共查询到20条相似文献,搜索用时 46 毫秒
1.
Ekaterina Baryshnikova Annarita Destro Maurizio Valentino Infante Silvio Cavuto Umberto Cariboni Marco Alloisio Giovanni Luca Ceresoli Romano Lutman Giorgio Brambilla Giuseppe Chiesa Gianni Ravasi Massimo Roncalli 《Clinical cancer research》2008,14(6):1913-1919
PURPOSE: The high mortality rate for lung cancer is likely to be reduced by the development of a panel of sensitive biological markers able to identify early-stage lung cancers or subjects at high risk. The aim of this study was to establish the frequency of K-ras and p53 mutations and p16(INK4A), RASSF1A, and NORE1A hypermethylation in sputum of a large cohort of cancer-free heavy smokers and to assess whether these markers are suitable for a routine use in the clinical practice for the early diagnosis of pulmonary cancer. EXPERIMENTAL DESIGN: Sputum samples were collected from 820 heavy smokers. Inclusion criteria consisted of radiologic and cytologic absence of pulmonary lesions, age at least 60 years, male gender, and a smoking history of at least 20 pack-years. RESULTS: The analysis identified 56 individuals (6.9%) with one molecular alteration. p53 mutation and p16(INK4A), RASSF1A, and NORE1A methylation frequencies were 1.9%, 5.1%, 0.8%, and 1.0%, respectively; no K-ras mutations were found. One patient with p53 mutations was diagnosed with an early-stage lung cancer after 3-years of follow-up. The molecular analysis of bronchoscopy samples confirmed in half of the cases alterations present in sputum without revealing additional molecular changes. CONCLUSIONS: Genetic and epigenetic abnormalities can be detected in cancer-free heavy smokers. Although the predictive value of the cancer risk is still to be established as it requires not less than 5 years of follow-up, p53 and p16(INK4A) are more promising candidates than K-ras, RASSF1A, and NORE1A for the pulmonary molecular screening of heavy smokers healthy individuals. 相似文献
2.
K-ras and p16(INK4A)alterations in sputum of NSCLC patients and in heavy asymptomatic chronic smokers 总被引:2,自引:0,他引:2
Destro A Bianchi P Alloisio M Laghi L Di Gioia S Malesci A Cariboni U Gribaudi G Bulfamante G Marchetti A Bosari S Infante M Ravasi G Roncalli M 《Lung cancer (Amsterdam, Netherlands)》2004,44(1):23-32
NSCLC rates among the most frequent and lethal neoplasm world-wide and a significant decrease in morbidity and mortality relies only upon effective early diagnostic strategies. We investigated K-ras mutations and p16(INK4A) hypermethylation in tumor tissue and sputum of 50 patients with NSCLC and correlated them with sputum cytology and with tumor staging, grading and location, to ascertain, in sputum, their potential diagnostic impact. The same genetic/epigenetic abnormalities and cytological features were also evaluated in sputum from 100 chronic heavy smokers. Genetic analysis identified molecular abnormalities in 64% tumors (14/50 K-ras mutations and 24/50 p16(INK4A) hypermethylation) and in 48% sputum (11/50 K-ras mutations and 16/50 p16(INK4A) hypermethylation). In tumors K-ras mutations and p16(INK4A) hypermethylation were mostly mutually exclusive, being found in the same patients in 3 cases only. Genetic abnormalities in sputum were detected only in molecular abnormal tumors. Molecular changes in sputum had rates of detection similar to cytology (42%) but the cyto-molecular combination increased the diagnostic yield up to 60%. Interestingly, the rate of detection of genetic changes in sputum of tumors at early stage (T1) was not significantly different from that of tumors at more advanced stage (T2-T4). In fact K-ras point mutations were frequently recognised in tumors at early stage while p16(INK4A) inactivation prevailed in tumors at advanced stage ( P=0.0063). As expected, diagnostic cytological findings were more frequently found in tumors at advanced stage (P=0.004). No correlation was found between tumor grading and location (central versus peripheral) and molecular changes. p16(INK4A) hypermethylation, but not K-ras mutations, was documented in sporadic cases of asymptomatic heavy smokers (4%) where it was uncoupled from cytological abnormalities. In conclusion the cyto-molecular diagnostic strategy adopted in this study was able to detect the majority of tumors but in order to be proposed as effective and early diagnostic tool, this molecular panel needs to be tested in prospective studies with adequate follow-up. 相似文献
3.
