Toward an early diagnosis of lung cancer: an autoantibody signature for squamous cell lung carcinoma

Serum‐based diagnosis offers the prospect of early lung carcinoma detection and of differentiation between benign and malignant nodules identified by CT. One major challenge toward a future blood‐based diagnostic consists in showing that seroreactivity patterns allow for discriminating lung cancer patients not only from normal controls but also from patients with non‐tumor lung pathologies. We addressed this question for squamous cell lung cancer, one of the most common lung tumor types. Using a panel of 82 phage‐peptide clones, which express potential autoantigens, we performed serological spot assay. We screened 108 sera, including 39 sera from squamous cell lung cancer patients, 29 sera from patients with other non‐tumor lung pathologies, and 40 sera from volunteers without known disease. To classify the serum groups, we employed the standard Naïve Bayesian method combined with a subset selection approach. We were able to separate squamous cell lung carcinoma and normal sera with an accuracy of 93%. Low‐grade squamous cell lung carcinoma were separated from normal sera with an accuracy of 92.9%. We were able to distinguish squamous cell lung carcinoma from non‐tumor lung pathologies with an accuracy of 83%. Three phage‐peptide clones with sequence homology to ROCK1, PRKCB1 and KIAA0376 reacted with more than 15% of the cancer sera, but neither with normal nor with non‐tumor lung pathology sera. Our study demonstrates that seroreactivity profiles combined with statistical classification methods have great potential for discriminating patients with squamous cell lung carcinoma not only from normal controls but also from patients with non‐tumor lung pathologies. © 2008 Wiley‐Liss, Inc.     

肺鳞癌组织Hsa-mir-182差异表达的研究

目的:寻找肺鳞状细胞癌组织中与正常组织中差异表达的微小RNA(miRNA),并对其进行生物学功能的预测及验证。方法:应用芯片技术筛选30例肺鳞癌组织中与正常组织中差异表达的miRNA。选取差异表达的mir-182家族进行定量PCR验证,通过生物信息学网站预测其靶基因,并在体外进行荧光素酶报告基因验证。结果:Hsa-mir-182家族在肺鳞癌组织中表达丰度较正常组织明显升高。生物信息学网站预测发现,RASA1可能是mir-182的靶基因。体外过表达mir-182后,发现RASA1表达量显著下降,验证了RASA1确实为mir-182的靶基因。结论:Hsa-mir-182家族在肺鳞癌组织中显著高表达,而且RASA1基因系mir-182的靶基因。     

Differential diagnosis between primary lung squamous cell carcinoma and pulmonary metastasis of head and neck squamous cell carcinoma

Differentiation between lung squamous cell carcinoma and pulmonary metastasis of head and neck squamous cell carcinoma is clinically important because the prognoses and therapeutic options are considerably different. However, the clinical, pathological, and immunohistochemical diagnostic methods have not yet been fully established. Although various molecular methods have been developed, they have not yet been practically applied. A combined approach involving molecular and immunohistochemical analysis, such as one that uses antibodies selected on the basis of comprehensive genetic analysis results, may be effective. We suggest a new diagnostic criteria using the clinical characteristics and the result of immunohistochemical analysis. However, there are two underlying problems in the development of new diagnostic methods: tumor heterogeneity and determination of the diagnostic accuracy.     

p16 protein expression is associated with a poor prognosis in squamous cell carcinoma of the lung

An immunohistochemical analysis for p16 protein was performed in 171 patients with non-small-cell lung cancer (NSCLC). Sixty-two carcinomas (36.3%) were classified as p16-negative. p16-negative tumours in squamous cell carcinomas (SCCs) were significantly more than those in adenocarcinomas (P = 0.039). There was no significant difference in survival according to tumour p16 status in patients with NSCLCs or in patients with adenocarcinomas. In contrast, of patients with SCCs, the 5-year survival rate of patients with p16-negative tumours was significantly lower than those with p16-positive tumours (P = 0.001). Especially, the survival of patients with p16-negative tumours was significantly worse than that of patients with p16-positive tumours in the early stage of the SCC, e.g. stage I (P = 0.005). Multivariate analysis showed that p16 status and nodal status were significant prognostic factors for the survival of patients with SCCs of the lung (P = 0.024 and P = 0.008 respectively). In conclusion, our study showed that alteration of p16 was one of the significant factors of a poor prognosis in SCCs of the lung, and that p16 might play an important role in some SCCs of the lung due to its high prevalence and prognostic value.     

