence patient survival in either the entire patient group or among patients with p53 mutant tumors. In summary, the p53 Pro allele is associated with an increased frequency of p53 mutations in NSCLC.     

非小细胞肺癌p53、FHIT、K-RAS基因突变与吸烟相关性Meta分析

目的：从循证医学的角度对非小细胞肺癌患者p53、FHIT、K-RAS基因突变异常表达与吸烟相关性进行Meta分析。方法：检索中国学术期刊网全文数据库（CNKI）、中国科技期刊数据库（维普资讯网）、美国国立图书馆PubMed数据库,美国临床肿瘤学会（ASCO）论文集,辅以手工检索;检索时间段为1990年-2010年。检索出p53、FHIT、K-RAS基因突变与吸烟关系研究的文献197篇,最终符合纳入标准的文献26篇。对纳入文献进行方法学质量评价,采用Meta分析专用软件Review Manager 5.0进行统计分析。结果：共纳入26个研究,分别对有相同统计内容且可以合并统计的p53、FHIT、K-RAS基因突变与吸烟关系合并OR值并计算95%CI。分别为：吸烟人群p53基因突变率较高,表现为低表达,[OR=3.50,95%CI（2.45-5.00）,总体效应检验Z=6.88,P〈0.0001];吸烟人群K-RAS基因突变率明显偏高,表现为高表达,[OR=4.50,95%CI（3.00-6.75）,总体效应检验Z=7.26,P〈0.0001];吸烟人群FHIT基因突变率较高,表现为低表达,[OR=2.99,95%CI（1.01-8.88）,总体效应检验Z=1.98,P=0.005]。结论：吸烟与p53、FHIT、K-RAS基因突变率呈正相关,其中p53、FHIT基因高表达为保护性因素,K-RAS基因高表达为危险因素。     

Association between p53 mutation and clinicopathological features of non-small cell lung cancer

Genetic alterations in exons 5-8 of the p53 gene, determined by single-strand conformation polymorphism and sequencing analyses, and the clinicopathological characteristics of 108 patients with non-small cell lung cancer were compared. Mutations in this gene were found in 37 of the 108 patients (34%): in 30% (23/76) of those with adenocarcinomas, 46% (12/26) of those with squamous cell, 33% (1/3) of those with large cell and 33% (1/3) of those with adenosquamous carcinomas. No associations between the incidence of p53 mutations and the histological or cytological subtypes of adenocarcinomas were found. The analysis of types of mutations, however, showed that GC transversion was relatively common in papillary and clara subtypes, whereas it accounted for only 17% at most of p53 mutations in tubular and bronchial surface epithelial cell subtypes of adenocarcinomas. Univariate analyses revealed that large tumor size, high nodal stage and positive vascular invasion of non-small cell lung cancers, and high nodal stage and high-grade nuclear atypia of adenocarcinomas were associated significantly with p53 mutations. Multivariate analyses showed that the tumor sizes of non-small cell lung cancer correlated with p53 mutations with marginal significance (P = 0.099) whereas nuclear atypia of adenocarcinomas correlated significantly (P = 0.028). No differences between the overall or relapse-free survival rates of patients with and without p53 mutations in non-small cell lung cancers or adenocarcinomas were found. These findings indicate that p53 mutations in adenocarcinomas of the lung are associated with the malignant phenotype of tumor cells, but not with patient survival.      

p53 mutations predict non-small cell lung carcinoma response to radiotherapy

In vitro and animal studies, the effect of loss of p53 function on radiosensitivity is controversial. p21Waf1/Cip1 is a potent inhibitor of cyclin-dependent kinases and p21 gene polymorphisms are associated with some human cancers. We sought to determine whether p53 mutations or p21 polymorphisms affect response to radiotherapy in patients with recurrent non-small cell lung carcinoma (NSCLC). Thirty-four patients with NSCLC who underwent radiotherapy for recurrent tumors after potentially curative resection were studied. Gene alterations or polymorphisms were analyzed in DNA from the primary tumor tissue, and the response to radiotherapy was based on the metastatic lesion. Mutations in exons 5-8 of the p53 gene were detected by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. p21 gene polymorphisms were identified by restriction digestion (BsmAI or PstI) of PCR products. Mutations in p53 were found in 13 of 34 patients (38.2%). The response rates (complete plus partial) were 15.4% for patients with tumors having p53 mutations and 61.9% for patients with wild-type p53 (P = 0.013). There was no significant difference between p21 polymorphisms and response to radiation. p53 gene mutations predict response to radiotherapy in NSCLC. Our results provide clinical support for the in vitro model that loss of p53 function decreases radiosensitivity.     