Ramírez N Bandrés E Navarro A Pons A Jansa S Moreno I Martínez-Rodenas F Zárate R Bitarte N Monzó M García-Foncillas J 《European journal of cancer (Oxford, England : 1990)》2008,44(17):2689-2695
Gene inactivation by promoter hypermethylation has been demonstrated in the colonic mucosa of colorectal cancer (CRC) patients. However, current data do not prove direct involvement of this epigenetic modification in the early stages of CRC. Promoter methylation profiles of E-cadherin, hMLH1, MGMT, p16(INK4a), p15(INK4b) and p14(ARF); mutations of K-ras, B-raf and TP53 and microsatellite instability (MSI) were examined in normal and cancerous colonic mucosal tissue in 82 CRC patients using methylation-specific PCR assays. Methylation of hMLH1 and MGMT in normal mucosa correlated significantly with MSI and K-ras activation in neighbouring cancerous mucosal tissues. Similarly, poorly differentiated tumours were associated with methylated p16(INK4a) and E-cadherin in neighbouring normal colonic tissues (NCTs). Our results indicate that epigenetic changes in mucosa surrounding colorectal neoplastic lesions may describe a 'field cancerisation' phenomenon that may occur previous to genetic alterations in early stages of carcinogenesis. 相似文献
4.
Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status 总被引:32,自引:0,他引:32
Esteller M Tortola S Toyota M Capella G Peinado MA Baylin SB Herman JG 《Cancer research》2000,60(1):129-133
The INK4a/ARF locus encodes two cell cycle-regulatory proteins, p16INK4a andp14ARF, which share an exon using different reading frames. p14ARF antagonizes MDM2-dependent p53 degradation. However, no point mutations in p14ARF not altering p16INK4a have been described in primary tumors. We report that p14ARF is epigenetically inactivated in several colorectal cell lines, and its expression is restored by treatment with demethylating agents. In primary colorectal carcinomas, p14ARF promoter hypermethylation was found in 31 of 110 (28%) of the tumors and observed in 13 of 41 (32%) colorectal adenomas but was not present in any normal tissues. p14ARF methylation appears in the context of an adjacent unmethylated p16INK4a promoter in 16 of 31 (52%) of the carcinomas methylated at p14ARF. Although p14ARF hypermethylation was slightly overrepresented in tumors with wild-type p53 compared to tumors harboring p53 mutations [19 of 55 (34%) versus 12 of 55 (22%)], this difference did not reach statistical significance. p14ARF aberrant methylation was not related to the presence of K-ras mutations. Our results demonstrate that p14ARF promoter hypermethylation is frequent in colorectal cancer and occurs independently of the p16INK4a methylation status and only marginally in relation to the p53 mutational status. 相似文献
5.
p16(INK4A) Hypermethylation detected by fluorescent methylation-specific PCR in plasmas from non-small cell lung cancer. 总被引:6,自引:0,他引:6
Alessandra Bearzatto Davide Conte Milo Frattini Nadia Zaffaroni Francesca Andriani Debora Balestra Luca Tavecchio Maria Grazia Daidone Gabriella Sozzi 《Clinical cancer research》2002,8(12):3782-3787
PURPOSE: The p16(INK4A) tumor suppressor gene is inactivated in many solid tumors, including non-small cell lung cancers (NSCLCs), through promoter hypermethylation. Presence of p16(INK4A) hypermethylation in precursor lesions of NSCLC and in body fluids of individuals at risk makes it a potential candidate for early disease detection. However, the current low sensitivity of p16(INK4A) hypermethylation detection in plasma limits its consideration in a diagnostic grid. EXPERIMENTAL DESIGN: A fluorescent methylation-specific PCR assay (F-MSP) was established to evaluate p16(INK4A) promoter hypermethylation in 35 NSCLC and paired plasma samples and in 15 plasmas from healthy donors. F-MSP sensitivity was investigated in combination with microsatellite alterations on 3p (evaluated by fluorescent PCR), K-ras mutations (determined by a mutant-enriched PCR), and quantification of circulating DNA. Assay results were analyzed by two-sided chi(2) or Fisher's exact tests. RESULTS: p16(INK4A) promoter hypermethylation, detectable by F-MSP in 22 of 35 NSLCs (63%) and in 12 of 22 (55%) plasmas from patients with methylated tumors, was independent of microsatellite alterations (detectable in 57% of tumors and 50% of paired plasmas), K-ras mutations (detectable in 31% of tumors but in no paired plasma), or amount of circulating DNA. p16(INK4A) methylation in association with microsatellite alterations identified 62% (18 of 29) of plasma samples from patients presenting the same alteration in their tumors, and its sensitivity increased to 80% when combined with the amount of circulating DNA. CONCLUSIONS: The establishment of F-MSP remarkably improved p16(INK4A) promoter hypermethylation detection in plasmas from NSCLC patients. Microsatellite alterations, circulating DNA quantification, and p16(INK4A) hypermethylation might contribute to a diagnostic grid for NSCLC. 相似文献
6.