肺鳞癌骨转移因素分析

目的:分析肺癌诊断因素与肺鳞癌全身骨显像骨转移之间的关系。方法:回顾性分析185例肺鳞癌患者的全身骨显像及肺癌有关的肿瘤标志物,以全身骨显像为诊断骨转移的金标准。单因素方差分析和ROC工作曲线下面积比较,得出肺癌肿瘤标志物与肺鳞癌全身骨显像骨转移之间的关系。结果:单因素方差分析结果:NSE、CEA、ProGRP、ALP,均P＞0.05,差异无统计学意义,与骨转移无关;CYFRA21-1、SCC、CA125,均P＜0.05,差异有统计学意义,与骨转移有关;ROC受试者工作曲线结果:CEA(AUC=0.542,P=0.395)、ProGRP(AUC=0.577,P=0.116)、ALP(AUC=0.506,P=0.900),AUC均近于0.5,诊断准确性不高,且其P＞0.05,差异无统计学意义;CYFRA21-1(AUC=0.687,P=0.000)、NSE(AUC=0.679,P=0.000)、SCC(AUC=0.638,P=0.005)、CA125（AUC=0.660,P=0.001）,AUC近于0.7,诊断准确性较高,均P＜0.05,差异有统计学意义,与骨转移有关。结论:CEA、ProGRP、ALP与骨转移无关,不具有对肺鳞癌骨转移的预测和诊断意义;CA125、CTFRA21-1、NSE、SCC与骨转移有关,对肺鳞癌骨转移具有预测和诊断意义。     

MSCT灌注成像在肺鳞癌诊断中的临床价值

目的：通过肺癌MSCT灌注成像及相关灌注参数分析,研究MSCT灌注成像在肺鳞癌诊断中的应用价值。方法：对32例肺癌患者,先行常规CT扫描,确定肿瘤的中心层面,然后采用电影技术对肿瘤中心层面进行连续扫描,以获得该层面内组织的时间-密度曲线,计算出血流量（BF）、血容量（BV）、平均通过时间（MTT）、表面渗透性（PS）,以此评价肿瘤灌注情况,并与病理分型进行对比分析。结果：分别以BF≤37.51ml/（min×100g）、BV≤7.59ml/100g、PS≤8.43ml/（min×100g）为肺鳞癌的诊断阈值,则其灵敏度分别为69.23%、69.23%、76.92%,特异度分别为73.68%、78.94%、84.21%。结论：当BF≤37.51ml/（min×100g）、BV≤7.59ml/100g且PS≤8.43ml/（min×100g）综合判定时,肺鳞癌的诊断特异度明显提高达93.75%。     

FEZ1、Survivin在肺小细胞癌及低分化鳞状细胞癌蛋白表达及其在凋亡中的作用

Objective:To detect the expressions of FEZ1 and Survivin in small cell lung cancer (SCLC) and poorly differentiated squamous cell carcinoma (PDSCC),and to approach a theoretical basis for clinical diagnosis and treatment.Methods:Immunohistochemical and flow cytometry method were used to detect the expressions of FEZ1 and Survivin.Apoptosis ratio and cell proliferation index in normal lung tissue,SCLC and POSCC were analyzed.Results:The expressions of FEZ1 and Survivin were significantly different between SCLC and PDSCC (P＜0.05).The apoptosis ratio and proliferation index of normal lung tissue were lower than those of PDSCC and SCLC,with a significant difference (P＜0.05).Conclusion:The expressions of FEZ1 and Survivin are significantly different between SCLC and PDSCC,indicating that detecting the expressions of the two indexes may be helpful for clinical diagnosis.     

Renal metastasis from squamous cell carcinoma of the lung

Symptomatic renal metastases from primary malignancy elsewhere in the body is an uncommon feature in disseminated cancer. Postmortem diagnosis is more frequent. A case is reported here of a patient with renal metastasis from lung carcinoma who presented with haematuria.     

