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1.  GOLPH3 is a novel marker of poor prognosis and a potential therapeutic target in human renal cell carcinoma 
Xue, Y | Wu, G | Liao, Y | Xiao, G | Ma, X | Zou, X | Zhang, G | Xiao, R | Wang, X | Liu, Q | Long, D | Yang, J | Xu, H | Liu, F | Liu, M | Xie, K | Huang, R
British Journal of Cancer  2014;110(9):2250-2260.
Background:
Golgi phosphoprotein 3 (GOLPH3) has been reported to be involved in the development of several human cancers. The present study was conducted to investigate the expression of GOLPH3 and its prognostic significance in renal cell carcinoma (RCC). Meanwhile, the function of GOLPH3 in human RCC was further investigated in cell culture models.
Methods:
Expression of GOLPH3 was examined in 43 fresh RCC tissues and paired adjacent normal renal tissues by real-time quantitative PCR and western blotting. Immunohistochemistry for GOLPH3 was performed on additional 218 RCC tissues. The clinical significance of GOLPH3 expression was analysed. Downregulation of GOLPH3 was performed using small-interfering RNA (siRNA) in Caki-1 and 786-O cells with high abundance of GOLPH3, and the effects of GOLPH3 silencing on cell proliferation, migration, invasion in vitro, and tumour growth in vivo were evaluated.
Results:
Expression of GOLPH3 was upregulated in the majority of the RCC clinical tissue specimens at both mRNA and protein levels. Clinicopathological analysis showed that GOLPH3 expression was significantly correlated with T stage (P<0.001), lymph-node status (P=0.003), distant metastasis (P<0.001), tumour-node-metastasis (TNM) stage (P<0.001), and Fuhman grade (P=0.001). Expression of GOLPH3 was inversely correlated with both overall and recurrence-free survival of RCC patients. Multivariate analysis showed that GOLPH3 expression was an independent prognostic indicator for patient's survival. Knockdown of the GOLPH3 expression reduced cell proliferation, anchorage-independent growth, migration, invasion, and tumour growth in xenograft model mice.
Conclusions:
These results suggest that GOLPH3 expression is likely to have important roles in RCC development and progression, and that GOLPH3 is a prognostic biomarker and a promising therapeutic target for RCC.
doi:10.1038/bjc.2014.124
PMCID: PMC4007226  PMID: 24595000
renal cell carcinoma; Golgi phosphoprotein-3 (GOLPH3); prognosis; small-interfering RNA
2.  High CXC chemokine receptor 4 expression is an adverse prognostic factor in patients with clear-cell renal cell carcinoma 
An, H | Xu, L | Zhu, Y | Lv, T | Liu, W | Liu, Y | Liu, H | Chen, L | Xu, J | Lin, Z
British Journal of Cancer  2014;110(9):2261-2268.
Background:
Aberrant CXC chemokine receptor 4 (CXCR4) expressions in malignant tissues have been reported; however, its role in kidney cancer prognosis remains unknown. The aim of this study was to determine the prognostic value of CXCR4 expression in patients with clear-cell renal cell carcinoma (ccRCC).
Methods:
The study included 225 patients with ccRCC. The cohort was split into a training set (n=125) and a validation set (n=100). CXC chemokine receptor 4 expression was analysed by immunohistochemical staining and its correlations with clinicopathologic features and prognosis were evaluated.
Results:
CXCR4-staining intensity increased gradually accompanied with disease progression from TNM stages I to IV in 225 patients with ccRCC. Moreover, high CXCR4 expression indicated reduced overall survival (OS) in the training (P<0.001) and validation (P<0.001) sets, especially for patients with early-stage (TNM stage I+II) diseases. Furthermore, CXCR4 expression was identified as an independent prognostic factor for OS, and combining TNM stage with CXCR4 expression showed a better prognostic value for OS in both sets.
Conclusions:
High CXCR4 expression, an independent adverse prognostic factor, could be combined with TNM stage to generate a predictive nomogram for clinical outcome in patients with ccRCC.
doi:10.1038/bjc.2014.179
PMCID: PMC4007240  PMID: 24714746
ccRCC; CXCR4; overall survival; nomogram; prognostic model
3.  TBLR1 is a novel prognostic marker and promotes epithelial–mesenchymal transition in cervical cancer 
Wang, J | Ou, J | Guo, Y | Dai, T | Li, X | Liu, J | Xia, M | Liu, L | He, M
British Journal of Cancer  2014;111(1):112-124.