Cirincione R Lintas C Conte D Mariani L Roz L Vignola AM Pastorino U Sozzi G 《International journal of cancer. Journal international du cancer》2006,118(5):1248-1253
We evaluated the aberrant promoter methylation profile of a panel of 3 genes in DNA from tumor and sputum samples, in view of a complementary approach to spiral computed tomography (CT) for early diagnosis of lung cancer. The aberrant promoter methylation of RARbeta2, p16(INK4A) and RASSF1A genes was evaluated by methylation-specific PCR in tumor samples of 29 CT-detected lung cancer patients, of which 18 had tumor-sputum pairs available for the analysis, and in the sputum samples from 112 cancer-free heavy smokers enrolled in a spiral CT trial. In tumor samples from 29 spiral CT-detected patients, promoter hypermethylation was identified in 19/29 (65.5%) cases for RARbeta2, 12/29 (41.4%) for p16(INK4A) and 15/29 (51.7%) for RASSF1A. Twenty-three of twenty-nine (79.3%) samples of the tumors exhibited methylation in at least 1 gene. In the sputum samples of 18 patients, methylation was detected in 8/18 (44.4%) for RARbeta2 and 1/18 (5%) for both RASSF1A and p16(INK4A). At least 1 gene was methylated in 9/18 (50%) sputum samples. Promoter hypermethylation in sputum from 112 cancer-free smokers was observed in 58/112 (51.7%) for RARbeta2 and 20/112 (17.8%) for p16, whereas methylation of the RASSF1A gene was found in only 1/112 (0.9%) sputum sample. Our study indicates that a high frequency of hypermethylation for RARbeta2, p16(INK4A) and RASSF1A promoters is present in spiral CT-detected tumors, whereas promoter hypermethylation of this panel of genes in uninduced sputum has a limited diagnostic value in early lung cancer detection. 相似文献
7.
M Seike A Gemma Y Hosoya S Hemmi Y Taniguchi Y Fukuda N Yamanaka S Kudoh 《Clinical cancer research》2000,6(11):4307-4313
The p16INK4 gene, which is a tumor suppressor gene, is frequently altered in lung cancers. Hypermethylation of the promoter region of the p16INK4 gene seems to be the major mechanism through which p16INK4 become inactivated. Hypermethylation of the p16INK4 gene was reported to occur at an early stage in lung cancer. To determine whether the change in p16INK4 methylation status occurs at the late stage in the progression of primary lung cancers, we analyzed the primary and metastatic tumor tissues and normal lung samples from 29 cases of advanced lung cancer with distant metastasis. In each tissue sample, we analyzed the p16INK4 and p15INK4b genes for mutations and the methylation status of both genes using PCR-single strand conformation polymorphism, direct sequencing, and methylation-specific PCR analysis. We also analyzed a subset of the samples for p16INK4 protein expression. Genetic mutations in the coding region of the p16INK4 and p15INK4b genes were not found in any of the examined specimens. The promoter region of the p16INK4 gene was hypermethylated in the tumor samples of the primary or metastatic site of 37.0% (10 of 27) of the subjects. The promoter region of the p16INK4 gene was hypermethylated at both the primary and metastatic sites in two of the 10 cases and at only the metastatic site in 8 cases. By immunohistochemical analysis, we confirmed the presence of p16INK4 protein at the primary site of all cases in which the promoter region of the p16INK4 gene was hypermethylated at only the metastatic site. Interestingly, all 8 cases with a hypermethylated p16INK4 promoter region, at only the metastatic site, did not have p53 mutation. The results of this study indicate that tumor cells in which the p16INK4 gene has been inactivated by hypermethylation of the promoter region could have an advantage in progression and metastasis in non-small cell lung cancers, especially in the tumors with normal p53, and that the frequency of p16INK4 gene inactivation by hypermethylation could vary in clinical course. 相似文献
8.
