非小细胞肺癌组织MET和EGFR基因扩增与预后相关性分析

目的：探讨非小细胞肺癌（non-smfllleelllungcancer,NSCLC）患者中肝细胞生长因子受体（MET）基因和表皮生长因子受体（epidermalgrowthfactorreceptor,EGFR）基因扩增与临床病理特征及预后的关系。方法：回顾分析唐山市协和医院（48例）和唐山市人民医院（109例）2001—01—2007—01手术切除的NSCLC石蜡包埋标本157例。应用荧光原位杂交（fluorescenceinsituhybridization,FISH）检测NSCLCMET、EGFR基因扩增情况,并结合临床病理资料进行统计分析。应用SPSS16．0进行统计分析,Kaplan-Meier模型分析中住生存期（overallsurvival,0S）,Log—rank检验比较生存曲线,多因素分析采用Cox回归模型。结果：157例NSCLC患者标本中,EGFR基因扩增70例（44．6％）。EGFR基因扩增与年龄、性别、吸烟状态、组织类型和TNM分期无关,P〉0．05。157例NSCLC患者标本中,MET基因扩增25例（15．9％）。EGFR扩增患者MET扩增率为22．9％,高于无EGFR扩增患者MET扩增率10．3％,P=0．033。MET基因扩增与年龄、性别、吸烟状态、组织类型和TNM分期无关,P〉0．05。Kaplan-Meier生存分析显示,I＋Ⅱ期中位生存期为51个月,明显高于Ⅲ＋Ⅳ期中位生存期29个月,P=0．001。EGFRFISH阳性患者中位0s为33个月与EGFRFISH阴性患者中位0s39个月比较,差异无统计学意义,P=0．495。METFISH阳性患者中位0S为29个月,低于METFISH阴性患者37个月,P=0．044。患者0s与病理类型、年龄、性别和吸烟状态无相关性,P〉0．05。多因素分析显示,临床分期、MET基因扩增与OS有关（相对危险度为12．573、6．892,P值分别为0．015、0．018）。结论：临床Ⅲ＋Ⅳ期和MET基因扩增NSCLC患者预后不良,EGFR基因扩增与NSCLC患者预后无关。     

Relationship between epidermal growth factor receptor gene copy number and protein expression in oral cavity squamous cell carcinoma

This study was designed to explore the relationship between epidermal growth factor receptor (EGFR) copy number and EGFR protein expression in oral cavity squamous cell carcinoma (OSCCs) in Taiwan. A total of 160 oral cavity squamous cell carcinomas were examined for EGFR protein overexpression using immunohistochemistry and for copy number using a fluorescence in situ hybridization (FISH) assay. Overexpression and increased gene copy numbers of EGFR were found in 75 (46.88%) and 50 (31.25%) cases, respectively. The concordance rate for EGFR gene amplification and protein overexpression was 100%. EGFR overexpression was associated with a poor prognosis both in terms of disease-free survival (DFS) and overall survival (OS). On the other hand, the association between an increase in EGFR gene copies and DFS or OS was insignificant. This was despite the observed significant associations between gene copy number and tumor stage, depth of tumor invasion, lymph node metastasis, bone invasion and perineural invasion. EGFR protein overexpression is closely related to EGFR copy number. Standard methodological and interpretation criteria need to be established that allows EGFR copy number combined with EGFR protein expression to be determined in a manner that allows individualized EGFR targeted therapy in OSCC patients.     

Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients.

