Expression of BCRP gene in the normal lung tissue and lung cancer

The development of multidrug resistance during chemotherapy was found to be correlated with over-expression of two transmembrane xenobiotic transporter protein, P-glycoprotein (Pgp) and the multidrug resistance protein (MRP).[1(6] Because the discordance between drug efflux and P-glycoprotein expression in human leukemic cells and unclear drug resistance exhibited during chemotherapy in advanced breast cancer patients, a alternative multidrug resistance transporter might be existed and has b…     

Allelic distribution of the CYP1A1 in lung cancer patients, middle-aged tissue donors and in elderly people without cancer

The genetic polymorphism of metabolizers of tobacco smoke carcinogens can influence individual susceptibility to lung cancer. The study was concerned with the Mspl-polymorphism of the CYP1A1 gene responsible for encoding aryl hydrocarbon hydroxylase. It also plays a role in the activation of polycyclic aromatic hydrocarbons (PAH). The CYP1A1 alleles and genotype distribution in 146 lung cancer patients was compared with that in 230 healthy donors. Another control group consisted of 259 "cancer-resistant" subjects, i.e. tumor-free smokers and non-smokers aged 75 and more. The CYP1A1 allele incidence (19%) in patients with squamous lung cancer was significantly higher than in the control cohorts (11%) which is consistent with the leading role of PAH in the etiology of this pathology.     

人类白细胞抗原HLA-DQA1基因多态性在尘肺肺癌患者中的表达

目的 检测人类白细胞抗原(HLA) DQA1位点基因多态性在尘肺肺癌患者与非职业性肺癌患者的表达差异.方法 用多重聚合酶链反应-连接酶检测反应分型法(PCR-LDR),分别检测21例尘肺并发肺癌患者及40例非职业性肺癌患者的HLA-DQA1共6个位点的等位基因,并分析其和尘肺肺癌发病的相关性.结果 尘肺肺癌组患者HLA-DQA1 0301基因频率19％,非职业性肺癌组患者HLA-DQA1 0301基因频率2.5％,差异有统计学意义(x2=10.022,P=0.002),其余等位基因两组差异无统计学意义.结论 HLA-DQA1的基因多态性可能与尘肺肺癌易感性相关.DQA1 0301是尘肺并发肺癌的重要的调控基因之一,可能为尘肺肺癌易感的危险因素.     

MDR1 gene expression and prognostic factors in primary breast carcinomas

To prospectively assess the role of the MDR1 gene in breast carcinomas, MDR1 RNA levels of breast carcinoma specimens were determined by slot blot analysis. In 59 evaluable patients with primary breast carcinomas, MDR1 RNA levels of the carcinomas were negative in 54%, low in 29% and high in 17% of the patients. No differences in age, menopause status, oestrogen and progesterone receptor levels, tumour size, lymph node involvement and c-erbB-2/neu gene expression were observed between MDR1 RNA negative patients and MDR1 RNA positive patients.     

人肺癌中FHIT基因表达的临床病理生理意义及与预后的关系研究

目的　研究FHIT基因表达与人肺癌临床病理生理特征和预后的关系 ,探讨FHIT基因在人肺癌发生、发展过程中的可能作用。方法　应用免疫组化法检测了 1 66例肺癌组织标本及其癌旁肺组织和 37例肺良性病变组织中FHIT基因的表达水平。结果　肺癌组织中FHIT基因表达阳性率 (63 .0 3 %± 2 6 .41 % )显著低于癌旁组织 (83 .74%± 1 7.46 % ) ,而癌旁组织又显著低于肺良性病变组织 (92 .98%± 5 .56 % ) (P <0 .0 1 ) ;肺癌组织中FHIT基因表达水平降低与肺癌组织学类型、细胞分化程度 ,患者P TNM分期、淋巴结转移程度存在相关性 (P <0 .0 5) ;吸烟组肺癌患者的肺癌组织中FHIT基因表达阳性率 (55 .1 4 %± 2 7.55 % )明显低于非吸烟组 (71 .93%± 2 2 .0 5 % ) (P <0 .0 1 ) ;FHIT基因低表达组肺癌患者的术后长期生存率显著低于高表达组 (P <0 .0 5)。结论　FHIT基因的表达下降可能与肺癌的发生、发展过程有关。吸烟是导致肺癌患者FHIT基因表达下降的重要原因之一。     