9.
Frequent p16INK4a promoter hypermethylation in human papillomavirus-infected female lung cancer in Taiwan 总被引:2,自引:0,他引:2
Wu MF Cheng YW Lai JC Hsu MC Chen JT Liu WS Chiou MC Chen CY Lee H 《International journal of cancer. Journal international du cancer》2005,113(3):440-445
Inactivation of p16INK4a gene through promoter hypermethylation has been frequently observed in non small cell lung cancer; however, various studies have shown a controversial correlation between p16INK4a hypermethylation and cigarette smoking. Our recent report showed that human papillomarvirus (HPV) 16/18 infections were associated with the development of nonsmoking female lung cancer in Taiwan and we further speculated that HPV infection may be linked with p16INK4a hypermethylation. To verify the influence of environmental exposure, including cigarette smoking, environmental carcinogen exposure and HPV infections on p16INK4a hypermethylation, tumors from 162 lung patients, including 67 smoking males, 41 nonsmoking males and 58 nonsmoking females, were subjected to p16INK4a hypermethylation analysis by methylation-specific PCR. As the results showed, p16INK4a hypermethylation was detected in 40 (59.7%) of 67 smoking male, 15 (36.6%) of 41 nonsmoking male and 35 (60.3%) of 58 nonsmoking female lung tumors. This result seemed to reveal that gender and cigarette smoking both possess an equal influence on p16INK4a hypermethylation. This result also led to a speculation that HPV infection may promote p16INK4a hypermethylation in nonsmoking female lung cancer patients. From our data, p16INK4a hypermethylation frequency in nonsmoking female lung tumors with HPV infection was as high as 70% (30 of 43) compared to those without HPV infection (33%; 5 of 15). In fact, the correlation between HPV infection and p16INK4a hypermethylation was only observed in nonsmoking female lung tumors (p = 0.017), but not in smoking male or nonsmoking male lung tumors. Moreover, the reverse correlation between p16INK4a immunostaining and p16INK4a promoter hypermethylation was also only observed in nonsmoking female lung tumors. These results strongly suggested that the involvement of HPV infection in lung tumorigenesis of nonsmoking female cancer patients in Taiwan may be mediated at least in part through the increase of hypermethylation to cause p16INK4a inactivation. 相似文献
10.
Breuer RH Snijders PJ Sutedja GT Sewalt RG Otte AP Postmus PE Meijer CJ Raaphorst FM Smit EF 《Lung cancer (Amsterdam, Netherlands)》2005,48(3):299-306
It is generally assumed that squamous cell carcinoma develops in a stepwise manner from normal bronchial epithelium towards cancer by the accumulation of (epi)genetic alterations. Several mechanisms including mutations and homozygous deletions or hypermethylation of the p16(INK4a) promoter region can cause loss of p16 expression. Recent studies suggest overexpression of the polycomb-group gene BMI-1 might also down-regulate p16 expression. In this study, we analyzed the p16 expression in relation to the methylation status of the p16 promoter region of the p16(INK4a) gene and the expression of BMI-1 in bronchial squamous cell carcinomas (SCC) and its premalignant lesions. Nine (69%) SCC showed loss of p16 expression and 10 (77%) showed expression of BMI-1. Of four p16 positive samples two (50%) were BMI-1 positive, whereas among nine p16 negative samples, eight (89%) revealed BMI-1 staining. Four (44%) p16 negative samples were hypermethylated at the p16(INK4a) promoter region; the other p16 negative tumors that showed no hypermethylation revealed BMI-1 staining. Only two premalignant lesions showed absence of p16 expression, of which one (carcinoma in situ) was hypermethylated at the p16(INK4a) promoter region and the other (severe dysplasia) showed BMI-1 expression. In total, 11 precursor lesions (48%) revealed BMI-1 expression. In conclusion, the results of this study suggest that loss of p16 expression by promoter hypermethylation is inconsistently and occurs late in the carcinogenic process at the level of severe dysplasia. To what extent overexpression of the polycomb-group protein BMI-1 attributes to down regulating of p16 expression remains unclear. 相似文献
11.