PURPOSE: In non-small-cell lung cancer (NSCLC), response to tyrosine kinase inhibitors (TKIs) is significantly associated with the presence of increased copy number and/or activating mutations of the epidermal growth factor receptor gene (EGFR). Preclinical data indicate that HER2, a member of the EGFR family, could enhance TKI sensitivity. PATIENTS AND METHODS: HER2 gene copy numbers per cell were evaluated by fluorescent in situ hybridization (FISH) in 102 NSCLC patients treated with gefitinib, and previously evaluated for EGFR status by FISH, immunohistochemistry, and presence of mutations. RESULTS: Patients with HER2 high copy number (high polysomy and gene amplification [HER2 FISH positive]) represented 22.8% of patients, and compared with patients with no or low gain (HER2 FISH negative), had significantly better objective response (OR, 34.8% v 6.4%; P = .001), disease control rate (DCR, 56.5% v 33.3%; P = .04), time to progression (TTP, 9.05 v 2.7 months; P = .02), and a trend toward longer overall survival (OS, 20.8 v 8.4 months; P = .056). HER2 protein expression investigated by immunohistochemistry was positive in only five of 72 (7%) patients analyzed and all 89 patients tested by DNA sequencing were negative for mutations in HER2 exon 20. Patients with HER2 FISH-positive tumors displaying increased expression of EGFR protein, gene gain, or mutations (EGFR positive) had a significantly better OR, DCR, TTP, and OS than patients negative for both receptors. CONCLUSION: Increased copy number of the HER2 gene is associated with gefitinib sensitivity in EGFR-positive patients, supporting use of HER2 FISH analysis for selection of patients for TKI therapy.     

A phase II clinical trial of celecoxib combined with platinum-based regimen as first-line chemotherapy for advanced non-small cell lung cancer patients with cyclooxygenase-2 positive expression

Objective: To evaluate the efficacy and safety of celecoxib plus platinum-doublet as first-line chemotherapy in treatment of advanced non-small cell lung cancer (NSCLC), and to determine the subgroup benefiting from celecoxib combined therapy by molecular analysis. Methods: A total of 44 treatment-naive patients of advanced NSCLC with positive cyclooxygenase-2 (COX-2) expression confirmed by immunohistochemical (IHC) staining were designed to receive celecoxib plus platinum-doublet chemotherapy (cisplatin plus gemcitabine, novelbine or docetaxol) from February 2005 to May 2007. On 5(7 day before chemotherapy, 400 mg celecoxib was administered twice a day orally until obvious evidence of disease progression or intolerable toxicity was found. Adverse events were recorded according to NCI-CTC criteria. The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), 1-year survival rate, response rate (RR) and safety. Additionally, we detected epithelial growth factor receptor (EGFR) status including EGFR gene amplification by real-time PCR and gene mutations by DHPLC followed by sequencing. Results: The response rate was 45% (20/44), and the disease control rate (DCR) was 59% (26/44). The median progression-free survival time and median survival time were 6 m and 18 m, respectively. The 1-year survival rate was 68%. Chemotherapy cycle numbers and best response were found to be the predictive factors for PFS by COX model analysis (P=0.023 and P=0.000, respectively). No factor was found to affect OS. The most common toxicities included neutropenia and nausea/vomit. EGFR gene amplification was an independent prognostic factor influencing OS (P=0.0002). Patients with EGFR mutations (exon 21) had a tendency of disease progression (P=0.041). Conclusion: Encouraging activities of celecoxib combined with platinum-doublet chemotherapy were demonstrated in treatment-naive patients with advanced NSCLC, with good tolerances. For COX-2 IHC positive patients, positive EGFR amplification and mutation might be related to poor clinical outcomes.     

Clinical relevance of stem cell surface markers CD133, CD24, and CD44 in colorectal cancer

Colon cancer stem cells (CSC) identified by cell surface markers CD133, CD24, and CD44, have been shown to be involved with tumor formation, chemotherapy resistance, and the progression of metastatic disease. Using an in silico translational approach, we hypothesize that a combination of these CSC markers has prognostic value in a large cohort of patients with colorectal cancer. Clinicopathologic and RNA expression data from a total of 594 colorectal cancer (CRC) patients from TCGA were analyzed. The expression of CD133, CD24, and CD44 was individually defined as “high” or “low” based on the median expression. Disease specific survival (DSS) and overall survival (OS) were not associated with tumors that are CD133-high or CD44-high alone. Patients with CD24-high tumors have significantly better DSS (P<0.001) and OS (P = 0.043). CD24-high, CD44-high and CD133-high tumors were associated with significantly greater EGFR, KRAS and Ki67 expression (all P<0.001). CD133, CD24 and CD44-high tumors were independently enriched for conventional stemness-related signaling pathways such as Wnt/β-catenin and Hedgehog signaling pathways. There was no survival difference linked to CD133-high/CD44-low patients, but CD44-high/CD24-low patients have worse DSS (P = 0.005) compared with CD44-low/CD24-high patients. CD133-high/CD24-low tumors show significant negative enrichment of MYC targets, E2F targets, G2M checkpoint and mitotic spindle gene sets, suggesting less cell proliferation in these tumors. Patients with CD133-high/CD24-low tumors have worse DSS (P = 0.004) and OS (P = 0.044), and are more likely to have early and late recurrences. In conclusion, we demonstrated that CD133-high/CD24-low tumors may predict colorectal cancer prognosis.     

