Hybrid Models Identified a 12-Gene Signature for Lung Cancer Prognosis and Chemoresponse Prediction

Background

Lung cancer remains the leading cause of cancer-related deaths worldwide. The recurrence rate ranges from 35–50% among early stage non-small cell lung cancer patients. To date, there is no fully-validated and clinically applied prognostic gene signature for personalized treatment.

Methodology/Principal Findings

From genome-wide mRNA expression profiles generated on 256 lung adenocarcinoma patients, a 12-gene signature was identified using combinatorial gene selection methods, and a risk score algorithm was developed with Naïve Bayes. The 12-gene model generates significant patient stratification in the training cohort HLM & UM (n = 256; log-rank P = 6.96e-7) and two independent validation sets, MSK (n = 104; log-rank P = 9.88e-4) and DFCI (n = 82; log-rank P = 2.57e-4), using Kaplan-Meier analyses. This gene signature also stratifies stage I and IB lung adenocarcinoma patients into two distinct survival groups (log-rank P<0.04). The 12-gene risk score is more significant (hazard ratio = 4.19, 95% CI: [2.08, 8.46]) than other commonly used clinical factors except tumor stage (III vs. I) in multivariate Cox analyses. The 12-gene model is more accurate than previously published lung cancer gene signatures on the same datasets. Furthermore, this signature accurately predicts chemoresistance/chemosensitivity to Cisplatin, Carboplatin, Paclitaxel, Etoposide, Erlotinib, and Gefitinib in NCI-60 cancer cell lines (P<0.017). The identified 12 genes exhibit curated interactions with major lung cancer signaling hallmarks in functional pathway analysis. The expression patterns of the signature genes have been confirmed in RT-PCR analyses of independent tumor samples.

Conclusions/Significance

The results demonstrate the clinical utility of the identified gene signature in prognostic categorization. With this 12-gene risk score algorithm, early stage patients at high risk for tumor recurrence could be identified for adjuvant chemotherapy; whereas stage I and II patients at low risk could be spared the toxic side effects of chemotherapeutic drugs.     

Model Comparison for Breast Cancer Prognosis Based on Clinical Data

We compared the performance of several prediction techniques for breast cancer prognosis, based on AU-ROC performance (Area Under ROC) for different prognosis periods. The analyzed dataset contained 1,981 patients and from an initial 25 variables, the 11 most common clinical predictors were retained. We compared eight models from a wide spectrum of predictive models, namely; Generalized Linear Model (GLM), GLM-Net, Partial Least Square (PLS), Support Vector Machines (SVM), Random Forests (RF), Neural Networks, k-Nearest Neighbors (k-NN) and Boosted Trees. In order to compare these models, paired t-test was applied on the model performance differences obtained from data resampling. Random Forests, Boosted Trees, Partial Least Square and GLMNet have superior overall performance, however they are only slightly higher than the other models. The comparative analysis also allowed us to define a relative variable importance as the average of variable importance from the different models. Two sets of variables are identified from this analysis. The first includes number of positive lymph nodes, tumor size, cancer grade and estrogen receptor, all has an important influence on model predictability. The second set incudes variables related to histological parameters and treatment types. The short term vs long term contribution of the clinical variables are also analyzed from the comparative models. From the various cancer treatment plans, the combination of Chemo/Radio therapy leads to the largest impact on cancer prognosis.     

Expression of Notch1 Correlates with Breast Cancer Progression and Prognosis

Various studies have evaluated the significance of Notch1 expression in breast cancer, but the results have ever been disputed. By using 21 studies involving 3867 patients, this meta-analysis revealed that the expression of Notch1 was significantly higher in breast cancer than in normal tissues (OR=7.21; 95%CI, 4.7-11.07) and that higher Notch1 expression was associated with transition from ductal carcinoma in situ (DCIS) to invasive cancer (OR=3.75; 95% CI, 1.8-7.78). Higher Notch1 activity was observed in the basal subtype of breast cancer (OR=2.53; 95% CI, 1.18-5.43). Moreover, patients with Notch1 overexpression exhibited significantly worse overall and recurrence-free survival. Our meta-analysis suggests that Notch inhibitors may be useful in blocking the early progression of DCIS and that the outcomes of clinical trials for Notch1-targeting therapeutics could be improved by the molecular stratification of breast cancer patients.     