Background:
Invasion and metastasis remain a critical issue in cervical cancer. However, the underlying mechanism of it in cervical cancer remains unclear. The newly discovered protein, TBLR1, plays a crucial role in regulating various key cellular functions.
Methods:
In this study, western blot, real-time RT–PCR, immunohistochemical staining, 3D morphogenesis Matrigel culture, wound healing and Boyden chamber invasion assays, xenografted tumour model, luciferase assays, and chromatin immunoprecipitation assays were used.
Results:
The expression of TBLR1 in cervical cancer cell lines and tissues was significantly upregulated at both the RNA and protein levels compared with that in normal cervical cells. Statistical analysis suggested that TBLR1 as an independent prognostic factor was significantly correlated with the clinical stage, survival time and recurrence. Moreover, overexpression of TBLR1 in Hela and Siha cell lines promoted invasion in vitro and in vivo with the increases of the mesenchymal factors vimentin and fibronectin and decreases of the epithelial marker α-catenin. In contrast, RNAi-mediated knockdown of TBLR1 inhibited epithelial–mesenchymal transition in vitro and in vivo. Further study indicated that this might be mediated via the NF-κB and Wnt/β-Catenin signalling pathway, and involve regulation of Snail and Twist.
Conclusions:
The TBLR1 protein may be a prognostic marker in cervical cancer and play an important role in the invasion and metastasis of human cervical cancer.
doi:10.1038/bjc.2014.278
PMCID: PMC4090741  PMID: 24874481
cervical cancer; pelvic lymph node metastasis; epithelial–mesenchymal transition; TBLR1
4.  Prognostic value of magnetic resonance imaging-detected cranial nerve invasion in nasopharyngeal carcinoma 
Liu, X | Liu, L-Z | Mao, Y-P | Chen, L | Tang, L-L | Zhou, G-Q | Sun, Y | Yue, D | Lin, A-H | Li, L | Ma, J
British Journal of Cancer  2014;110(6):1465-1471.
Background:
We previously reported that magnetic resonance imaging evidence of cranial nerve invasion was an unfavourable prognostic factor in nasopharyngeal carcinoma. However, the prognostic value of this evidence in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy remains unknown.
Methods:
We retrospectively analysed 749 nasopharyngeal carcinoma patients who underwent intensity-modulated radiotherapy.
Results:
Cranial nerve invasion was observed in 299 (39.9%) patients with T3–4 disease. In T3–4 nasopharyngeal carcinoma, magnetic resonance imaging-detected cranial nerve invasion was associated with inferior 5-year overall survival, distant metastasis-free survival, and locoregional relapse-free survival (P=0.002, 0.003, and 0.012, respectively). Multivariate analyses confirmed that cranial nerve invasion was an independent prognostic factor for distant metastasis-free survival (hazard ratio, 1.927; P=0.019) and locoregional relapse-free survival (hazard ratio, 2.605; P=0.032). Furthermore, the receiver-operating characteristic curves verified that the predictive validity of T classifications was significantly improved when combined with magnetic resonance imaging-detected cranial nerve invasion in terms of death, distant metastasis, and locoregional recurrence (P=0.015, 0.021 and 0.008, respectively).
Conclusions:
Magnetic resonance imaging-detected cranial nerve invasion is an independent adverse prognostic factor in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy.
doi:10.1038/bjc.2014.27
PMCID: PMC3960608  PMID: 24496459
nasopharyngeal neoplasms; perineural invasion; magnetic resonance imaging; prognosis; prognostic factor
5.  Tumour-infiltrating inflammation and prognosis in colorectal cancer: systematic review and meta-analysis 
Mei, Z | Liu, Y | Liu, C | Cui, A | Liang, Z | Wang, G | Peng, H | Cui, L | Li, C
British Journal of Cancer  2014;110(6):1595-1605.