Clinicopathologic features and prognostic implications of epidermal growth factor receptor (EGFR) gene copy number and protein expression in non-small cell lung cancer

Increased epidermal growth factor receptor (EGFR) gene copy numbers and mutations predict sensitivity to EGFR tyrosine kinase inhibitor in non-small cell lung cancer (NSCLC). However, the clinicopathologic features of EGFR gene copy status in NSCLC remain unclear. We retrospectively analyzed 262 cases of NSCLC, including 135 squamous cell carcinomas (SCC) and 112 adenocarcinomas (ADC), for which paraffin blocks of the resected primary lung mass were available. None had received EGFR-targeted therapy. EGFR gene copy number was evaluated using fluorescence in situ hybridization (FISH), and EGFR expression was determined immunohistochemically using a tissue microarray. A high EGFR gene copy (EGFR FISH-positive) was found in 30.2% of the cases (amplification in 11.1% and high polysomy in 19.1%). There was no significant difference in EGFR FISH status with respect to SCC and ADC histology. The EGFR FISH-positive rate was higher in non-smokers than in smokers in the multivariate analysis (p=0.012). EGFR expression was significantly associated with a high EGFR gene copy and SCC histology (p=0.000). In the univariate survival analysis, EGFR FISH-positivity predicted worse survival in SCC (p=0.059), especially stage I SCC (p=0.04). EGFR amplification was associated with a shorter survival in node-positive SCC (p=0.015). However, the EGFR gene copy number or protein expression had no influence on the prognosis of ADC. In conclusion, the EGFR FISH-positive rate in Korean patients with NSCLC was similar to rates in Western populations, unlike the higher frequencies of EGFR mutation in East Asians. A high EGFR gene copy number was significantly more common in non-smokers, as were EGFR mutations. A high EGFR gene copy number predicted worse survival in SCC; therefore, the prognostic implications of the EGFR gene and protein should be analyzed in the context of histology and staging in NSCLC.     

Cyclin D1, p53, and p21Waf1/Cip1 expression is predictive of poor clinical outcome in serous epithelial ovarian cancer.

PURPOSE: Dysregulation of cell cycle control, in particular G(1)-S-phase transition, is implicated in the pathogenesis of most human cancers, including epithelial ovarian cancer (EOC). However, the prognostic significance of aberrant cell cycle gene expression in EOC remains unclear. EXPERIMENTAL DESIGN: The expression of selected genes from the pRb pathway that regulates G(1)-S-phase progression, including cyclin D1, p16(Ink4a), cyclin E, p27(Kip1), p21(Waf1/Cip1), and p53, was examined in a consecutive series of 134 serous EOC using immunohistochemistry and the results correlated to disease outcome. RESULTS: Molecular markers predictive of reduced overall survival in univariate analysis were overexpression of cyclin D1 (P = 0.03) and p53 (P = 0.03) and reduced expression of p27(Kip1) (P = 0.05) and p21(Waf1/Cip1) (P = 0.02), with the latter three also being prognostic for a shorter progression-free interval. In addition, patients displaying overexpression of p53 with concurrent loss of p21(Waf1/Cip1) had a significantly shorter overall (P = 0.0008) and progression-free survival (P = 0.0001). On multivariate analysis, overexpression of cyclin D1 and combined loss of p21(Waf1/Cip1) in the presence of p53 overexpression were independent predictors of overall survival. Similarly, the combination of p21(Waf1/Cip1) loss and p53 overexpression was independently predictive of a shorter progression-free interval. Overexpression of p53 and cyclin E and reduced expression of p27(Kip1) and p21(Waf1/Cip1) were significantly associated with increasing tumor grade. CONCLUSIONS: This study confirms that dysregulation of cell cycle genes is common in EOC, and that aberrant expression of critical cell cycle regulatory proteins can predict patient outcome in serous EOC.     