Expression of Polycomb Targets Predicts Breast Cancer Prognosis

Global changes in the epigenome are increasingly being appreciated as key events in cancer progression. The pathogenic role of enhancer of zeste homolog 2 (EZH2) has been connected to its histone 3 lysine 27 (H3K27) methyltransferase activity and gene repression; however, little is known about relationship of changes in expression of EZH2 target genes to cancer characteristics and patient prognosis. Here we show that through expression analysis of genomic regions with H3K27 trimethylation (H3K27me3) and EZH2 binding, breast cancer patients can be stratified into good and poor prognostic groups independent of known cancer gene signatures. The EZH2-bound regions were downregulated in tumors characterized by aggressive behavior, high expression of cell cycle genes, and low expression of developmental and cell adhesion genes. Depletion of EZH2 in breast cancer cells significantly increased expression of the top altered genes, decreased proliferation, and improved cell adhesion, indicating a critical role played by EZH2 in determining the cancer phenotype.     

High Bak Expression Is Associated with a Favorable Prognosis in Breast Cancer and Sensitizes Breast Cancer Cells to Paclitaxel

Breast cancer has become the leading cause of cancer-related death among women. A large number of patients become resistant to drug chemotherapy. Paclitaxel (Taxol) is an effective chemotherapeutic agent used to treat cancer patients. Taxol has been widely used in human malignancies including breast cancer because it can stabilize microtubules resulting in cell death by causing an arrest during the G2/M phase of the cell cycle. Pro-apoptotic Bcl-2 antagonist killer 1 (Bak) plays an important role in Taxol-induced apoptosis in breast cancer. In our present study, we investigated the expression of the Bak protein and clinicopathological correlations in a large sample of breast cancer tissues by immunohistochemistry. We found that the percentage of high scores of Bak expression in breast cancer was significantly lower than that of the non-cancerous breast control tissue. In addition, lower Bak expression was positively associated with the clinical TNM stage of breast cancer with a significant decrease in overall survival compared with those with higher Bak expression especially in the Luminal and HER2 subtypes. Importantly, higher Bak expression predicted a favorable clinical outcome in the cases treated with Taxol indicated by a higher overall survival than that of patients with lower Bak expression especially in Luminal and HER2 subtypes. Furthermore, these results were confirmed in vitro since overexpression of Bak sensitized breast cancer cells to Taxol by inhibiting proliferation and promoting apoptosis; in contrast, downregulation of Bak through siRNA transfection inhibited Taxol induced-apoptosis. Therefore, our results demonstrate that Bak acts as a sensitive biomarker and favorable prognostic factor for Taxol treatment in breast cancer. The restoration of Bak expression would be therapeutically beneficial for Taxol resistant breast cancer patients.     

乳腺癌患者预后的相关因素分析

目的:探讨影响乳腺癌患者预后的相关因素。方法:回顾性分析2008年1月~2009年2月我院收治的81例乳腺癌患者的临床、病理及随访资料。结果:所有患者均手术治疗并经病理证实,年龄45岁以上的乳腺癌患者的五年生存率为82.6%,显著高于45岁及其以下者(45.7%,P0.05);肿瘤直径为3 cm及其以下的乳腺癌患者的五年生存率为81.5%,显著高于肿瘤直径为3 cm以上者(40.7%,P0.05);无淋巴结转移的乳腺癌患者五年生存率明显高于有淋巴结转移的乳腺癌患者(P0.05);I期、II期、Ⅲ期、Ⅳ期的乳腺癌患者五年生存率分别为93.8%、73.0%、52.9%、0%,不同临床分期的乳腺癌患者的五年生存率比较差异均有统计学意义(P0.05)。结论:乳腺癌的治疗以手术为主,年龄、肿瘤大小、淋巴结转移、临床分期与患者的预后密切相关。     