目的 探讨p53、K-ras基因在肺癌患者癌组织及相应痰液中改变情况及其联合检测在肺癌早期诊断中的价值。方法 对59例肺癌组织和14例肺部良性组织及相应痰液,应用PCR-SSCP-银染法检测了p53基因第5~8外显子突变情况;应用PCR-RFLP法对K-ras基因突变进行了检测。结果 p53基因在肺癌组织中突变率为37.3%,K-ras基因在肺腺癌突变率为48.0%,其它类型肺癌突变率仅为8.8%。相应痰液中两基因突变率分别为33.8%和44.0%,与组织中的突变率无明显差异,P<0.01。良性组织及相应痰液中两基因均无突变。吸烟患者的突变率(48.7%,68.5%)明显高于非吸烟患者的突变率(15.0%,11.1%),P<0.01;两基因的联合检测在肺癌的早期诊断中的价值(54.2%)明显优于单基因的检测,P<0.05。结论 痰液和组织中的基因突变率基本相似,即痰液中脱落细胞的分子遗传学改变能反映肺组织情况。因此以痰液为目标多基因的联合检测可能有助于肺癌的诊断。 相似文献
12.
肺癌患者吸烟量与痰液细胞p53和Ki—ras基因突变的关系 总被引:2,自引:0,他引:2
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。 相似文献
13.
Detection of p53 and K-ras mutations in sputum of individuals exposed to smoky coal emissions in Xuan Wei County, China 总被引:3,自引:0,他引:3
Lung cancer mortality rates in the Xuan Wei County population are among the highest in China and are associated with exposure to indoor emissions from the burning of smoky coal. Previous studies of lung tumors from both non-smoking women and smoking men in this region showed high frequencies of mutations, consisting mostly of G-->T transversions in the p53 tumor suppressor gene and K-ras oncogene, suggesting that these mutations were caused primarily by polycyclic aromatic hydrocarbons. In this study sputum samples from 92 individuals with no evidence of lung cancer from Xuan Wei County were screened for p53 and K-ras mutations. Sputum cells were collected on glass slides by sputum cytocentrifugation, stained and cytopathologically analyzed. Cytologically non-malignant epithelial cells were taken from each sputum sample using a laser capture microdissection microscope and molecularly analyzed. Cells taken from the sputum of 15 (16.3%) individuals were mutation positive, including 13 (14.1%) individuals each with a p53 mutation, 1 (1.1%) individual with a K-ras mutation and 1 (1.1%) individual with a p53 and a K-ras mutation. p53 mutations were found in both the sputum of individuals with evidence of chronic bronchitis (3 of 46 or 6.5%) and those without evidence of this disease (11 of 46 or 23.9%). Therefore, mutations in the p53 gene and, to a lesser extent, the K-ras gene were frequent in non-malignant epithelial cells taken from the sputum of individuals without evidence of lung cancer who were exposed to smoky coal emissions in Xuan Wei County and were at a high risk for developing the disease. 相似文献
14.
Lin TS Lee H Chen RA Ho ML Lin CY Chen YH Tsai YY Chou MC Cheng YW 《Cancer letters》2005,226(1):77-84
Our recent report indicated that HPV infection may be associated with an increased frequency of p16INK4a promoter hypermethylation to cause p16 inactivation. In this study, we further speculated that the HPV infection may be linked with the expression of DNA methyltransferase (DNMT) protein in lung cancer patients and it was observed that an association of p16INK4a promoter hypermethylation with HPV infection existed, but only in female cases (P<0.0001). Interestingly, DNMT3b protein expression was significantly correlated with p16INK4a promoter hypermethylation (P=0.023) and HPV 16/18 infections (P<0.001), respectively. Moreover, the correlation between p16INK4a promoter hypermethylation and DNMT3b protein expression was exclusively seen in female cases (P=0.035). These results strongly suggested that the involvement of HPV infection in nonsmoking female lung tumorigenesis may be mediated, at least to a certain extent, through the increase of DNMT3b protein expression to cause p16INK4a promoter hypermethylation. 相似文献
15.