Epidermal growth factor receptor gene copy number and protein level are not associated with outcome of non-small-cell lung cancer patients treated with chemotherapy.

BACKGROUND: Survival benefit of non-small-cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors is predicted by high EGFR gene copy number and by strong EGFR protein expression. Clinical relevance of these features in patients treated with chemotherapy has not been reported. PATIENTS AND METHODS: This study included 82 NSCLC patients treated with chemotherapy. There were 45% of females, 6% of never smokers and 45% of patients diagnosed with adenocarcinoma. EGFR gene copy number was evaluated by fluorescence in situ hybridization and EGFR protein level by immunohistochemistry. RESULTS: High EGFR gene copy number and protein level were found in 33% and 71% of patients, respectively. Both markers were significantly associated (P = 0.01). For objective response and disease control, there was no difference between patients defined as negative or positive for both EGFR gene copy number (P = 0.39 and P = 1.00, respectively) and for EGFR protein (P = 1.00 and P = 0.80, respectively). There were no differences in progression-free and overall survival according to EGFR gene copy number (P = 0.76 and P = 0.82, respectively) and protein level (P = 0.67 and P = 0.62, respectively). CONCLUSION: In chemotherapy-treated NSCLC patients, EGFR gene copy number was positively associated with protein level but none of the features were predictive for either treatment response or survival.     

Predictive Value of CD44 for Prognosis in Patients with Breast Cancer

Background: Breast Cancer (BC), is one of the most common malignancies around the world. CD44 expression correlates with cell proliferation, infiltration, angiogenesis, metastasis and prognosis in breast cancer but the exact mechanism of CD44 function is still not clear. The present study evaluates the expression of CD44 in primary HER2-positive breast cancer. The results can be used to determine the disease-free and overall survival of patients with breast cancer. Methods: We studied specimens from 100 patients with HER2-positive invasive breast cancer between March 2011 and June 2019. Immunohistochemical staining for CD44 was performed in all the specimens. Their CD44 association with clinicopathologic parameters and prognosis was evaluated. Results: The high CD44 was expression in 68(68%) of the patients and Low expression in 32(32%). CD44 expression was significantly associated with stage (p=0.007). There were no significant associations between the DFS, OS and other clinicopathologic parameters except for the stage, respectively (HR= 3.67, 95% CI =1.16-11.56, P = 0.03) (HR= 0.8.56, 95% CI =2.22-32.90, P = 0.002).20% of patients had died by the end of the follow-up. There were no significant association between DFS, OS and CD44 expression, respectively. (Log-rank p=0.13). (Log-rank p=0.10). Conclusion: The results from this study suggest that CD44 is clinically associated with stage of breast cancers. From the survival analysis, there was no statistical difference in overall survival and disease free survival with respect to CD44 expression. Further studies larger sample sizes are recommended for further investigation.     

