Proteogenomic Analysis of Surgically Resected Lung Adenocarcinoma

Introduction

Despite apparently complete surgical resection, approximately half of resected early-stage lung cancer patients relapse and die of their disease. Adjuvant chemotherapy reduces this risk by only 5% to 8%. Thus, there is a need for better identifying who benefits from adjuvant therapy, the drivers of relapse, and novel targets in this setting.

Hsp90AB1在非小细胞肺癌中高表达并且与肺腺癌患者不良预后相关

背景与目的 热休克蛋白90ABl(heat shock protein 90 kDa alpha,classB member1,Hsp90AB1)是ATP依赖的高度保守的分子伴侣,在多种肿瘤细胞中过表达.在肿瘤发生发展的信号传导通路中起着重要作用的一些分子,如表皮生长因子受体(epidermal growth factor receptor,EGFR)、人类表皮生长因子受体-2(human epidermal growth factor receptor-2,HER2)等,均是Hsp90AB1的底物蛋白.Hsp90AB1与这些底物蛋白相互作用并参与细胞的多种病理生理过程.本研究通过检测Hsp90AB1在非小细胞肺癌(non-small cell lung cancer,NSCLC)组织中的蛋白表达情况以初步探讨其临床意义.方法 采用组织微阵列和免疫组织化学染色的方法检测Hsp90AB1在213例NSCLC及相应癌旁正常肺组织中的蛋白表达,并分析Hsp90AB1的表达与NSCLC临床病理参数及患者预后的关系.结果 Hsp90AB1在肺癌组织中的表达水平(阳性率54.0％)高于在正常肺组织中的表达水平(阳性率0.0％,P＜0.001).Hsp90AB1在肺腺癌中的表达阳性率为61.2％,高于肺鳞癌组织37.9％(P=0.002),并且其高表达与肺腺癌患者的不良预后相关(P=0.032).Hsp90AB1蛋白表达水平与临床分期、淋巴结转移、病理分级等因素无关(P＞0.05).结论 Hsp90AB1在NSCLC组织中高表达,并且其表达水平与肺癌的病理类型及肺腺癌患者总生存期相关.     

Long-Term Prognosis of Patients With Resected Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma of the Lung

IntroductionThe WHO classification of lung tumors defines adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) as cancers with no or limited histologic invasive components. The probability of patients with AIS or MIA being recurrence free for 5 years postoperatively has been found to be 100%. This study aimed to analyze the prognosis of patients with AIS or MIA after more than 5 postoperative years.MethodsWe reviewed the pathologic findings of 4768 patients who underwent resection for lung cancer between 1998 and 2010. Of these, 524 patients with curative resection for AIS (207 cases, 39.5%) and MIA (317 cases, 60.5%) were included. Postoperative recurrence, survival, and development of secondary primary lung cancer (SPLC) were analyzed.ResultsOf the included patients, 342 (65.3%) were of female sex, 333 (63.5%) were nonsmokers, and 229 (43.7%) underwent sublobar resection. Average pathologic total tumor diameter was 15.2 plus or minus 5.5 mm. Median postoperative follow-up period was 100 months (range: 1–237). No recurrence of lung cancer was observed for either AIS or MIA cases. Estimated 10-year postoperative disease-specific survival rates were 100% and 100% (p = 0.72), and overall survival rates were 95.3% and 97.8% (p = 0.94) for AIS and MIA cases, respectively. Estimated incidence rates of metachronous SPLC at 10 years after surgery were 5.6% and 7.7% for AIS and MIA, respectively (p = 0.45), and these were not correlated with the EGFR mutation status.ConclusionsAlthough the development of metachronous SPLC should be noted, the risk of recurrence is quite low at more than 5 years after resection of AIS and MIA. This finding strengthens the clinical value of distinguishing AIS and MIA from other adenocarcinomas of the lung.     