Proliferation genes in lung development associated with the prognosis of lung adenocarcinoma but not squamous cell carcinoma

There are many similarities between embryonic development and tumorigenesis, and gene expression profiles show that certain correlations exist between the gene signature during development and the clinical phenotypes of different cancers. Our group previously reported the gene expression profiles of human lung development, and the expression of one group of proliferation‐related genes (PTN1 genes) steadily decreased during lung development. Here, we examined the prognostic value of PTN1 genes in 5 independent lung adenocarcinoma (ADC) and 5 lung independent squamous cell carcinoma (SCC) microarray datasets and found that the expression levels of PTN1 genes were associated with survival in lung ADC but not lung SCC. All of the lung ADC datasets contained a set of highly correlated genes from PTN1 genes, but the lung SCC datasets had no similar set of genes. We identified 63 unique core genes from the PTN1 genes in the 5 lung ADC datasets: 17 of these core genes appeared in at least 4 of the lung ADC datasets, and the 17 corresponding proteins clearly interacted more strongly with each other in lung ADC than in lung SCC. Moreover, 16 of the 17 core genes play major roles in the G₂/M phase of the cell cycle. These data indicate that proliferation‐related genes in lung development have a significant prognostic value for lung ADC; the synergistic effects of the 17 core genes play an important role in lung ADC prognosis. These genes may have significant clinical implications for the treatment and prognosis of lung ADC.     

Race- and age-dependent alterations in global methylation of DNA in squamous cell carcinoma of the lung (United States)

Objective: The current study investigated the race- and age-dependent alterations in global DNA methylation on the development and progression of squamous cell carcinomas (SCCs) of the lung. Methods: Methylation status was evaluated in SCC and in the associated uninvolved bronchial mucosa (UBM) and epithelial hyperplasia (EH) of 53 Whites and 23 African Americans by using an antibody specific for 5-methylcytosine (5-mc). A low 5-mc score indicates global hypomethylation of DNA. Results: 5-mc scores of SCC were significantly lower compared to 5-mc scores of UBM and EH in Whites (p < 0.05). In African Americans, 5-mc scores of SCCs were not significantly different from 5-mc scores of UBM and EH, suggesting an involvement of methylation in the development of SCCs in Whites, but not in African Americans. 5-mc scores were lower in younger subjects compared to older subjects in Whites. Since cancers in younger subjects tend to be more aggressive than cancers in older subjects, these observations may suggest that hypomethylation may have contributed to aggressiveness cancers of younger Whites. Hypomethylation of SCCs in White men was associated with shorter survival from the disease. Conclusions: These preliminary results suggest that the methylation status of DNA may affect the development, aggressiveness, and prognosis of SCCs in Whites.     

A re-evaluation of squamous cell carcinoma antigen (SCC) as a serum marker for non-small cell lung cancer

Squamous cell carcinoma antigen (SCC) is still a widely used tumor marker for monitoring non-small cell lung cancer (NSCLC), although recent reports discourage its routine use because of low sensitivity. This is a study evaluating the efficacy of SCC and CYFRA21-1 in diagnosing NSCLC. A chart review was performed in a university hospital in Japan, covering a period of 10 years, up to October 2004. During the study period, 142 (35.5%) among 400 NSCLC patients diagnosed, received serum assays of both SCC and CYFRA21-1. Elevated SCC and CYFRA21-1 levels were found in 29.6% and 59.2% of patients, respectively. SCC sensitivity was only 13.0% but CYFRA21-1 sensitivity rose to 73.9% in metastatic patients. The adjunct of SCC increased the CYFRA21-1 sensitivity by 6.3% in the overall population and by only 2.2% for patients with metastases. SCC determination should be considered an inefficient method as a potential diagnosing tool for NSCLC patients, and it provides no additional value when used in combination with CYFRA21-1.     

Genetic polymorphism in myeloperoxidase but not GSTM1 is associated with risk of lung squamous cell carcinoma in a Chinese population