Detection of p53 gene mutations in exhaled breath condensate of non-small cell lung cancer patients

Early diagnosis of lung carcinoma is greatly desired. A potential source of early information regarding the process of cancerisation in the airways is exhaled breath condensate (EBC). The direct approach to detecting cancerisation is examining DNA from the area of chronic damage, i.e. airways and lung parenchyma. We therefore investigated DNA in EBC of patients with NSCLC and healthy volunteers. Human DNA was amplified by PCR in exhaled breath condensate and used to detect p53 mutations. A PCR of the beta-actin gene fragment was used to detect human DNA in each of the EBC samples. In 65.7% of the samples, the beta-actin gene was found. Extracted DNA as well as native EBC were equally suited as starting material for amplification. Mutations of the p53 gene were investigated in all EBC samples of NSCLC patients. p53 exons 5-8 were amplified using nested PCR and subsequently sequenced. Mutations were found in four of the patients (n=11; 36.4%) while no mutation was found in volunteers (n=10). Mutations detected in EBC were also compared with those of corresponding tumor tissue. Different point mutations in EBC and tumor tissue were revealed in all cases. Our findings demonstrate that exhaled breath condensate may be used for analysis of somatic gene mutations in an area of direct tobacco-related DNA damage.     

Correlation of genetic instability with mismatch repair protein expression and p53 mutations in non-small cell lung cancer.

To examine the etiological association of genetic instability in lung tumorigenesis, we investigated the frequency of microsatellite instability (MI) of eight dinucleotide repeat markers in 68 patients with non-small cell lung cancer. Twenty-eight patients (41.2%) evidenced instability in multiple tested microsatellite markers ranging from 3-7 and were defined as MI-positive patients. MI occurred more frequently in patients suffering from squamous cell lung carcinoma (P = 0.004). We examined the association between MI and expression of hMLH1 mismatch repair protein by immunohistochemical analysis of hMLH1 protein in paraffin-embedded tumors from 64 patients. Twenty MI-positive patients (76.9%) had no expression of hMLH1 protein. The data showed that MI was associated with altered hMLH1 expression (P = 0.03). To examine the role of genetic instability in the previous identified small intragenic deletion of the p53 gene, we explored the association between MI and p53 gene mutations. All patients, except one, containing small intragenic deletion in p53 gene showed MI (P = 0.018). In addition, we found that MI was not associated with the prognosis. Our data suggest that MI plays a significant role in non-small cell lung cancer tumorigenesis in Taiwan and that MI is associated with the altered expression of hMLH1 mismatch repair protein. In addition, MI may be involved in frequent small intragenic deletions of p53 gene.     

Clinical study of adenoviral mediated p53 gene therapy for non-small cell lung cancer in Japan

The prognosis in case of non-small cell lung cancer (NSCLC) remains poor, and novel treatment modalities are urgently needed for advanced NSCLC. Backed by advances in the understanding of cancer biology, gene therapy has been developed in recent years. The p53 gene is altered in over 50% of cancers and has been extensively studied as a tumor suppressor gene. Adenoviral-mediated p53 gene transfer is currently under clinical evaluation worldwide for the treatment of cancer. We are now conducting a phase I study of Ad-p53 for advanced NSCLC patients in Japan. As an interim report, we provide a brief summary of the current status of this study, highlighting the safety and clinical efficacy of Ad-p53. As of September 2002, 13 patients were enrolled to this study, and safety and antitumor effects have been noted.     