High Expression of KIF26B in Breast Cancer Associates with Poor Prognosis

To date, a great number of studies have demonstrated that altered expression of kinesins is associated with development and progression of various human cancers. Kinesin family member 26B (KIF26B), a member of the kinesin superfamily proteins (KIFs), is essential for kidney development. However, the role of KIF26B during tumorigenesis and progression is limited. Here, we demonstrate that both KIF26B mRNA and protein are overexpression in breast cancer tissues by RT-qPCR and western blot. Immunohistochemistry revealed that KIF26B expression significantly correlated with clinicopathological factors, including tumor size (P = 0.011), grade (P = 0.017), lymph node status (P = 0.009) and ER status (P = 0.012). Moreover, the Kaplan-Meier analysis indicated that breast cancer patients with high KIF26B expression had a shorter survival than those with low KIF26B expression. In addition, multivariate analysis indicated that KIF26B is an independent prognostic for outcome in breast cancer (HR, 2.356; 95%CI, 1.268–4.378; P = 0.007). Collectively, our study demonstrated that KIF26B was overexpression in breast cancer and could be served as a potential prognostic marker.     

High YKL-40 Serum Concentration Is Correlated with Prognosis of Chinese Patients with Breast Cancer

This study aimed to investigate the association between serum YKL-40 and prognosis of breast cancer in a Chinese population. Expression of YKL-40 of 120 Chinese patients with breast cancer and 30 controls (benign breast lesions) was measured in tumor tissue by immunohistochemistry and in serum by ELISA. Differences in YKL-40 positivity grouped by specific patients’ characteristics were compared using Pearson Chi-square test for rates of intratumoral staining, one-way ANOVA with a Bonferroni post-hoc comparison, or two-sample t-test for mean YKL-40 serum concentrations. Factors associated with overall survival were identified by univariate and multivariate cox-regression analyses. YKL-40 was elevated in approximately 75% of Chinese patients with breast cancer. A significantly higher percentage of patients with YKL-40 positive tumors had larger tumor size, higher TNM stage, and/or lymph node metastasis. Significantly higher mean YKL-40 serum concentrations were observed in patient subgroups with invasive lobular carcinoma (P<0.0167), higher TNM stage (P<0.001), and positive lymph node metastasis (P<0.001). The estimated mean survival time of patients with YKL-40 positive tumors was significantly shorter than for patients with YKL-40 negative tumors (55.13 months vs 65.78 months, P = 0.017). Multivariable Cox-regression analysis identified a significant association of overall survival time with YKL-40 serum concentration. Patients with YKL-40 positive tumors had significantly shorter disease free survival times than those with YKL-40 negative tumors. We propose that the potential utility of YKL-40 intratumoral staining or serum concentration as a biomarker for breast cancer is greatest within 5 years of diagnosis.     

Tumor Infiltrating Lymphocytes and NHERF1 Impact on Prognosis of Breast Cancer Patients

BACKGROUND: Breast cancer (BC) is a heterogeneous disease, and patients with apparently similar clinicopathological characteristics in clinical practice show different outcome. This study evaluated in primary BCs and in the subgroup of the triple-negative breast cancers (TNBCs) the level of tumor infiltrating lymphocytes (TILs), Na⁺/H⁺ exchanger regulatory factor 1 (NHERF1) expression, and their association respect to the clinical outcome of patients. MATERIAL AND METHODS: NHERF1 expression was assessed by immunohistochemistry in 338 BC samples; the analysis of TILs was examined using hematoxylin and eosin stained slides, according to International TILs Working Group 2014. RESULTS: Multivariate analysis identified TILs as an independent prognostic factor for DFS in the entire cohort and in the TNBC subgroup (HR, 0.32; 95% CI, 0.12–0.87; P = 0.026; and HR, 0.22; 95% CI, 0.06–0.80; P = 0.022, respectively). Univariate and survival analysis by Kaplan–Meier method revealed that patients with cytoplasmic (c) NHERF1^-/TILs⁺ expression had better DFS than other patients (P = 0.049), and this result was also found in the TNBC subgroup (P = 0.031). Moreover, TNBC patients with cNHERF1⁻/TILs⁻ expression had a worse DFS and OS than other patients (P = 0.057 and P = 0.002, respectively). CONCLUSIONS: In the complex scenario of BC and in the era of tumor immunogenicity and immunotherapy, we found an association of TIL levels and cNHERF1 expression that could be useful to identify BCs and particularly TNBC patients with different prognosis and clinical outcome.     