Microsatellite alteration in histologically normal lung tissue of patients with non-small cell lung cancer

Microsatellite alteration (MSA) has been observed in a fraction of non-small cell lung cancer (NSCLC). Most prior studies regarding MSA in lung cancer have usually used adjacent non-malignant lung tissues as a source of constitutional DNA. However, these normal tissues might have genetic alterations because the entire field of bronchial tree is exposed to the same carcinogenic insult. The aim of this study was to search if MSA is present in the histologically normal lung tissue of patients with NSCLC. Tumor and corresponding normal lung tissue specimens were obtained from 20 patients with NSCLC. Normal lung tissue specimens were obtained from either the opposite end of resected surgical samples or as distant from the tumor as possible. They were examined histopathologically and confirmed as normal by H-E stain. Patients' peripheral lymphocytes were used as the source for the normal DNA. Sixteen markers on 3p and 9p (nine and seven markers, respectively) were used. MSA was detected in seven of 20 (35%) histologically normal lung tissue specimens at a frequency similar to that observed in tumor tissue (eight of 20, 40%). Five cases showed MSA in both normal lung tissue and the corresponding tumor. In these five cases, MSA in normal lung tissue was detected at the same microsatellite markers which MSA was detected in the corresponding tumor. The number and size of novel bands in normal lung tissue was identical to that in tumor tissue except in one case. In which case, the same pattern of MSA was found in both normal lung tissue and corresponding tumor tissue at two markers. However, at one marker, while one identical novel band was detected in normal lung tissue and corresponding tumor tissue, another novel band was found only in tumor tissue. In two of 12 patients whose tumor was negative for the presence of MSA, MSA was detected in normal lung tissue. These results indicate that genetic alterations are widely distributed in the lung tissue of patients with lung cancer and provide considerable support for the field cancerization theory. Screening for MSA in resected normal lung tissue might be a new method to identify patients at high risk for developing second primary lung cancers.     

Oxytocin receptor pattern of expression in primary lung cancer and in normal human lung

In order to assess if oxytocin- and vasopressin-induced mitogenic effects detected on small-cell lung carcinoma (SCLC) cell lines could be transposed on primary SCLC, the aim of the present work was to identify mediators of these mitogenic actions on primary tumours samples. This was addressed on normal human lung tissue, on SCLC and on non-SCLC (NSCLC). Herein, we observe, in normal human lung, that OTR is colocalized with vascular endothelial cells of the lung and is not expressed by lung cells of epithelial nature. We detected mRNA amplification of V1aR, V2R and of a V2R variant. We observed that 86% of SCLC biopsies analyzed expressed at least the OTR and that 71% expressed the OTR, the V1aR and the V2R altogether. Comparatively, 50% of NSCLC biopsies tested expressed at least the OTR and 32% expressed the OTR, the V1aR and the V2R altogether. The occurrence of the V1bR/V3R is of 28 and 18% for SCLC and NSCLC, respectively. Nevertheless, for the SCLC biopsies analyzed in this study, V1bR/V3R expression correlates, in all cases, with the expression of all the other neurohypophysial peptide receptors. Our results suggest that neurohypophysial peptide antagonists may offer promise as a potential new therapeutic modality for the treatment of lung cancer expressing at least one of the neurhypophysial peptide receptor subtypes.     