表皮生长因子受体和肝细胞生长因子受体在非小细胞肺癌中的表达及其与预后的关系

目的 探讨非小细胞肺癌(NSCLC)组织中表皮生长因子受体(EGFR)和肝细胞生长因子受体(c-Met)基因和蛋白的表达情况,及其与NSCLC临床病理特征和预后的关系.方法 采用免疫组化法检测61例NSCLC组织中EGFR和c-Met蛋白的表达情况,采用实时荧光定量PCR法检测EGFR和c-Met DNA的相对拷贝数.结果 61例NSCLC组织中,EGFR和c-Met蛋白的阳性表达率分别为77.0%和57.4%.EGFR和c-Met蛋白在高、中分化NSCLC组织中的阳性表达率分别为61.5%和38.5%,均明显低于低分化的肿瘤组织(均P＜0.05).EGFR和c-Met DNA在吸烟患者中的相对拷贝数分别为0.22±0.22和0.20±0.21,均明显高于不吸烟患者(均P＜0.05);在腺癌中的相对拷贝数分别为0.24±0.26和0.23±0.25,均明显高于鳞癌患者(均P＜0.05).EGFR蛋白与c-Met蛋白表达、EGFR DNA相对拷贝数与c-Met DNA相对拷贝数、EGFR蛋白表达与EGFR DNA相对拷贝数之间均具有显著的相关性(均P＜0.05),但c-Met蛋白表达与c-Met DNA相对拷贝数之间没有相关性(P=0.259).EGFR DNA低拷贝组和高拷贝组患者的术后中位生存时间分别为48和36个月,差异有统计学意义(P=0.039);c-Met DNA低拷贝组和高拷贝组患者的术后中位生存时间分别为44和31个月,差异亦有统计学意义(P=0.022).结论 EGFR和c-Met的蛋白表达与NSCLC的分化程度有关;EGFR和c-Met DNA的相对拷贝数与NSCLC患者的吸烟史以及病理类型有关,有助于预测NSCLC患者的预后.     

肺癌驱动基因与非小细胞肺癌生存关系的相关性研究

目的探讨非小细胞肺癌驱动基因EGFR、KRAS、BRAF、PIK3CA、ALK、MET、HER-2、RET、ROS-1与患者预后相关性,寻找更有效防治分子靶标。方法利用Kaplan-Meier(KM)plotter在线数据库分析EGFR、KRAS、BRAF、PIK3CA、ALK、MET、HER-2、RET、ROS-1表达与非小细胞肺癌患者总生存期(overall survival OS),性别与吸烟状态等参数的相关性,并得出相应的危险比(Hazard ratio,HR)、95%置信区间(CI)和P值。结果研究结果显示:高表达EGFR、BRAF、MET、RET、ROS-1的患者有较好的OS。进一步引入吸烟状态和性别参数显示,BRAF、MET,PIK3CA、HER-2、ALK的表达与患者的吸烟状态存在相关性(P<0.05)。BRAF、MET、EGFR、ALK表达与OS的相关性存在性别差异(P<0.05)。结论各驱动基因在患者预后评判中既是独立因素,又相互作用,吸烟状态与性别也是决定患者预后的关键因素,提示临床治疗时要对患者进行综合的评判,要进行多基因的共同分析、多靶点的联合治疗才能使病人获得更大的收益。     

No Association between BRCA1 Immunohistochemical Expression and Tumor Grade,Stage or Overall Survival in Platinum-Treated Epithelial Ovarian Cancer Patients

Background: The aim of this work is to assess the frequency of BRCA1 protein immunohistochemical (IHC)expression in epithelial ovarian cancer (EOC) and to evaluate the association of BRCA1 expression with clinicaland pathological characteristics and the overall survival (OS) of patients treated with postoperative platinumbasedchemotherapeutic agents. Materials and Methods: This retrospective study was conducted on 35 cases ofepithelial ovarian cancer selected from the files of the Pathology Department, Faculty of Medicine, MansouraUniversity, Egypt. Immunohistochemistry (IHC) was performed for BRCA1 gene protein. BRCA1 expressionwas compared to patient’s age, tumor histology, grade, stage and OS time. Statistical analysis was carried outwith the SPSS version 16.0 to assess significant associations. Results: BRCA1 nuclear expression was detectedin 40% of EOC, in which a mild increase in the percentage of positive cases was observed with serous histology,stage IV, and grade 3 carcinomas. There was a significant statistical difference in BRCA1 expression with regardto histological subtypes of EOC (p=0.048), but not grade or stage. Mean OS and survival rate were slightly betterfor BRCA1 expressing group, but there was no statistically significant difference (p=0.528). Conclusions: Noassociation between BRCA1 immunohistochemical expression and tumor grade, stage or overall survival wasnoted in platinum-treated epithelial ovarian cancer patients.     