糖尿病对乳腺癌患者预后影响的Meta 分析

目的：评价中国地区糖尿病对乳腺癌患者预后的影响,为临床工作提供依据。方法：检索万方、中国知网、维普、Medline、Pubmed、Embase数据库有关糖尿病对乳腺癌患者预后影响的文章,收集数据,进行meta 分析,以合并OR 值作为效应指标。结果：meta 分析共纳入11 篇文献,总共有28589 个病例;合并糖尿病对乳腺癌患者5 年无病生存率有影响[OR=2.48,95%CI（1.81~3.40）;I2=0%,P(Q)=0.42];合并糖尿病对乳腺癌患者5 年总生存率有影响[OR=2.40,95%CI（1.75~3.29）;I2=81.67%,P(Q)<0.01]。结论：糖尿病对乳腺癌患者预后有影响,造成生存率降低。     

The Impact of Matrix Metalloproteinase 2 on Prognosis and Clinicopathology of Breast Cancer Patients: A Systematic Meta-Analysis

Backgrounds

Matrix metalloproteinase 2 (MMP-2) plays a crucial role in the progression of breast cancer (BC). The prognostic role of MMP-2 expression in BC patients has been widely reported, but the results were inconsistent. Thus, a meta-analysis was conducted to gain a better insight into the impact of MMP-2 expression on survival and clinicopathological features of BC patients.

Methods

Identical search strategies were used to search relevant literatures in electronic databases update to August 1, 2014. Individual hazard ratios (HRs) and odds ratios (ORs) with their 95% confidence intervals (CIs) were extracted and pooled to evaluate the strength of the association between positive MMP-2 expression and survival results and clinicopathological features of BC patients. Begg’s tests, Egger’s tests and funnel plots were used to evaluate publication bias. Heterogeneity and sensitivity analysis were also assessed. All the work was completed using STATA.

Results

Pooled HRs and 95% CIs suggested that MMP-2 expression had an unfavorable impact on both OS (HR: 1.53, 95% CI: 1.29–1.82) and DFS/RFS/DDFS (HR: 1.41, 95% CI: 1.07–1.86) in BC patients. Furthermore, MMP-2 expression was significantly associated with lymph node metastasis (positive vs negative: OR 1.91, 95% CI 1.17–3.12).

Conclusion

In conclusion, positive MMP-2 expression might be a significant predictive factor for poor prognosis in patients with BC.     

The Prognosis of Breast Cancer Patients after Mastectomy and Immediate Breast Reconstruction: A Meta-Analysis

BackgroundAn increasing number of patients with breast cancer are being offered immediate breast reconstruction (IBR). The aim of this study was to analyze the impact of IBR on the prognosis of patients with breast cancer.MethodsWe searched the electronic databases of Medline (Pubmed), ISI Web of Knowledge, Embase, and Google Scholar databases for studies reporting the overall recurrence, disease-free survival (DFS), and overall survival (OS) of patients after mastectomy only and mastectomy with IBR. With these data, we conducted a meta-analysis of the clinical outcomes.ResultsFourteen studies, including 3641 cases and 9462 controls, matched our criteria. Relevant information was extracted from these 14 studies. There was no significant heterogeneity (P for Q-statistic > 0.10 and I² < 25%). Patients who underwent IBR showed no increased risk of overall recurrence of breast cancer (RR = 0.89; 95% confidence interval [CI]: 0.75, 1.04; P = 0.14). Furthermore, patients receiving IBR had similar DFS (RR = 1.04; 95%CI: 0.99, 1.08); P = 0.10) and OS (RR = 1.02; 95%CI: 0.99, 1.05; P = 0.24)) as those of control patients.ConclusionThis meta-analysis provides evidence that IBR does not have an adverse effect on prognosis. These data suggest that IBR is an appropriate and safe choice for patients with breast cancer.     

A Genome Wide Meta-Analysis Study for Identification of Common Variation Associated with Breast Cancer Prognosis

Objective

Genome wide association studies (GWAs) of breast cancer mortality have identified few potential associations. The concordance between these studies is unclear. In this study, we used a meta-analysis of two prognostic GWAs and a replication cohort to identify the strongest associations and to evaluate the loci suggested in previous studies. We attempt to identify those SNPs which could impact overall survival irrespective of the age of onset.