Background:
The role of tumour-infiltrating inflammation in the prognosis of patients with colorectal cancer (CRC) has not been fully evaluated. The primary objective of our meta-analysis was to determine the impact of tumour-infiltrating inflammation on survival outcomes.
Methods:
Ovid MEDLINE and EMBASE were searched to identify studies reporting the prognostic significance of tumour-infiltrating inflammation for patients with CRC. The primary outcome measures were overall survival (OS), cancer-specific survival (CS) and disease-free survival (DFS).
Results:
A total of 30 studies involving 2988 patients were identified. Studies were subdivided into those considering the associations between CRC survival and generalised tumour inflammatory infiltrate (n=12) and T lymphocyte subsets (n=18). Pooled analyses revealed that high generalised tumour inflammatory infiltrate was associated with good OS (HR, 0.59; 95% CI, 0.48–0.72), CS (HR, 0.40; 95% CI, 0.27–0.61) and DFS (HR, 0.72; 95% CI, 0.57–0.91). Stratification by location and T lymphocyte subset indicated that in the tumour centre, CD3+, CD8+ and FoxP3+ infiltrates were not statistically significant prognostic markers for OS or CS. In the tumour stroma, high CD8+, but not CD3+ or FoxP3+ cell infiltrates indicated increased OS. Furthermore, high CD3+ cell infiltrate was detected at the invasive tumour margin in patients with good OS and DFS; and high CCR7+ infiltrate was also indicated increased OS.
Conclusion:
Overall, high generalised tumour inflammatory infiltrate could be a good prognostic marker for CRC. However, significant heterogeneity and an insufficient number of studies underscore the need for further prospective studies on subsets of T lymphocytes to increase the robustness of the analyses.
doi:10.1038/bjc.2014.46
PMCID: PMC3960618  PMID: 24504370
tumour-infiltrating inflammation; T lymphocytes; T regulatory cells; colorectal cancer; prognosis; tumour location; meta-analysis
6.  A nomogram predicting pulmonary metastasis of hepatocellular carcinoma following partial hepatectomy 
Li, J | Liu, Y | Yan, Z | Wan, X | Xia, Y | Wang, K | Liu, J | Lau, W Y | Wu, M | Shen, F
British Journal of Cancer  2014;110(5):1110-1117.
Background:
Pulmonary metastasis (PM) following curative hepatectomy for hepatocellular carcinoma (HCC) is indicative of a poor prognosis. This study aimed to develop a nomogram to identify patients at high risks of PM.
Methods:
A primary cohort of patients who underwent curative hepatectomy for HCC at the Eastern Hepatobiliary Surgery Hospital from 2002 to 2010 was prospectively studied. A nomogram predicting PM was constructed based on independent risk factors of PM. The predictive performance was evaluated by the concordance index (c-index), calibration curve and decision curve analysis (DCA). During the study period, a validation cohort was included at the First Affiliated Hospital of Fujian Medical University.
Results:
Postoperative PMs were detected in 106 out of 620 and 45 out of 218 patients, respectively, in two cohorts. Factors included in the nomogram were microvascular invasion, serum alpha-fetoprotein, tumour size, tumour number, encapsulation and intratumoral CD34 staining. The nomogram had a c-index of 0.75 and 0.82 for the two cohorts for predicting PM, respectively. The calibration curves fitted well. In the two cohorts, the DCA demonstrated positive net benefits by the nomogram, within the threshold probabilities of PM >10%.
Conclusion:
The nomogram was accurate in predicting PM following curative hepatectomy for HCC.
doi:10.1038/bjc.2014.19
PMCID: PMC3950869  PMID: 24481404
nomogram; pulmonary metastasis; hepatocellular carcinoma; hepatectomy; prognosis
7.  HER2, MET and FGFR2 oncogenic driver alterations define distinct molecular segments for targeted therapies in gastric carcinoma 
Liu, Y J | Shen, D | Yin, X | Gavine, P | Zhang, T | Su, X | Zhan, P | Xu, Y | Lv, J | Qian, J | Liu, C | Sun, Y | Qian, Z | Zhang, J | Gu, Y | Ni, X
British Journal of Cancer  2014;110(5):1169-1178.
