无预后标志性基因的急性B淋巴细胞白血病患儿随访10年复发因素的分析

目的:通过分析CCLG-ALL 2008方案治疗无预后标志性融合基因的急性B淋巴细胞白血病(B-ALL)患儿的疗效,并分析影响复发的相关因素。方法:回顾性分析239例于2008年3月至2012年12月在苏州大学附属儿童医院诊断为B-ALL、多重RT-PCR未检测到预后标志性融合基因,且接受CCLG-ALL 2008方案化疗的患儿,随防到2019年8月31日,中位随访时间92(0-136)个月。Kaplan-Meier分析无复发生存时间(RFS),COX多因素回归分析复发相关的独立因素。结果:239例患儿中男性140例,女性99例,男女比例1.41∶1,中位诊断年龄4.4岁,初诊白细胞中位数是4.98×10^(9)/L,复发77例,非复发162例,失访16例,死亡72例。复发率和死亡率分别为32.22%和30.1%,其中45例死于复发(占总死亡人数62.5%)。对复发危险因素进行单因素分析,发现初诊年龄≥6岁、初诊白细胞计数>100×10^(9)/L、d15骨髓原始细胞≥25%、第12周骨髓微小残留病(MRD)>10^(-4)以及最终危险度为高危是影响复发的主要因素(P<0.05)。多因素COX回归分析显示,年龄≥6岁、初诊白细胞数>100×10^(9)/L、第12周骨髓MRD>10^(-4)是复发的独立危险因素。结论:年龄、初诊白细胞计数、第12周骨髓MRD与无预后标志性融合基因B-ALL患儿复发相关,在临床工作中可作为评估患儿复发风险的预后指标。

与前列腺癌恩杂鲁胺耐药相关铁死亡基因的生物信息学分析

目的基于生物信息学方法分析与前列腺癌恩杂鲁胺耐药相关的铁死亡差异表达基因。方法从基因表达数据库(GEO)中下载恩杂鲁胺耐药与未耐药的前列腺癌细胞测序基因集(GSE104935、GSE78201),筛选差异表达基因;通过FerrDb数据库收集铁死亡相关基因。通过ImageGP维恩图工具将GEO数据库中差异表达基因及FerrDb数据库中铁死亡相关基因取交集,获得铁死亡相关恩杂鲁胺耐药前列腺癌的差异表达基因。将筛选出来的差异表达基因通过R软件进行GO功能(包括生物过程、分子功能、细胞成分)和KEGG作用通路富集分析。选取美国癌症研究所及美国人类基因组研究所收集处理的关于前列腺癌的测序数据和临床数据(TCGA-PRAD),通过R软件对铁死亡相关恩杂鲁胺耐药前列腺癌差异表达基因进行临床预后的单因素、多因素Cox回归分析,获得铁死亡相关恩杂鲁胺耐药前列腺癌的预后标志基因。用R软件在TCGA-PRAD队列中分析铁死亡相关恩杂鲁胺耐药前列腺癌预后标志基因的表达水平,Kaplan-Meier法比较预后标志基因高、低表达者的总生存期(OS)、无进展生存期(PFI)和疾病特异性生存期(DSS)。利用R软件绘制预测患者1、3、5年OS、PFI的受试者工作特征(ROC)曲线,通过曲线下面积(AUC)评价预测价值。结果从GEO、FerrDb数据库中共筛选获得铁死亡相关恩杂鲁胺耐药前列腺癌的差异表达基因31个。GO功能分析显示,铁死亡相关恩杂鲁胺耐药前列腺癌差异表达基因主要富集的生物过程为营养水平反应、细胞对外界刺激的反应、氧化应激反应等,主要富集的细胞成分为自噬体膜、次级溶酶体、自噬体等,主要富集的分子功能为类固醇脱氢酶活性、醛醇NADP+1-氧化还原酶、酰CoA连接酶活性等;KEGG作用通路分析显示,铁死亡相关恩杂鲁胺耐药前列腺癌差异表达基因主要富集的作用通路为花生四烯酸代谢、自噬、卡波西肉瘤相关疱疹病毒感染等。单因素、多因素Cox回归分析显示,LAMP2为铁死亡相关恩杂鲁胺耐药前列腺癌的预后标志基因。TCGA-PRAD队列中,LAMP2在前列腺癌组织中相对表达量低于正常组织(P<0.01),LAMP2低表达者OS、PFI均低于高表达者(P均<0.05),DSS与高表达者差异无统计学意义。ROC曲线结果显示,LAMP2预测前列腺癌患者1、3、5年OS的AUC分别为0.825、0.747、0.770,预测前列腺癌患者1、3、5年PFI的AUC分别为0.539、0.601、0.568。结论LAMP2、VEGFA、ACSF2等铁死亡相关恩杂鲁胺耐药前列腺癌差异表达基因主要富集在营养水平反应、细胞对外界刺激的反应、氧化应激反应等功能及花生四烯酸代谢、自噬、卡波西肉瘤相关疱疹病毒感染等作用通路。LAMP2为铁死亡相关恩杂鲁胺耐药前列腺癌的预后标志基因,LAMP2异常低表达是前列腺癌患者预后不良的独立危险因素,其对患者预后具有良好的预测价值。