Long noncoding RNA TC0101441 induces epithelial–mesenchymal transition in epithelial ovarian cancer metastasis by downregulating KiSS1

Peritoneal metastasis is a critical feature and clinical challenge in epithelial ovarian cancer (EOC). We previously identified a novel long noncoding RNA (lncRNA, TC0101441) in epithelial ovarian cancer (EOC) using microarrays. However, the impact of TC0101441 on EOC metastasis and prognosis remains unclear. TC0101441 expression in EOC tissues and its correlation with clinicopathological factors and prognosis were examined. A series of in vitro and in vivo assays were performed to elucidate the roles and mechanism of TC0101441 in EOC metastasis. We found that TC0101441 levels were elevated in EOC tissues compared with those in normal controls and significantly correlated with an advanced clinical stage and lymph node metastasis. TC0101441 was determined to be an independent prognostic predictor of overall survival (OS) and disease-free survival (DFS). Furthermore, loss-of-function assays showed that TC0101441 promoted the invasive and metastatic capacities of EOC cells both in vitro and in vivo. Mechanistically, the prometastatic effects of TC0101441 were linked to the induction of epithelial–mesenchymal transition (EMT). Importantly, KiSS1 was identified as a downstream target gene of TC0101441 and was downregulated by TC0101441 in EOC cells. After TC0101441 was silenced, the corresponding phenotypes of EOC cell invasion and EMT were reversed by the overexpression of KiSS1. Taken together, our data suggest that TC0101441 functions as a potential promigratory/invasive oncogene by promoting EMT and metastasis in EOC through downregulation of KiSS1, which may represent a novel prognostic marker and therapeutic target in EOC.     

Membranous expressions of Lewis y and CAM-DR-related markers are independent factors of chemotherapy resistance and poor prognosis in epithelial ovarian cancer

Background: Chemotherapy resistance is a common problem faced by patients diagnosed with epithelial ovarian cancer (EOC). Currently there are no specific or sensitive clinical biomarkers that maybe implemented to identify chemotherapy resistance and give insight to prognosis. The aim of this study is to investigate the roles of Lewis y antigen and the markers associated with cell-adhesion-mediated drug resistance (CAM-DR) in patients with EOC. Methods: 92 EOC patients who were treated with systemic chemotherapy after cytoreductive surgery were included in this analysis. Patients were divided into two groups, chemotherapy sensitive (n = 56) and resistant (n = 36). Immunohistochemical (IHC) staining for Lewis y and CAM-DR-related cell surface proteins including CD44, CD147, HE4 (Human epididymis protein 4), integrin α5, β1, αv and β3 were conducted on tissues collected during primary debulking surgery. Using multivariate logistic regressions, IHC results were compared to clinical variables and chemotherapy resistance to determine possible correlations. The relationships between IHC expression and progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier method and Cox regression analysis. Results: Membranous expression of Lewis y and all these CAM-DR-related markers were significantly higher in the resistant group than that of the sensitive group (all P < 0.01). Multivariate regression analysis revealed that high expression of Lewis y, CD44, HE4, integrin α5 and β1 as well as advanced FIGO stage were independent risk factors for chemotherapy resistance (all P < 0.05). Advanced FIGO stage, lymph node metastasis and high expression of Lewis y, CD44, CD147, HE4, integrin α5, β1 were associated with a shorter PFS and OS (all P < 0.05). Moreover, multivariate COX analysis demonstrated that the following variates were independent predictors of worse PFS and OS survival: late FIGO stage (P = 0.013, 0.049), high expressions of Lewis y (P = 0.010, 0.036), HE4 (P = 0.006, 0.013) and integrin β1 (PFS, P = 0.003), integrin α5 (OS, P = 0.019). Conclusion: Membranous expression of Lewis y and CAM-DR-related markers including CD44, CD147, HE4, integrin α5, β1, αv and β3 are associated with the development of chemotherapy resistance. High expression of Lewis y antigen and CAM-DR-related markers including CD44, CD147, HE4, integrin α5 and β1 are independent markers for PFS and OS, in which Lewis y and HE4 are the most significant.     