Background:
Gastric cancer (GC) is a leading cause of cancer deaths worldwide. Since the approval of trastuzumab, targeted therapies are emerging as promising treatment options for the disease. This study aimed to explore the molecular segmentation of several known therapeutics targets, human epidermal growth factor receptor 2 (HER2), MET and fibroblast growth factor receptor 2 (FGFR2), within GC using clinically approved or investigational kits and scoring criteria. Knowledge of how these markers are segmented in the same cohort of GC patients could improve future clinical trial designs.
Methods:
Using immunohistochemistry (IHC) and FISH methods, overexpression and amplification of HER2, FGFR2 and MET were profiled in a cohort of Chinese GC samples. The correlations between anti-tumour sensitivity and the molecular segments of HER2, MET and FGFR2 alterations were further tested in a panel of GC cell lines and the patient-derived GC xenograft (PDGCX) model using the targeted inhibitors.
Results:
Of 172 GC patients, positivity for HER2, MET and FGFR2 alternations was found in 23 (13.4%), 21 (12.2%) and 9 (5.2%) patients, respectively. Positivity for MET was found in 3 of 23 HER2-positive GC patients. Co-positivity for FGFR2 and MET was found in 1 GC patient, and amplification of the two genes was found in different tumour cells. Our study in a panel of GC cell lines showed that in most cell lines, amplification or high expression of a particular molecular marker was mutually exclusive and in vitro sensitivity to the targeted agents lapatinib, PD173074 and crizotinib was only observed in cell lines with the corresponding high expression of the drugs' target protein. SGC031, an MET-positive PDGCX mouse model, responded to crizotinib but not to lapatinib or PD173074.
Conclusions:
Human epidermal growth factor receptor 2, MET and FGFR2 oncogenic driver alterations (gene amplification and overexpression) occur in three largely distinct molecular segments in GC. A significant proportion of HER2-negative patients may potentially benefit from MET- or FGFR2-targeted therapies.
doi:10.1038/bjc.2014.61
PMCID: PMC3950883  PMID: 24518603
personalised medicine; gastric cancer; targeted therapies; growth factor receptors; predictive markers
8.  MicroRNA-29a promotes colorectal cancer metastasis by regulating matrix metalloproteinase 2 and E-cadherin via KLF4 
Tang, W | Zhu, Y | Gao, J | Fu, J | Liu, C | Liu, Y | Song, C | Zhu, S | Leng, Y | Wang, G | Chen, W | Du, P | Huang, S | Zhou, X | Kang, J | Cui, L
British Journal of Cancer  2013;110(2):450-458.
Background:
Growing evidence suggests that miR-29a has an important role in regulating tumourigenesis and development of various types of cancer. However, the role and the underlying mechanism of miR-29a in colorectal cancer (CRC) remain largely unknown.
Methods:
MiR-29a targeted gene was identified by the luciferase assay and western blot. MiR-29a function was analysed by invasion assays and the orthotopic transplantation mouse model. The miR-29a pathway was assayed by real-time PCR, western blot and chip analysis.
Results:
KLF4 was identified as a direct target gene of miR-29a. MiR-29a promoted CRC cell invasion, which was blocked by re-expression of KLF4. In addition, MMP2 was identified as a novel direct target of KLF4. Both miR-29a overexpression and KLF4 knockdown promoted MMP2 expression but inhibited E-cadherin expression. Furthermore, clinical data indicated that both miR-29a high expression and KLF4 mRNA low expression were associated with metastasis and poor prognosis in CRC patients, and KLF4 protein expression was inversely correlated with MMP2 but positively correlated with E-cad protein expression.
Conclusion:
Increased expression of miR-29a promoted CRC metastasis by regulating MMP2/E-cad through direct targeting KLF4, which highlights the potential of the miR-29a inhibitor as a novel agent against CRC metastasis.
doi:10.1038/bjc.2013.724
PMCID: PMC3899762  PMID: 24281002
miR-29a; colorectal cancer; metastasis; KLF4
9.  PA28gamma emerges as a novel functional target of tumour suppressor microRNA-7 in non-small-cell lung cancer 
Xiong, S | Zheng, Y | Jiang, P | Liu, R | Liu, X | Qian, J | Gu, J | Chang, L | Ge, D | Chu, Y
British Journal of Cancer  2013;110(2):353-362.