Associations between polymorphisms in DNA repair genes and TP53 mutations in non-small cell lung cancer

This study was conducted to identify genetic factors predisposing to TP53 mutations in patients with non-small cell lung cancer (NSCLC). A comprehensive panel of potentially functional single nucleotide polymorphisms (SNPs) in DNA repair genes was evaluated in relation to TP53 mutations. Thirty-seven SNPs in 28 DNA repair genes were genotyped by a sequenome mass spectrometry-based genotyping assay in 173 NSCLCs and the associations with TP53 mutations in the entire coding exons (exons 2-11), including splicing sites of the gene, were analyzed. Four SNPs (XPA rs1800975, OGG1 rs1052133, ADPRT rs1136410, and NBS1 rs1805794) were significantly associated with the prevalence of TP53 mutations in multivariate analysis for each SNP. When the 4 SNPs were combined, the prevalence of TP53 mutations was increased as the number of bad genotypes increased (P_trend = 0.001). Patients with 3 and 4 bad genotypes had a significantly higher frequency of TP53 mutations than those with 0-1 bad genotypes (adjusted odds ratio = 5.18, 95% confidence interval = 1.51-17.81, P = 0.01 and adjusted odds ratio = 18.26, 95% confidence interval = 2.87-116.09, P = 0.002, respectively). These findings suggest that the 4 SNPs may modulate the occurrence of TP53 mutations and contribute to lung carcinogenesis. However, larger studies are required to confirm our findings in other ethnic populations.     

p53 status and prognosis in stage I-IIIa non-small cell lung cancer

To investigate the role of p53 abnormalities in predicting the survival of patients with non-small cell lung cancer (NSCLC), polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and immunohistochemical analyses were performed on 74 and 67 tumor samples, respectively, from patients with pathological stage I-IIIa NSCLC. An abnormally migrating SSCP band was observed in 21 of 74 (28%) tumor specimens. DNA sequence analysis revealed 23 intragenic mutations including 3 small deletions and 20 point mutations. Immunohistochemical analysis using the DO-7 monoclonal antibody showed abnormal expression of p53 in 27 of 67 (40%) patients. The concordance rate between immunohistochemical and PCRSSCP analyses was 73% (49/67) in this study. Univariate and multivariate analyses demonstrated that abnormal expression of p53 may be associated with prolonged survival (p=0.0997 and 0.0099, respectively). In contrast, no relationship was observed between p53 mutation and overall survival (0.6968). These results suggest that p53 status and the survival outcome changes between immunohistochemical and mutational analyses in stage I-IIIa NSCLC.     

Microsatellite instability at selected tetranucleotide repeats is associated with p53 mutations in non-small cell lung cancer

Microsatellite alterations are useful clonal markers for the early detection of cancer. An increase in microsatellite instability has been observed at certain tetranucleotide repeat markers (AAAGn) in lung, head and neck, and bladder cancer. However, the genetic mechanism underlying these elevated microsatellite alterations at selected tetranucleotide repeat (EMAST) tumors is still unknown. The p53 gene plays an important role in maintaining genome integrity by repairing damaged DNA. Therefore, we tested 88 non-small cell lung cancers with a panel of 13 microsatellite markers previously shown to exhibit frequent instability and also performed p53 sequence analysis in these tumors. Thirty-one of these 88 cancers (35%) demonstrated a novel allele [EMAST(+)] in > or =1 of these 13 microsatellite markers. p53 mutations were detected in 50 of 88 (57%) cancers and were significantly (P = 0.001) more common in EMAST(+) tumors (25 of 31; 81%) than in EMAST(-) tumors (25 of 57; 44%). Among squamous cell cancers, p53 mutations were detected significantly (P = 0.04) more frequently in EMAST(+) tumors (17 of 19; 89%) than in EMAST(-) tumors (10 of 18; 55%). Similarly, among primary adenocarcinomas, p53 mutations were present in 67% of the EMAST(+) tumors and in 35% of EMAST(-) adenocarcinomas. None of the 31 EMAST(+) tumors demonstrated high frequency microsatellite instability when examined with a reference panel of five mono- and dinucleotide markers. Primary lung cancers with microsatellite alterations at selected tetranucleotide repeats have a high frequency of p53 mutations and do not display a phenotype consistent with defects in mismatch repair.     