Hypermethylation of p16INK4a in Chinese lung cancer patients: biological and clinical implications 总被引:11,自引:0,他引:11
Promoter hypermethylation of the p16INK4a gene was investigated in 111 cases of tumor tissue, as well as in 136 circulating plasma and 95 sputum samples from Chinese patients with primary lung cancer, using a modified protocol of semi-nested methylation-specific-PCR (MSP). The results showed hypermethylated p16 sequence in 80.2% of tumor tissues and frequencies of 75.7 and 74.7% in plasma and sputum specimens, respectively. Among the patients, 50 cases of matched plasma, sputum and tumor tissue from the same individual were analyzed. Of these, hypermethylation of the p16 promoter was detected in 84.0% of the tumor tissues, with frequencies of 72.0 and 76.0% in the corresponding plasma and sputum, respectively. Notably, only patients whose tumor tissue showed hypermethylation of p16 exhibited the same aberrant methylation in their sputum and/or plasma. Hypermethylation of p16 in sputum and plasma samples may provide a more sensitive approach to molecular diagnosis of lung cancer than relying on conventional cytological analysis. Our data show that a combination of cytological analysis of sputum and examination of p16 hypermethylation in sputum and plasma identified 92.0% (46/50) of the lung cancer patients studied, offering an effective means of early detection of lung cancer. 相似文献
16.
17.
痰标本p16和MGMT基因甲基化对肺癌的诊断价值 总被引:3,自引:0,他引:3
目的:分析肺癌患者痰标本中p16和MGMT基因启动子区甲基化的改变情况,评价该指标作为肺癌辅助诊断分子标志物的价值。方法:运用甲基化特异性PCR技术,检测77例原发性肺癌患者痰标本和部分对应肿瘤组织(53例),以及30例正常对照者痰标本中p16和MGMT基因启动子区域的甲基化改变。结果:49例(63.6%)肺癌患者痰标本中检测到了pi6基因异常甲基化,34例(44.2%)检测到了MGMT基因异常甲基化,77例患者痰标本中2个基因中至少有1个基因出现甲基化为64例(83.1%),对肿瘤的检出灵敏度较高。长期吸烟史是影响肺鳞状细胞癌痰标本p16(P=0.001)基因启动子区甲基化的因素。随TNM分期增高,肺鳞状细胞癌患者痰标本中p16基因甲基化比例增高(P=0.021);随TNM分期增高,肺腺癌患者痰标本MGMT基因甲基化比例增高(P=0.023)。对照组正常人痰液标本未发现p16和MGMT基因启动子区甲基化。结论:痰标本中p16和MGMT基因甲基化是临床肺癌辅助诊断的有效生物标志物之一。 相似文献
18.
We determined inactivation of the CDKN2A (p16(INK4a) and p14(ARF)) gene in 21 cases of oesophageal squamous cell carcinoma (OSCC). The tumours were also analysed for mutations in exons 5-8 and allelic losses in the p53 gene. In addition, we screened the CDKN2B (p15 INK4b), CDKN2C (p18 INK4c), CDK4 and p53R2 genes for mutations in the tumour tissues. Besides concomitant alterations in the CDKN2A and p53 loci in more than half of the cases, our results showed that in 18 OSCC (86%) the CDKN2A (p16(INK4a) and p14(ARF) ) gene was affected through mutations, homozygous/hemizygous deletions and promoter hypermethylation. Eight out of 10 tumours with mutations or promoter hypermethylation specific to the CDKN2A/p16 INK4a gene showed loss of the wild-type allele. One tumour with a single base deletion in the N-terminus (codon 8) of the CDKN2A/p16(INK4a) gene carried a novel germ-line mutation or a rare polymorphism (Ile51Met) in exon 2 of the CDK4 gene. Promoter hypermethylation in the CDKN2A/p14 ARF gene was detected in 11 tumours. In the p53 gene 15 mutations were detected in 14 tumours. We detected an inverse relationship between CDKN2A/p16 INK4a inactivation and frequency of loss of heterozygosity at the p53 locus (OR 0.09, 95% CI 0.01-0.98; Fisher exact test, P-value approximately 0.03). Screening of nine exons of the p53R2 [Human Genome Organisation (HUGO) official name RRM2B] gene resulted in identification of a novel polymorphism in the 5' untranslated region, which was detected in four cases. Our results suggest that the CDKN2A (p16(INK4a) and p14(ARF) ) and p53 genes involved in the two cell cycle pathways are major and independent targets of inactivation in OSCC. 相似文献
19.