Methods

To facilitate the meta-analysis and to refine the association signals, SNPs were imputed using data from the 1000 genomes project. Cox-proportional hazard models were used to estimate hazard ratios (HR) in 536 patients from the POSH cohort (Prospective study of Outcomes in Sporadic versus Hereditary breast cancer) and 805 patients from the HEBCS cohort (Helsinki Breast Cancer Study). These hazard ratios were combined using a Mantel-Haenszel fixed effects meta-analysis and a p-value threshold of 5×10⁻⁸ was used to determine significance. Replication was performed in 1523 additional patients from the POSH study.

Results

Although no SNPs achieved genome wide significance, three SNPs have significant association in the replication cohort and combined p-values less than 5.6×10⁻⁶. These SNPs are; rs421379 which is 556 kb upstream of ARRDC3 (HR = 1.49, 95% confidence interval (CI) = 1.27–1.75, P = 1.1×10⁻⁶), rs12358475 which is between ECHDC3 and PROSER2 (HR = 0.75, CI = 0.67–0.85, P = 1.8×10⁻⁶), and rs1728400 which is between LINC00917 and FOXF1.

Conclusions

In a genome wide meta-analysis of two independent cohorts from UK and Finland, we identified potential associations at three distinct loci. Phenotypic heterogeneity and relatively small sample sizes may explain the lack of genome wide significant findings. However, the replication at three SNPs in the validation cohort shows promise for future studies in larger cohorts. We did not find strong evidence for concordance between the few associations highlighted by previous GWAs of breast cancer survival and this study.     

成骨细胞特异性转录因子2与乳腺癌

Runx2为成骨细胞特异性转录因子,调控成骨细胞分化和骨组织的形成.近年来研究表明,Runx2在乳腺癌中可以激活与癌症转移相关的骨基质、黏附蛋白、金属蛋白酶以及血管内皮生长因子,并且Runx2可以与一些联合抑制剂或激活剂形成调控复合体,在亚核结构域中存在,调节基因的转录以及间接地影响乳腺癌细胞的信号通路.除此之外,Runx2还可以与雌激素受体相互作用在某种程度上解除雌激素及其受体在乳腺癌发展中的调控作用.本文主要概括Runx2在乳腺癌中的作用机制,重点综述Runx2在乳腺癌中与雌激素受体相互作用的研究进展.     

老年乳腺癌患者的临床病理特点及其辅助治疗模式的研究

目的:探讨老年乳腺癌患者的临床病理特点及其辅助治疗模式,为老年乳腺癌患者的临床治疗提供参考。方法:选取2008年1月-2012年1月期间我院收治的50例老年乳腺癌患者作为研究对象,同时选取同期收治的50例中青年乳腺癌患者,比较两组患者的临床病理特征,并采用新辅助内分泌疗法治疗本组50例老年乳腺癌患者,治疗4个月后观察治疗效果。结果:老年乳腺癌患者的病灶5cm比例以及ER和PR阳性率均明显高于中青年患者,两组患者数据比较差异有统计学意义(P0.05);老年乳腺癌患者的淋巴结转移率、Ki67阳性率以及HER-2阳性率均低于中青年患者,两组患者数据比较差异均有统计学意义(P0.05);本组50例老年乳腺癌患者治疗总有疗效为82.0%,ER、PR均为阳性患者的治疗有效率为90.0%,明显高于ER和PR非双阳性患者(76.9%,57.1%),数据比较差异均有统计学意义(P0.05);TNM I期患者的治疗有效率为93.8%,明显高于TNM II期(76.9%)或TNM III期患者(20.0%),数据比较差异均有统计学意义(P0.05)。患者在治疗期间均未出现严重不良反应。结论:老年乳腺癌患者的生物学行为较好,病灶大、淋巴转移率低以及ER和PR阳性率高;新辅助内分泌治疗老年乳腺癌患者,尤其对ER、PR均为阳性以及TNM分期低的患者临床效果安全有效,不良反应发生率低,值得临床推广应用。