高分辨熔解曲线法检测非小细胞肺癌p53基因的突变

背景与目的 p53基因与人类多种肿瘤相关,突变型具有致癌作用,主要分布在外显子5-8.本研究旨在建立高分辨熔解曲线(high resolution melting,HRM)检测非小细胞肺癌(non-small cell lung cancer,NSCLC)患者p53基因突变的方法,探讨p53基因突变的特点及其在NSCL...     

Loss of heterozygosity is related to p53 mutations and smoking in lung cancer

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.     

Distant metastases in ovarian cancer: association with p53 mutations.

Distant metastases are unusual occurrences at presentation and during the progression of epithelial ovarian cancer. There are no good clinical predictors of this phenomenon. Because p53 dysfunction is common in ovarian cancer, we chose to investigate whether specific types of mutations predicted a predisposition to distant metastasis. We hypothesized that the complete absence of intact p53 protein as seen with p53 null mutations may be associated with an enhanced tendency to develop distant metastatic disease. The complete coding sequence of 130 tumor DNA samples was screened for p53 mutations by single-strand conformational polymorphism analysis. Abnormal single-strand conformational polymorphism findings were correlated with the specific DNA sequence abnormalities and outcome. Ninety-four (72%) tumors carried p53 mutations. Sixty-two were missense mutations, and 32 were null mutations (6 nonsense mutations, 23 frameshift mutations, and 3 splice-site mutations). Twenty-eight patients were found to have distant metastases (pericardium, brain, parenchymal liver, spleen, or lung) either at presentation or during the course of their treatment. Distant metastases were nearly 8-fold more common in patients whose tumors carried a null mutation (66%) than in those with either missense mutations (8%) or wild-type p53 (8%; P<0.001). When a null mutation was present, 25% of the tumors were associated with distant metastases at initial diagnosis. No individual with wild-type p53 or a missense mutation in the tumor presented with distant metastasis. Tumors with null mutations were more likely to be associated with lymph node metastasis (P = 0.003), advanced stage (stage III/IV; P<0.001) and high grade (grade II/III; P<0.001), at presentation. These tumors progressed with distant metastases more swiftly than did tumors with either missense mutations (mean, 1.18 versus 2.71 years; P = 0.04) or wild-type p53 (3.57 years; P = 0.015). In contrast to the popular dogma, distant metastases in ovarian cancer do not necessarily result from prolonged treatment of disease. They may be predicted to occur early in the disease course due to a specific molecular genetic abnormality: null mutation of the p53 tumor suppressor gene. These findings need to be carefully considered when choosing between regional versus systemic treatment modalities.     

Identification of Fas (APO-1/CD95) and p53 gene mutations in non-small cell lung cancer.

Fas (APO-1/CD95) is a broadly expressed death receptor involved in a series of physiological and pathological apoptotic processes. One of the possible mechanisms for resistance to apoptosis signaling in the immune system as well as in the pathogenesis of non-lymphoid malignancies is the presence of Fas mutations within the entire gene. We investigated, in 79 non-small cell lung cancer (NSCLC) samples, the promoter and the entire coding region of the Fas gene by polymerase chain reaction, single strand conformation polymorphism and DNA sequencing in order to detect putative alterations. Sixteen of 79 tumor samples (20.2%) were found to have Fas alterations, either in promoter or exon region. Since the loss of Fas apoptotic function might be linked to p53 alterations, which are often involved in the development of NSCLC, we analyzed p53 status in 40 of the 79 NSCLC samples. p53 mutations were found to be more frequently present than Fas gene alterations (25 out of 40 cases, 62.5%). These data increase the knowledge regarding mutations of apoptosis-genes involved in the pathogenesis of NSCLC, and give benefits for the clinical management of this type of tumor.     