婆罗双树样基因4在非小细胞肺癌中的表达及其与临床病理和分子特征的相关性

目的:探讨婆罗双树样基因4(SALL4)在非小细胞肺癌(NSCLC)组织中的表达及其与NSCLC临床病理因素和分子特征之间的关系。方法:选取136例NSCLC患者手术切除标本、165例晚期肺腺癌患者穿刺活检标本,采用免疫组织化学方法检测SALL4蛋白、干细胞标志物CD44、上皮间质转化(EMT)相关标志物(E-cadherin、Vimentin)和ALK蛋白(D5F3)的表达,核酸分子原位杂交技术检测Snail mRNA,利用基因突变扩增阻滞系统(ARMS)检测EGFR和KRAS基因突变。结果:癌旁组织SALL4阴性,136例手术切除原发性NSCLC组织SALL4阳性率21.3%,有淋巴结转移、UICC分期Ⅲ期、低分化的NSCLC组SALL4阳性强度均高于相应对照组(P<0.05),SALL4阳性NSCLC患者术后无进展生存率、总体生存率均低于SALL4阴性者(P<0.05)。165例晚期肺腺癌穿刺活检组织中SALL4阳性率21.8%,其中腺泡型腺癌SALL4阳性率高于其他类型,基因检测结果显示EGFR突变组SALL4阳性率高于野生型组(P<0.05);SALL4的阳...     

Gene expression patterns of chemoresistant and chemosensitive serous epithelial ovarian tumors with possible predictive value in response to initial chemotherapy

Chemotherapy (CT) resistance in ovarian cancer is broad and encompasses diverse, unrelated drugs, suggesting more than one mechanism of resistance. We aimed to analyze the gene expression patterns in primary serous epithelial ovarian cancer (EOC) samples displaying different responses to first-line CT in an attempt to identify specific molecular signatures associated with response to CT. Initially, the expression profiles of 15 chemoresistant serous EOC tumors [time to recurrence (TTR) or =30 months) were independently analyzed which allowed the identification of specific sets of differentially expressed genes that might be functionally implicated in the evolution of the chemoresistant or the chemosensitive phenotype. Our data suggest that the intrinsic chemoresistance in serous EOC cells may be attributed to the combined action of different molecular mechanisms and factors linked with drug influx and efflux and cell proliferation, as possible implications of other molecular events including altered metabolism, apoptosis and inflammation cannot be excluded. Next, gene expression comparison using hierarchical clustering clearly distinguished chemosensitive and chemoresistant tumors from the 25 serous EOC samples (training set), and consecutive class prediction analysis was used to develop a 43-gene classifier that was further validated in an independent cohort of 15 serous EOC patients and 2 patients with other ovarian cancer histotypes (test set). The 43-gene predictor set properly classified serous EOC patients at high risk for early (< or =22 months) versus late (>22 months) relapse after initial CT. Thus, gene expression array technology can effectively classify serous EOC tumors according to CT response. The proposed 43-gene model needs further validation.     

Gender-related survival differences associated with EGFR polymorphisms in metastatic colon cancer

Evidence is accumulating supporting gender-related differences in the development of colonic carcinomas. Sex steroid hormone receptors are expressed in the colon and interact with epidermal growth factor receptor (EGFR), a gene widely expressed in colonic tissue. Increased EGFR expression is linked with poor prognosis in colon cancer. Within the EGFR gene there are two functional polymorphisms of interest: a polymorphism located at codon 497 (HER-1 R497K) and a dinucleotide (CA)(n) repeat polymorphism located within intron 1. These germ-line polymorphisms of EGFR were analyzed in genomic DNA from 318 metastatic colon cancer patients, 177 males and 141 females, collected from 1992 to 2003. Gender-related survival differences were associated with the HER-1 R497K polymorphism (P(interaction) = 0.003). Females with the HER-1 497 Arg/Arg variant had better overall survival (OS) when compared with the Lys/Lys and/or Lys/Arg variants. In males the opposite was true. The EGFR dinucleotide (CA)(n) repeat also trended with a gender-related OS difference (P(interaction) = 0.11). Females with both short <20 (CA)(n) repeat alleles had better OS than those with any long >or=20 (CA)(n) repeats. In males the opposite was true. Combination analysis of the two polymorphisms taken together also revealed the same gender-related survival difference (P(interaction) = 0.002). These associations were observed using multivariable analysis. The two polymorphisms were not in linkage disequilibrium and are independent of one another. This study supports the role of functional EGFR polymorphisms as independent prognostic markers in metastatic colon cancer. As a prognostic factor, these variants had opposite prognostic implications based on gender.     

MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors

We analyzed MET protein and copy number in NSCLC with or without EGFR mutations untreated with EGFR tyrosine kinase inhibitors (TKIs). MET copy number was examined in 28 NSCLC and 4 human bronchial epithelial cell lines (HBEC) and 100 primary tumors using quantitative real‐time PCR. Positive results were confirmed by array comparative genomic hybridization and fluorescence in‐situ hybridization. Total and phospho‐MET protein expression was determined in 24 NSCLC and 2 HBEC cell lines using Western blot. EGFR mutations were examined for exon 19 deletions, T790M, and L858R. Knockdown of EGFR with siRNA was performed to examine the relation between EGFR and MET activation. High‐level MET amplification was observed in 3 of 28 NSCLC cell lines and in 2 of 100 primary lung tumors that had not been treated with EGFR‐TKIs. MET protein was highly expressed and phosphorylated in all the 3 cell lines with high MET amplification. In contrast, 6 NSCLC cell lines showed phospho‐MET among 21 NSCLC cell lines without MET amplification (p = 0.042). Furthermore, those 6 cell lines harboring phospho‐MET expression without MET amplification were all EGFR mutant (p = 0.0039). siRNA‐mediated knockdown of EGFR abolished phospho‐MET expression in examined 3 EGFR mutant cell lines of which MET gene copy number was not amplified. By contrast, phospho‐MET expression in 2 cell lines with amplified MET gene was not down‐regulated by knockdown of EGFR. Our results indicated that MET amplification was present in untreated NSCLC and EGFR mutation or MET amplification activated MET protein in NSCLC. © 2008 Wiley‐Liss, Inc.     

卵巢上皮性癌组织中长链非编码RNA PURPL的表达及其意义

  目的  检测长链非编码RNA PURPL（p53 upregulated regulator of p53 levels）在卵巢上皮性癌（epithelial ovarian cancer,EOC）组织中的表达情况,探讨其在卵巢癌发生发展中的作用。  方法  选用开放医学数据库lncRNASNP2、GEPIA和Kaplan-Meier Plotter检索PURPL在EOC组织中的表达及其与预后的关系。收集2012年10月至2015年10月郑州大学第一附属医院105例患者的临床病理资料,其中包括正常卵巢组织20例、良性卵巢上皮性肿瘤组织20例、EOC组织65例,采用实时荧光定量PCR检测上述不同卵巢组织中的PURPL表达情况,分析EOC组织中PURPL表达与EOC临床病理指标的关系,Kaplan-Meier法分析PURPL表达对EOC患者生存的影响。  结果  数据库检索显示,EOC组织中PURPL的表达显著高于正常卵巢组织,PURPL表达升高与EOC患者的总生存（overall survival,OS）率和无复发生存期（recurrence-free survival,RFS）缩短相关。实时荧光定量PCR检测显示,晚期EOC组织中的PURPL表达为0.530±0.004,显著高于正常卵巢组织的0.029±0.001、良性卵巢上皮性肿瘤组织的0.135±0.001和早期EOC组织的0.488±0.006的表达（P<0.0001）。临床分期越晚（χ2=10.785,P=0.001）、有淋巴结转移（χ2=4.481,P=0.034）的EOC组织中的PURPL高表达。PURPL表达水平相对较高的EOC患者的OS和RFS,明显短于PURPL表达水平相对较低的患者（P<0.05）。  结论  PURPL高表达提示EOC患者预后不良,可作为EOC预后监测的潜在标记物。