TP53, p14ARF,p16INK4a and H-ras gene molecular analysis in intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses 总被引:2,自引:0,他引:2
Perrone F Oggionni M Birindelli S Suardi S Tabano S Romano R Moiraghi ML Bimbi G Quattrone P Cantu G Pierotti MA Licitra L Pilotti S 《International journal of cancer. Journal international du cancer》2003,105(2):196-203
Intestinal-type adenocarcinoma (ITAC) of the nasal cavity and paranasal sinuses is an uncommon tumor associated with occupational exposure to dusts of different origin. Few investigations addressed molecular alterations in ITAC mainly focused on TP53, K-ras and H-ras gene mutations. The occurrence of TP53, p14(ARF) and p16(INK4a) deregulation and H-ras mutations was investigated in 21 consecutive and untreated ITACs cases, 17 with known professional exposure. No H-ras mutations were found. In patients with known exposure, cumulative evidence of TP53 or p14(ARF) alterations accounted for 88% and the evidence of p16(INK4a) alterations for 65%, respectively. TP53 mutations were present in 44% of the ITACs, consisted of G:C-->A:T transitions in 86%, and involved the CpG dinucleotides in 50% of the cases. LOH at the locus 17p13 and an uncommon high rate of p53 stabilization were detected in 58% and 59% of the cases, respectively. p14(ARF)and p16(INK4a) promoter methylation accounted for 80% and 67% respectively, and LOH at the locus 9p21 occurred in 45% of the cases. Interestingly, all dust-exposed tumors with p16(INK4a) alterations shared TP53 or p14(ARF) deregulation. The present results show a close association of this occupational tumor with TP53, p14(ARF) and p16(INK4a) gene deregulation. Given the important role that these genes play in cell growth control and apoptosis, the knowledge of ITAC genetic profile may be helpful in selecting more tailored treatments. 相似文献
20.
p16(INK4a) Promoter hypermethylation of non-tumorous tissue adjacent to gastric cancer is correlated with glandular atrophy and chronic inflammation 总被引:14,自引:0,他引:14
Jang TJ Kim DI Shin YM Chang HK Yang CH 《International journal of cancer. Journal international du cancer》2001,93(5):629-634
The p16(INK4a) tumor suppressor gene can be inactivated by promoter region hypermethylation in many tumor types including gastric cancers. However, p16(INK4a) promoter hypermethylation in the surrounding non-tumorous tissues of gastric cancers has not been studied in detail. We therefore examined 46 gastric cancers, corresponding adjacent non-tumorous tissue samples and 8 gastric tissue samples of chronic gastritis by performing methylation-specific polymerase chain reaction, and we analyzed p16(INK4a) protein expression using immunohistochemistry and Western blot. p16(INK4a) promoter hypermethylation was observed in 43% of gastric cancers and 59% of adjacent non-tumorous tissues; however, none of the samples retrieved from the chronic gastritis patients displayed p16(INK4a) promoter hypermethylation. Gastric cancers showed an inverse correlation between vascular invasion and p16(INK4a) promoter hypermethylation, and adjacent non-tumorous tissues displayed a close association among the grade of chronic inflammation, presence of glandular atrophy and p16(INK4a) promoter hypermethylation. p16(INK4a) expression was markedly decreased in samples with p16(INK4a) promoter hypermethylation when compared with samples without p16(INK4a) promoter hypermethylation. These results suggest that p16(INK4a) promoter hypermethylation is an early and frequent event in gastric carcinogenesis and may serve as a new prognostic biomarker for the risk of gastric cancers. 相似文献