Background:
MicroRNA-7 (miR-7) has been reported to be a tumour suppressor gene. However, whether it has a role in the growth of non-small-cell lung cancer (NSCLC) and what is its target involved in the tumour growth is still under investigation.
Methods:
NSCLC tissue sample, NSCLC cell lines and tissue microarray were investigated in this study. Total RNA, miRNA and protein were used for RT-PCR and western blot analysis. Immunohistochemistry was performed in tissues microarray. Cell culture and intervention experiments were performed in vitro and in vivo. Bioinformatics prediction, western blot and luciferase assay were identified the target of miR-7.
Results:
In this study, we found that the expression of miR-7 was significantly downregulated not only in NSCLC cell lines, but also in human NSCLC tissues compared with the matched adjacent tissues. Restoration of its expression through miR-7 mimics in A549 and H1299 NSCLC cells inhibited cell proliferation, colony formation, and cell-cycle progression in vitro. More importantly, the tumorigenicity in nude mice was reduced after administration of miR-7 in vivo. In advance, through bioinformatic analysis, luciferase assay and western blot, we identified a novel target of miR-7, PA28gamma (a proteasome activator) to be enrolled in the regulation with tumour. PA28gamma mRNA and protein levels are markedly upregulated in NSCLC cell lines and tumour samples, exhibiting a strong inverse relation with that of miR-7. In addition, knockdown of PA28gamma induced similar effects as overexpression of miR-7 in NSCLC cells. Furthermore, miR-7 overexpression or silencing of PA28gamma reduced the cyclinD1 expression at mRNA and protein level in NSCLC cell lines.
Conclusion:
All these findings strongly imply that the overexpression of PA28gamma resulted from miR-7 downexpression in NSCLC has an important role in promoting cancer cell progress and consequently results in NSCLC growth. Thus, strategies targeting PA28gamma and/or miR-7 may become promising molecular therapies in NSCLC treatment.
doi:10.1038/bjc.2013.728
PMCID: PMC3899764  PMID: 24281003
NSCLC; microRNA; miR-7; PA28gamma; tumour suppressor
11.  Statin use in primary inflammatory breast cancer: a cohort study 
British Journal of Cancer  2013;109(2):318-324.
Background:
Some studies have suggested that statins, which have cholesterol-lowering and anti-inflammatory properties, may have antitumor effects. Effects of statins on inflammatory breast cancer (IBC) have never been studied.
Methods:
We reviewed 723 patients diagnosed with primary IBC in 1995–2011 and treated at The University of Texas MD Anderson Cancer Center. Statin users were defined as being on statins at the initial evaluation. Based on Ahern et al's statin classification (JNCI, 2011), clinical outcomes were compared by statin use and type (weakly lipophilic to hydrophilic (H-statin) vs lipophilic statins (L-statin)). We used the Kaplan–Meier method to estimate the median progression-free survival (PFS), overall survival (OS) and disease-specific survival (DSS), and a Cox proportional hazards regression model to test the statistical significance of potential prognostic factors.
Results:
In the multivariable Cox model, H-statins were associated with significantly improved PFS compared with no statin (hazard ratio=0.49; 95% confidence interval=0.28–0.84; P<0.01); OS and DSS P-values were 0.80 and 0.85, respectively. For L-statins vs no statin, P-values for PFS, DSS, and OS were 0.81, 0.4, and 0.74, respectively.
Conclusion:
H-statins were associated with significantly improved PFS. A prospective randomised study evaluating the survival benefits of statins in primary IBC is warranted.
doi:10.1038/bjc.2013.342
PMCID: PMC3721387  PMID: 23820253
inflammatory breast cancer; statin; hydrophilic; lipophilic; progression-free survival; overall survival
12.  A step-by-step guide to the systematic review and meta-analysis of diagnostic and prognostic test accuracy evaluations 
Liu, Z | Yao, Z | Li, C | Liu, X | Chen, H | Gao, C
British Journal of Cancer  2013;108(11):2299-2303.