EXPRESSION OF FRAGILE HISTIDINE TRIAD AND P53 IN NON-SMALL CELL LUNG CANCER

Objective： To investigate the expression offragile histidine triad （FHIT） and p53 protein in non-small cell lung cancer （NSCLC） and explore the relationship between their expressions and the clinicopathological features. Methods： FHIT protein and p53 protein were detected by immunohistochemistry in 76 cases of NSCLCs and matched normal lung tissues. Results： Fifty-one cases （67.1%） showed negative expression of FHIT （apparent reduction or loss） and thirty-seven cases （48.7%） showed p53 positive expression （overexpression）. The difference was significant （P=0.04）. However, there was no significant difference in FHIT expression between the p53-positive group and the p53-negative group （64.9% versus 69.2%, P=0.686）. The negative rate of FHIT protein expression was higher in squamous cell carcinoma than in adenocarcinoma, in moderately and poorly differentiated carcinoma than in well-differentiated carcinoma, and in cases with smoking history than in cases without smoking history （P〈0.05）. There was no relationship between FHIT expression and clinical stage or lymph node metastasis. The negative FHIT expression was not an independent predictor of overall survival （P=0.338）. Conclusion： The frequency of negative expression of FHIT protein is higher than that of positive expression of p53 in NSCLCs. The negative expression of FHIT is independent of the expression of p53. The change of expression of FHIT may play a role in the smoking related lung tumorigenesis while it may have no relationship with the progress of NSCLC or prognosis of the patients.     

Prognostic relevance of proliferating cell nuclear antigen and p53 expression in non-small cell lung cancer.

Prognostic value of p53 and PCNA expression in non-small cell lung cancer (NSCLC) remains controversial. In this study we determined the relevance of these abnormalities in terms of overall survival and disease-free survival in 95 NSCLC patients who underwent curative pulmonary resection. Expression of p53 was found in 44 samples (45%), expression of PCNA-in 79 samples (83%), and expression of both markers-in 35 samples (36%). There was no relationship between expression of either protein and major clinicopathological characteristics. Median survival for patients with and without p53 expression was 36 and 33 months, respectively and 5-year survival probability-29 and 37%, respectively (P=0.73). Median survival for patients with and without PCNA expression was 36 and 27 months, respectively and 5-year survival probability-35 and 25%, respectively (P=0.60). There was no significant difference in overall survival between particular groups of patients with tumors carrying four possible p53/PCNA phenotypes. In multivariate analysis including patient age, sex, tumor stage, tumor type and differentiation, p53 and PCNA expression, the only variable important for survival was stage of disease. These results suggest the lack of prognostic relevance of p53 and PCNA expression in surgically treated NSCLC patients.     

肺癌患者吸烟量与痰液细胞p53和Ki—ras基因突变的关系

目的　了解痰液细胞癌基因突变是否与肺癌患者的吸烟量有相关性。方法　将痰液 0 .5毫升加入痰处理液制备细胞沉淀液 ,酚氯仿提取DNA ;应用SSCP PCR银染和RFLP PCR方法对痰液中p5 3、K ras突变情况进行检测。统计肺癌患者的香烟消耗量 ,分析p5 3、K ras突变与吸烟量的关系。结果　在确诊的 110例肺癌中 ,存在p5 3或K ras基因突变者有 76例 ,突变率达 69.1% ,其中 16例为p5 3和K ras基因均有突变。全组中有 71例重度吸烟者吸烟指数 (≥ 40 0支·年 ) ,71例中 5 5例有p5 3或K ras基因突变 ,突变率达 77.5 % ,显著高于非吸烟组 (P <0 .0 0 1) ;p5 3和K ras突变患者的平均吸烟指数分别达到 861和 63 0支·年 ;而未突变的平均吸烟指数为 2 84和 5 5 4支·年 ,二者之间有显著性差异 ( χ2 =3 6.5 6,P =0 .0 0 2 ,双尾检验 )。结论　痰液细胞癌基因突变检测具有简便、实用、可行的特点 ,吸烟的肺癌患者中癌基因突变率显著高于非吸烟的肺癌患者 ,提示吸烟尤其是重度吸烟可能是支气管癌基因突变的主要原因之一 ,值得临床进一步开展深入的研究。