KAI1在肺癌组织芯片中的表达及其生物学意义

背景与目的　KAI1基因是新发现的转移抑制基因,它在多种肿瘤中有表达。该研究通过分析KAI1蛋白在肺良性病变组织、癌前组织、原发癌组织及局部淋巴结肺转移癌组织中的表达及其与临床病理生理特征之间的关系,探讨其在肺癌发生、发展、浸润、转移中的作用。方法　应用组织芯片技术和免疫组化S P方法检测肺癌组织中KAI1蛋白的表达。统计学方法采用χ2 检验、Fisher确切概率。结果　KAI1 蛋白在10例肺良性病变组织中阳性表达率为100.0%,在12例癌前病变组织中为66.7%,而在89例肺原发癌组织中表达仅为24.7%,在淋巴结转移肺癌病灶中更是显著下调(0)(P<0.05);原发癌组织中KAI1 蛋白的表达与患者年龄、性别、大体病理类型均无明显关系(P>0.05),而与肿瘤的组织学类型、分化程度、病理分期以及是否伴有淋巴结转移密切相关(P<0.05)。结论　KAI1 蛋白的异常表达可能参与了肺癌的恶性进展,它的表达降低促进了肿瘤的浸润转移,检测肺癌组织中KAI1 表达对肺癌的诊断及预后判断有一定的参考价值。     

Prediction of lymph node metastasis by gene expression profiling in patients with primary resected lung cancer

While lymph node metastasis is a major factor associated with poor prognosis in cancer, little is known of its molecular mechanisms. The aim of this study was to identify genes differentially expressed between non-cancerous and cancerous lung tissues, and to investigate the gene expression profiles of 41 primary lung adenocarcinomas to select sets of gene predictors for lymph node metastasis of lung cancer. Gene expression profiles were obtained using oligonucleotide microarrays, and predictor sets constructed by evaluating the statistical significance of expression levels of selected genes. Gene analysis revealed 15 predictor genes for lymph node metastasis of lung adenocarcinoma. Using the most suitable set of genes, it was possible to predict the lymph node metastasis of patients with lung cancer. The prediction scoring system yielded 71.4% accuracy for forecasting lymph node metastasis in 14 independent test cases. Survival was also significantly better in 18 cases that were pathologically LN negative and predicted to be LN negative according to molecular classification, compared with 23 cases that were pathologically LN positive or predicted to be LN positive according to molecular classification. Gene expression analysis combined with statistical analysis successfully distinguished lymph node metastasis. The findings of this study showed that pathological diagnosis combined with molecular classification clearly distinguished patients with good prognoses from patients with poor prognoses.     

CYP1A1和GSTM1基因多态性及其对个体肺癌易感性的联合效应:meta分析

背景与目的谷胱甘肽转移酶M1(glutathione S-transferase M1,GSTM1)和细胞色素P4501A1(cyto-chrome P450A1,CYP1A1)均存在基因多态性,并且对肺癌发病风险有一定的影响,两者联合作用对肺癌发病风险的影响尚无确切定论。本研究旨在探讨CYP1A1和GSTM1基因多态性及其联合效应与肺癌危险性的关系。方法在PubMed数据库、EMBASE数据库、中国生物医学文献数据库(china biology medicine,CBM)和中国知识基础设施工程数据库(china national knowledge infrastructure,CNKI)中查询文献,时间范围从各数据库建库至2011年3月。使用STATA10软件进行meta分析统计,对于每篇入选的文献均计算肺癌发生危险性调整混杂因素后优势比(odd ratio,OR)及其95%置信区间(confidence interval,CI)。结果 15篇文献最终被纳入本次研究。Meta分析显示GSTM1基因缺失时CYP1A1基因IIe/Val位点为纯合突变型时肺癌发病风险明显高于杂合型与纯合突变型联合,总体OR分别...     

A race-specific genetic polymorphism in the CYP1A1 gene is not associated with lung cancer in African Americans