Myeloperoxidase (MPO), an enzyme derived from neutrophils, metabolically activates a wide range of carcinogens, whereas glutathione S-transferase M1 (GSTM1) detoxifies various electrophilic metabolites. A -463G-->A polymorphism in the promoter region of the MPO gene diminishes the expression of MPO and has been consistently shown to be associated with reduced risk of lung cancer in different ethnic populations. In our study, we have assessed the role of this polymorphism in lung cancer risk in a Chinese population. Genotypes of MPO and GSTM1 were determined by PCR-SSCP and multiplex PCR in 314 patients with lung cancer and 320 frequency-matched controls. The allele frequency for MPO -463A was found to be 0.155 in controls and 0.114 in cases. Subjects with the MPO -463GG genotype were at an increased risk of squamous cell carcinoma (SCC) of the lung compared to those having at least one -463A variant allele (adjusted odds ratio [OR] 2.35; 95% confidence interval [CI] 1.40-3.94). Stratified analysis suggested an interaction between heavy smoking (> or =26 pack-years) and the MPO-463GG genotype. The adjusted OR of lung SCC for those having MPO-463GG genotype and smoked > or =26 pack-years was 20.50 (95% CI 5.58-75.33) compared to 6.22 (95% CI 1.72-22.47) for those smoked > or =26 pack-years but having at least one variant A allele (p = 0.023, test for homogeneity). This effect of the MPO polymorphism was not observed in lung adenocarcinoma. GSTM1 deletion was quite common in both controls (49.4%) and cases (50.3%) but was not associated with risk of lung cancer alone or in combination with the MPO polymorphism. Our results confirm the previous reports showing that the variant A allele of MPO has a protective effect against risk of lung cancer.     

肺鳞癌治疗新靶点FGFR的研究进展

肺癌是目前全球发病率和死亡率均居前列的恶性肿瘤,其中肺鳞癌经手术、放化疗等综合治疗后,其疗效仍不满意。随着分子靶向治疗在肺腺癌中取得了令人瞩目的成果,而肺鳞癌患者中EGFR基因突变及ALK融合基因少见,急需探索新的靶点指导肺鳞癌患者的临床治疗。研究表明,FGFR家族（FGFR1-4）是肺鳞癌中突变频率较高的基因,FGFR基因的激活突变和扩增与肺鳞癌的发生和发展密切相关,同时许多小分子 FGFR 抑制剂在临床应用中已经取得较好的治疗效果。目前,许多FGFR抑制剂治疗肺鳞癌的临床试验也正在进行研究,针对FGFR靶点的基因治疗可为肺鳞癌的治疗提供一种新的策略。本文就FGFR在肺鳞癌的靶向治疗中的最新研究进展进行综述。     

尼妥珠单抗治疗晚期肺鳞癌的临床观察

目的：观察尼妥珠单抗治疗晚期肺鳞癌的临床疗效和安全性。方法回顾性分析12例使用尼妥珠单抗治疗肺鳞癌患者的临床资料,并进行疗效和安全性评估。结果3例ⅢB期患者中,2例一线使用尼妥珠单抗联合同步放化疗治疗,病情进展（PD）;1例二线使用尼妥珠单抗联合化疗,病情稳定（SD）,无进展生存时间为12.0个月。9例Ⅳ期患者中,7例一线使用尼妥珠单抗联合化疗,部分缓解（PR）患者4例,SD患者3例,客观有效率（ORR）57.1%,疾病控制率（DCR）100%;2例二线使用尼妥珠单抗联合化疗,均为SD。治疗期间出现的不良反应包括：中性粒细胞减少7例（58.3%）,血小板减少3例（25.0%）,呕吐1例（8.3%）,乏力3例（25.0%）,神经毒性5例（41.7%）,脱发10例（83.3%）。这些不良反应多与联合使用的化疗药物相关。结论尼妥珠单抗联合化疗治疗晚期肺鳞癌的客观有效率、疾病控制率高,且不良反应可控,值得临床推广。     

microRNA34a／p53信号通路在大鼠肺鳞癌发生过程中的表达及意义

目的：探讨microRNA34a／p53信号通路在大鼠肺癌发生过程中的表达及意义。方法：用免疫组化检测大鼠模型不同组织中p53蛋白表达情况;qRT－PCR技术检测正常大鼠肺组织、低级别上皮内瘤变、高级别上皮内瘤变（原位癌）、浸润癌中microRNA34a的相对表达量。结果：p53蛋白阳性表达率在正常对照组0（0／40）、低级别上皮内瘤变组45．5％（5／11）、高级别上皮内瘤变组（原位癌）76．5％（13／17）和浸润性癌组80．0％（16／20）中表达逐渐增高,阳性强度增高。p53蛋白在正常对照组与低、高级别上皮内瘤变、浸润癌阳性表达比较,差异有统计学意义（P＜0．05）。microRNA34a在正常对照组、低级别上皮内瘤变组、高级别上皮内瘤变组、浸润癌组中平均表达量逐渐降低,分别为0．9890±0．0942、0．8654±0．0356、0．0446±0．0017、0．0091±0．0041,浸润癌表达水平显著低于对照组、低级别上皮内瘤变组、高级别上皮内瘤变组（P＜0．05）。p53蛋白与microRNA34a在肺癌中的表达呈负相关性（P＜0．01）。结论：microRNA34a／p53通路与肺癌的发生发展具有密切关系,联合检测有利于肺癌的早期诊断。     