Prognostic Factors for Surgically Treated Lung Adenocarcinoma Patients, with Special Reference to Smoking Habit

Prognostic factors for lung adenocarcinoma patients who had been treated surgically at the Center for Adult Diseases, Osaka, in 1978–87 (N = 267) were analyzed In terms of year of operation, sex, age at operation, postsurgical stage, grade of differentiation, and smoking habit. Survival was improved for later year of operation (1983–87), younger age at operation, stage I or II, well or moderately differentiated adenocarcinoma, and nonsmoking status in univariate analysis. A proportional hazards model including the above variables showed that stage III and stage IV patients had 4.06 and 8.81 times higher risk of death compared to stage I and II patients. Poorly differentiated adenocarcinoma showed 2.01 times higher risk of death than well or moderately differentiated adenocarcinoma. Earlier year of operation and female status showed 1.70 and 1.82 times higher risk of death, respectively, as compared to each reference group. All these hazard ratios showed statistical significance. Current smokers who smoked 1,000 or more on the cigarette index showed 2.38 times higher risk of death than nonsmokers with statistical significance. This indicates that smoking is another independent prognostic factor for patients who undergo operations for adenocarcinoma of the lung.     

Prognostic Factors in Completely Resected Node-Negative Lung Adenocarcinoma of 3 cm or Smaller

IntroductionThe role of adjuvant chemotherapy for patients with stage I NSCLC remains unknown. The prognostic value of histological subtypes in resected node-negative small lung adenocarcinoma has not been widely investigated. This study investigated the prognostic factors in patients with node-negative lung adenocarcinoma 3 cm or smaller to find potential candidates for adjuvant chemotherapy.MethodsA total of 726 patients with completely resected node-negative lung adenocarcinoma 3 cm or smaller were included in the study. Prognostic factors for overall survival or probability of freedom from recurrence (FFR) were investigated.ResultsDuring follow-up, recurrence developed in 59 patients (8.1%). Univariate analysis showed that the micropapillary/solid predominant pattern group was associated with a significantly lower probability of FFR (p = 0.001) in node-negative lung adenocarcinoma 3 cm or smaller. Those with greater tumor size (p = 0.001) and the micropapillary/solid predominant pattern group (p = 0.035) had a significantly lower probability of FFR in multivariate analysis. For tumors 2 cm or smaller, the micropapillary/solid predominant pattern group had a trend toward a lower probability of FFR (p = 0.053) in multivariate analysis. Presence of the solid pattern was a prognostic factor for lower probability of FFR (p = 0.001) in multivariate analysis.ConclusionsThe new adenocarcinoma classification has significant impact on recurrence in node-negative lung adenocarcinoma 3 cm or smaller. Patients with the micropapillary/solid predominant pattern have a significantly higher risk for recurrence. For tumors 2 cm or smaller, presence of the solid pattern was a prognostic factor for higher probability of recurrence. This information is useful for patient stratification for adjuvant therapy.     

肺腺癌患者列线图预后模型的构建与验证

目的 基于SEER数据库的大样本数据,构建肺腺癌患者生存预后的列线图预测模型.方法 回顾性分析SEER数据库收集的2010—2015年诊断为肺腺癌患者的临床数据.根据影响肺腺癌患者预后的独立因素,采用Lasso Cox回归分析构建列线图模型.C指数和校准曲线评估列线图的判别和校准能力.使用NRI和DCA曲线评估列线图的...     

Lung Adenocarcinoma With MUC4 Expression Is Associated With Smoking Status,HER2 Protein Expression,and Poor Prognosis: Clinicopathologic Analysis of 338 Cases

Background

MUC4 is a transmembrane glycoprotein that plays a role in the cell growth signaling pathway and has been studied in various organ malignancies. This study aimed to analyze MUC4 expression in resected lung adenocarcinomas (ADCs) to define the clinicopathologic characteristics of MUC4-positive cancers.