In a case-control study, we tested the hypothesis that a previouslydescribed African American-specific polymorphism in an intron3' to the coding region of the CYP1A1 gene was associated withthe occurrence of lung cancer. The study population included72 African Americans with newly diagnosed, untreated lung cancerwho presented to collaborating clinicians at the Universityof Texas M.D.Anderson Cancer Center and from county, communityand Veterans Administration hospitals in the Houston metropolitanarea. Controls were 97 African Americans, frequency-matchedon gender and age, recruited from community centers, churches,cancer screening programs and from among hospital employees.The prevalence of the variant CYP1A1 genotype did not differbetween the cases and controls. The odds ratio for individualswith one or more copies of the variant allele was 0.64 [ 95%confidence interval (CI) 0.3– 1.4]. Overall, 20.7% ofthe population had one or more variant alleles; the prevalencein cases was 16.7% and in controls it was 23.7%. Two individualswith the homozygous variant genotype were controls while oneindividual with lung cancer was found to have the homozygousvariant genotype. The lack of an association between genotypeand lung cancer persisted after subgroup analysis for lifetimecigarette smoking history and tumor histology was performed.The sample size of this study is sufficient to detect odds ratiosof three or greater; associations of this magnitude are similarto those reported in studies of a different polymorphism inthe same region of the CYP1A1 gene in Japanese. Thus, it isunlikely that this polymorphism is associated with sizable risksfor tobacco-induced lung cancer in this population subgroup.     

肺癌前病变、肺癌中FHIT基因表达的临床研究

背景与目的FHIT基因为近年发现的新的候选抑癌基因，位于3p14．2，跨越FRA3B易脆点，在包括肺癌在内的多种人类肿瘤中均存在异常表达。本研究旨在观察FHIT基因在人肺癌前病变、肺癌中的表达情况，探讨FHIT基因在肺癌发生、发展过程中的可能作用。方法采用免疫组化方法检测298例甲醛固定、石蜡包埋的标本（包括161例肺癌、51例肺癌前病变、30例正常肺组织、23例肺良性病变和33例肺癌转移淋巴结）中FHIT蛋白表达情况。结果FHIT蛋白在正常肺组织及肺良性病变组织中均无失表达，癌前病变组织和肺癌组织中失表达率分别为54．9％（28／51）和59．0％（95／161），肺癌转移淋巴结组织中失表达率为78．8％（26／33）；肺癌前病变、肺癌及转移淋巴结组织中FHIT蛋白失表达率显著高于正常肺组织及肺良性病变组织（P〈0．001）。肺癌组织中FHIT基因表达水平与肺癌组织学类型、肿瘤细胞分化程度、患者pTNM分期、淋巴结转移有密切关系（P〈O．05）。FHIT蛋白失表达组肺癌患者的术后5年生存率显著低于表达组（P〈0．01）。吸烟组患者FHIT基因失表达率69．1％显著高于无吸烟组49．5％（P〈0．01）。结论FHIT蛋白失表达可能是肺癌发生过程中的早期分子事件，与肺癌的发生、发展及预后有关；吸烟导致FHIT蛋白表达下降可能是诱发肺癌的原因之一。     

AZGP1 mRNA levels in normal human lung tissue correlate with lung cancer disease status

Evidence in animal models has suggested an association between susceptibility to lung tumorigenesis and gene-expression profiles in normal lung. Here, we compared RNA pools from normal lung tissue of lung adenocarcinoma patients (cases) or non-lung cancer patients (controls) by hybridization of whole-human genome expression arrays. Principal component analysis identified a gene-expression signature of 85 genes that distinguishes cases from controls as well as smokers from nonsmokers. Elevated mRNA levels of one of these genes, AZGP1, were significantly associated with disease status. These results support the hypothesis that differences in the gene-expression levels of the normal tissue may be predictive of genetic predisposition to lung cancer in humans.     

Profiles of prostaglandin biosynthesis in normal lung and tumor tissue from lung cancer patients