基于竞争性内源RNA网络探讨豆甾醇干预肺鳞癌的作用机制

目的：利用生物信息学和网络药理学方法,对肿瘤基因组图谱（TCGA）数据库进行分析,探究豆甾醇与肺鳞癌（LUSC）发生发展相关的调控网络及药物作用机制。方法：综合TCGA RNA-seq数据,利用R 4.0.2进行加权基因共表达网络分析（WGCNA）、差异表达分析、基因本体论（GO）分析和蛋白相互作用网络（PPI）分析筛选核心基因,构建竞争性内源RNA（ceRNA）网络,基于网络药理学进行分子对接,分析豆甾醇作用于LUSC的机制。结果：WGCNA联合差异表达分析共确定801个信度高的基因,它们与染色体分离、有丝分裂核分裂、染色体着丝粒区域等功能密切相关。基于PPI分析得出前10个关键基因（CDC20、BUB1、CCNB2、BUB1B、CDK1、CCNB1、KIF2C、NDC80、CDCA8、CENPF）,且均与生存率密切相关,最终构建了CDCA8与上游miRNA hsa-let-7b-5p及与之关联的14个lncRNAs的ceRNA网络。豆甾醇与CDCA8对接良好。结论：14个lncRNAs与hsa-let-7b-5p竞争性调控CDCA8,可能在肺鳞癌发生发展过程中发挥重要作用,可能是豆甾醇干预LUSC的潜在机制。     

基于竞争性内源RNA网络探讨豆甾醇干预肺鳞癌的作用机制

目的：利用生物信息学和网络药理学方法,对肿瘤基因组图谱（TCGA）数据库进行分析,探究豆甾醇与肺鳞癌（LUSC）发生发展相关的调控网络及药物作用机制。方法：综合TCGA RNA-seq数据,利用R 4.0.2进行加权基因共表达网络分析（WGCNA）、差异表达分析、基因本体论（GO）分析和蛋白相互作用网络（PPI）分析筛选核心基因,构建竞争性内源RNA（ceRNA）网络,基于网络药理学进行分子对接,分析豆甾醇作用于LUSC的机制。结果：WGCNA联合差异表达分析共确定801个信度高的基因,它们与染色体分离、有丝分裂核分裂、染色体着丝粒区域等功能密切相关。基于PPI分析得出前10个关键基因（CDC20、BUB1、CCNB2、BUB1B、CDK1、CCNB1、KIF2C、NDC80、CDCA8、CENPF）,且均与生存率密切相关,最终构建了CDCA8与上游miRNA hsa-let-7b-5p及与之关联的14个lncRNAs的ceRNA网络。豆甾醇与CDCA8对接良好。结论：14个lncRNAs与hsa-let-7b-5p竞争性调控CDCA8,可能在肺鳞癌发生发展过程中发挥重要作用,可能是豆甾醇干预LUSC的潜在机制。     

Surfactant protein B gene variations enhance susceptibility to squamous cell carcinoma of the lung in German patients

Genetic factors are thought to influence the risk for lung cancer. Since pulmonary surfactant mediates the response to inhaled carcinogenic substances, candidate genes may be among those coding for pulmonary surfactant proteins. In the present matched case-control study a polymorphism within intron 4 of the gene coding for surfactant specific protein B was analysed in 357 individuals. They were divided into 117 patients with lung cancer (40 patients with small cell lung cancer, 77 patients with non small cell lung cancer), matched controls and 123 healthy individuals. Surfactant protein B gene variants were analysed using specific PCR and cloned surfactant protein B sequences as controls. The frequency of the intron 4 variation was similar in both control groups (13.0% and 9.4%), whereas it was increased in the small cell lung cancer group (17.5%) and the non small cell lung cancer group (16.9%). The gene variation was found significantly more frequently in patients with squamous cell carcinoma (25.0%, P=0.016, odds ratio=3.2, 95%CI=1.24-8.28) than in the controls. These results indicate an association of the surfactant protein B intron 4 variants and/or its flanking loci with mechanisms that may enhance lung cancer susceptibility, especially to squamous cell carcinoma of the lung.