Correlation Between EGFR Mutations and Serum TumorMarkers in Lung Adenocarcinoma Patients

Background: Mutations affecting the epidermal growth factor receptor (EGFR) are good predictors ofclinical efficacy of EGFR tyrosine kinase inhibitors (TKI) in patients with non-small cell lung cancer. Serumcarcinoembryonic antigen (CEA) levels are also regarded as predictive for the efficacy of EGFR-TKI andEGFR gene mutations. This study analyzed the association between EGFR gene mutations and clinical features,including serum tumor marker levels in lung adenocarcinomas patients. Patients and Methods: A total of70 lung adenocarcinoma patients with complete clinical data and pathological specimens were investigated.EGFR gene mutations at exons 19 and 21 were assessed. Serum tumor markers were detected by protein chipchemiluminescenceat the corresponding time, and correlations were analyzed. Results: Mutations of the EGFRgene were detected in 27 of the 70 patients and the serum CEA and CA242 concentrations were found to besignificantly associated with the incidence of EGFR gene mutations (P<0.05). The AUCs for CEA and CA242 were0.724 (95% CI: 0.598~0.850, P<0.05) and 0.769 (95% CI: 0.523~0.800, P<0.05) respectively. Conclusions: SerumCEA and CA242 levels are associated with mutations of the EGFR gene in patients with lung adenocarcinomas.     

Prophylactic Cranial Irradiation for Patients with Surgically Resected Small Cell Lung Cancer

IntroductionData on prophylactic cranial irradiation (PCI) after complete resection of SCLC are limited. The purpose of this study was to investigate the impact of PCI in this population.MethodsWe retrospectively identified completely resected SCLC at the Shanghai Chest Hospital between January 2006 and January 2014.ResultsA total of 349 patients (115 patients who received PCI [the PCI-treated cohort] and 234 patients who did not [the non–PCI-treated cohort]) were included in the study. The results demonstrated that the PCI-treated cohort had longer overall survival than the non–PCI-treated cohort among patients with pathologic stage (p-stage) II (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.30–0.99, p = 0.047) and p-stage III (HR = 0.54, 95% CI: 0.34–0.86, p = 0.009) disease. Among patients with p-stage III disease, there was a significantly higher risk for cerebral recurrence from the time of diagnosis in the non–PCI-treated cohort (p = 0.018). With regard to patients with p-stage I disease, neither overall survival benefit (HR = 1.61, 95% CI: 0.68–3.83, p = 0.282) nor risk for cerebral recurrence (p = 0.389) was significant between the PCI-treated and non–PCI-treated cohorts.ConclusionsThe data presented in the current study support using PCI in patients with p-stage II/III disease but not in patients with p-stage I disease. A relatively lower risk for brain metastases in p-stage I patients might explain the inferior efficacy of PCI in this population.     

Down-regulation of Protease-activated Receptor 4 in Lung Adenocarcinoma is Associated with a More Aggressive Phenotype

The role of protease-activated receptors (PARs) in lung tumors is controversial. Although PAR4 ispreferentially expressed in human lung tissues, its possible significance in lung cancer has not been defined. Thestudies reported herein used a combination of clinical observations and molecular methods. Surgically resectedlung adenocarcinomas and associated adjacent normal lung tissues were collected and BEAS-2B and NCI-H157cell lines were grown in tissue culture. PAR4 expression was evaluated by RT-PCR, RT-qPCR, Western blottingand immunohistochemistry analysis. The results showed that PAR4 mRNA expression was generally decreasedin lung adenocarcinoma tissues as compared with matched noncancerous tissues (67.7%) and was associatedwith poor differentiation (p=0.017) and metastasis (p=0.04). Western blotting and immunohistochemical analysisalso showed that PAR4 protein levels were mostly decreased in lung adenocarcinoma tissues (61.3%), and werealso associated with poor differentiation (p=0.035) and clinical stage (p=0.027). Moreover, PAR4 expression wasdecreased in NCI-H157 cells as compared with BEAS-2B cells. In conclusion, PAR4 expression is significantlydecreased in lung adenocarcinoma, and down-regulation of PAR4 is associated with a more clinically aggressivephenotype. PAR4 may acts as a tumor suppressor in lung adenocarcinoma.