早期非小细胞肺癌预后基因标志研究现状与思考

非小细胞肺癌同一TNM分期患者的预后存在巨大差异，即便是早期（I、Ⅱ期）患者根治术后的生存率亦明显低于预期，说明基于解剖学特征的现有TNM分期系统尚不足以充分反映预后。更兼早期肿瘤生长的不充分，限制了解剖学特征的预后反映力度，由此而产生一系列着眼于肿瘤组织本身生物学特性的研究，以期找到对不良预后有提示作用的基因标志。这一系列研究主要基于生物芯片和定量PCR技术，运用生物信息学方法进行数据分析。目前研究现状错综复杂，背景相似的不同研究所获标志基因甚少重叠，一方面亟需研究流程的标准化，另一方面需跳出若干基因简单组合的窠臼，基于肿瘤信号通路组合预后基因标志的思路或更具有科学性、系统性，是未来的重要发展方向。

Thioredoxin and thioredoxin-interacting protein as prognostic markers for gastric cancer recurrence

AIM:To evaluate the potential of thioredoxin (TXN) and thioredoxin-interacting protein (TXNIP) expression as biomarkers for predicting gastric cancer recurrence. METHODS:TXN and TXNIP expression levels were acquired from gene expression microarray data for 65 human gastric cancer tissues. We determined whether each gene expression level was associated with cancer recurrence and investigated the relationship between the two genes. For validation, the expression levels of TXN and TXNIP were measured by quantitative real- time reverse transcription polymerase chain reaction in 68 independent stage Ⅲ gastric cancer patients. The correlation between gene expression and cancer prognosis was evaluated. Immunohistochemical staining was performed to investigate the protein expression levels of TXN and TXNIP and to characterize the expression patterns of each protein. RESULTS:TXN was a prognosis-related gene (P = 0.009), whereas TXNIP, a TXN inhibitor, demonstrated a negative correlation with TXN in the gene expression microarray data. In the 68 stage Ⅲ patients, the expression levels of both TXN and TXNIP had a statistically significant effect on recurrence-free survival (RFS, P = 0.008 and P = 0.036, respectively). The low TXN and high TXNIP expression group exhibited a better prognosis than the other groups, and the high TXN and low TXNIP expression group exhibited a poorer prognosis (P < 0.001 for RFS and P = 0.001 for overall survival). More than half of the patients in the simulta-neously high TXN and low TXNIP expression group ex- perienced a recurrence within 1 year after curative surgery, and the 5-year survival rate of the patients in this group was 29%, compared with 89% in the low TXN and high TXNIP expression group. The TXN protein was overexpressed in 65% of the gastric cancer tissues, whereas the TXNIP protein was underexpressed in 85% of the cancer cells. In a correlation analysis, TXN and TXNIP were highly correlated with many oncogenes and tumor suppressors as well as with genes related to energy, protein synthesis and autophagy. CONCLUSION:TXN and TXNIP are promising prognostic markers for gastric cancer, and performing personalized adjuvant treatment based on TXN and TXNIP expression levels would be an effective practice in the treatment of gastric cancer.

RRAS:A key regulator and an important prognostic biomarker in biliary atresia

AIM:To characterize the differentially expressed gene profiles in livers from biliary atresia (BA) patients including,ascertain genes,functional categories and pathways that play a central role in the pathogenesis of BA,and identify the novel prognostic markers for BA.METHODS:Liver tissue samples from control patients,neonatal cholestasis patients,and BA patients at the age of < 60 d,60-90 d,and > 90 d were pooled for DNA microarray analysis.Bioinformatics analysis was performed using,series test cluster of gene ontology,and Pathway-Finder software.Reverse-transcription polymerase chain reaction was performed to confirm changes in selected genes.Relation between RRAS gene expression and prognosis of 40 BA patients was analyzed in a 2-year follow-up study.RESULTS:The 4 identified significant gene expression profiles could confidently separate BA liver tissue from normal and other diseased liver tissues.The included genes were mainly involved in inflammation response and reconstruction of cellular matrix.The significant pathways associated with BA were primarily involved in autoimmune response,activation of T lymphocytes and its related cytokines.The RRAS,POMC,SLC26A6 and STX3 genes were important regulatory modules in pathogenesis of BA.The expression of RRAS was negatively correlated with the elimination rate of jaundice and positively correlated with the occurrence rate of cholangitis.CONCLUSION:Autoimmune response mediated by T lymphocytes may play a vital role in the pathogenesis of BA.The RRAS gene is an important regulatory module in the pathogenesis of BA,which may serve as a novel prognostic marker for BA.