prostaglandin (PG) biosynthetic profiles from endogenous arachidonic acid were determined by capillary gas chromatography-mass spectrometry in matched fresh normal lung (NL) and lung cancer (LC) tissue fragments obtained from 42 individual LC patients at the time of diagnostic thoracotomy. The histological diagnoses represented were squamous cell carcinoma (N = 20), adenocarcinoma (N = 7), small cell carcinoma (N = 4), mixed cell carcinoma (N = 2), bronchioloalveolar cell carcinoma (N = 2), large cell undifferentiated carcinoma (N = 3), bronchial carcinoid (N = 1), and metastatic tumors (N = 3). When PG biosynthesis was determined in NL tissue separately, low mean levels of PGE2 and PGF2 alpha (less than 2 pmol/mg protein/15 min), intermediate levels of PGD2 and 6-keto-PGF1 alpha (6KPGF1 alpha) (2-7 pmol/mg protein/15 min), and high levels of thromboxane B2 (TXB2) (greater than 7 pmol/mg protein/15 min) were observed. There was no particular correlation with cigarette smoking history and PG biosynthesis in NL. When PG production in LC tissue was evaluated separately, high levels of PGE2, PGF2 alpha, and 6KPGF1 alpha as well as TXB2 and low levels of PGD2 were noted. In addition, LC tissue from cigarette smokers demonstrated elevated levels of PGE2, 6KPGF1 alpha, and TXB2 when compared to current nonsmokers with LC (P less than 0.05 in all instances). Simultaneous comparison of PG production in matched LC and NL tissue from individual patients indicated increased biosynthesis of PGE2 and PGF2 alpha and low levels of PGD2 in LC compared to NL tissue (P less than 0.05 in all instances; paired, two-tailed, Student's t test). Individual comparison of PG biosynthesis according to LC histological cell type revealed that PGE2 and PGF2 alpha were consistently elevated in all four common primary LC histological cell types, the only exception being large cell undifferentiated carcinoma. Interestingly, this latter LC histological cell type presented a unique profile with lower levels of PGE2 and PGD2 in LC than in NL tissue (P less than 0.05 in both instances). In addition, the biosynthesis of all 5 PGs studied was consistently higher in primary than metastatic adenocarcinomas of the lung (P less than 0.05 in all instances). No differences were observed in NL and LC tissue for the major LC histological cell types when PGD2, TXB2, or 6KPGF1 alpha biosyntheses were compared. These findings indicate that the profiles of PG biosynthesis in LC and NL tissue from individual patients may differ substantially. These differences may reflect, in part, contributions to the PG biosynthetic profile unique to malignant cells.     

Elderly patients with lung cancer: biases and evidence

Opinion statement Although 60% of those diagnosed with non-small-cell lung cancer are 60 years of age or older, the elderly are often undertreated. Furthermore, those older than age 70 are under-represented in clinical research trials. Tremendous bias exists against treating the elderly; therapeutic nihilism and constrained societal/financial resources conspire to maintain the status quo. In limited stage small cell carcinoma of the lung (SCLC), a pivotal meta-analysis by Pignon et al. showed no obvious benefit for chemoradiation over chemotherapy alone in patients older than 70 years of age. However, more recent trials have revealed a clear-cut benefit for fit elderly patients to receive combined modality therapy versus chemotherapy alone, even though outcome generally remains superior for younger patients. For patients with locally advanced non-small-cell lung cancer, conflicting results exist. Individual trials evaluating combined modality therapy have shown no impairment in survival for older patients, but retrospective analyses of the Radiation Therapy Oncology Group database have demonstrated that increased therapeutic intensity does not translate into improved outcome compared with standard, single daily fraction radiation alone. Weighted survival analyses that deduct time spent with progressive disease or significant toxicity have reinforced this notion. In advanced non-small-cell lung cancer, fit elderly patients who receive platinum-based regimens do as well, or nearly as well, as patients younger than age 70, although the incidence of neutropenia and fatigue is often higher. Platinum doses above 75 mg/m2 every 3 weeks to 4 weeks are relatively more toxic in the elderly than are lower doses. Three separate studies from Italy have formally assessed the elderly. One showed superiority for single-agent vinorelbine versus best supportive care regarding survival rates and quality of life. A second showed a marked survival advantage for combination vinorelbine and gemcitabine versus vinorelbine alone. However, a much larger, more credible study demonstrated no benefit for combination vinorelbine and gemcitabine versus the constituent single agents. To date, no elderly-specific trials have addressed the role of taxanes or of platinum-based combination therapy versus non-platinum monotherapy or doublets. Comprehensive evaluation of comorbidities and their influence on outcome have not been conducted, and there are virtually no data for patients older than age 80.