In evidence-based medicine (EBM), systematic reviews and meta-analyses have been widely applied in biological and medical research. Moreover, the most popular application of meta-analyses in this field may be to examine diagnostic (sensitivity and specificity) and prognostic (hazard ratio (HR) and its variance, standard error (SE) or confidence interval (CI)) test accuracy. However, conducting such analyses requires not only a great deal of time but also an advanced professional knowledge of mathematics, statistics and computer science. Regarding the practical application of meta-analyses for diagnostic and prognostic markers, the majority of users are clinicians and biologists, most of whom are not skilled at mathematics and computer science in particular. Hence, it is necessary for these users to have a simplified version of a protocol to help them to quickly conduct meta-analyses of the accuracy of diagnostic and prognostic tests. The aim of this paper is to enable individuals who have never performed a meta-analysis to do so from scratch. The paper does not attempt to serve as a comprehensive theoretical guide but instead describes one rigorous way of conducting a meta-analysis for diagnostic and prognostic markers. Investigators who follow the outlined methods should be able to understand the basic ideas behind the steps taken, the meaning of the meta-analysis results obtained for diagnostic and prognostic markers and the scope of questions that can be answered with Systematic Reviews and Meta-Analyses (SRMA). The presented protocols have been successfully tested by clinicians without meta-analysis experience.
doi:10.1038/bjc.2013.185
PMCID: PMC3681011  PMID: 23695015
systematic review; meta-analysis; prognostic marker; diagnostic marker; sensitivity and specificity; hazard ratio
13.  Distinct association between aberrant methylation of Wnt inhibitors and genetic alterations in acute myeloid leukaemia 
British Journal of Cancer  2011;105(12):1927-1933.
Background:
Aberrant activation of Wnt signalling through hypermethylation of Wnt inhibitor genes is involved in several human malignancies, including acute myeloid leukaemia (AML). It remains unclear whether hypermethylation of Wnt inhibitors is associated with molecular gene mutations in the development of AML.
Methods:
We investigated the association of the promoter hypermethylation of six Wnt inhibitors (Wif-1, SFRP1, SFRR2, SFRP4, SFRP5, and DKK1) with gene aberrations in the leukaemogenesis of 269 AML patients.
Results:
In total, 166 patients (61.7%) had hypermethylation of at least one Wnt inhibitor. The majority (68.5%) of patients with Wnt inhibitor hypermethylation had concurrent Class II gene mutations that affect transcription factors or cofactors. There was a close association of Wif-1 hypermethylation with t(15;17) (P=0.0005) and CEBPA mutation (P<0.0001), DKK1 hypermethylation with t(8;21) (P<0.0001) and ASXL1 mutation (P=0.0078), SFRP-1 hypermethylation with t(8;21) (P<0.0001), SFRP-2 hypermethylation with AML1/RUNX1 mutation (P=0.0012), and SFRP-5 hypermethylation with MLL/PTD (P=0.0505). On the other side, hypermethylation of Wnt inhibitors was always negatively associated with NPM1 mutation and FLT3/ITD.
Conclusion:
There was distinct association between hypermethylation of individual Wnt inhibitors and specific gene aberrations, especially Class II mutations. The Wnt inhibitor hypermethylation might interact with genetic alterations in the leukaemogenesis.
doi:10.1038/bjc.2011.471
PMCID: PMC3251886  PMID: 22095226
Wnt pathway inhibitors; methylation; genetic alteration; acute myeloid leukaemia
14.  Prevalence and risk factors for esophageal squamous cell cancer and precursor lesions in Anyang, China: a population-based endoscopic survey 
He, Z | Zhao, Y | Guo, C | Liu, Y | Sun, M | Liu, F | Wang, X | Guo, F | Chen, K | Gao, L | Ning, T | Pan, Y | Li, Y | Zhang, S | Lu, C | Wang, Z | Cai, H | Ke, Y
British Journal of Cancer  2010;103(7):1085-1088.
Background:
The etiology of esophageal squamous cell cancer (ESCC) in high prevalence regions of China remains unclear.
Methods:
Endoscopic biopsies were conducted among 7381 inhabitants aged from 25 to 65 of Anyang, China.
Results:
In this study, 2.57, 0.20 and 0.16% of the participants had mild, moderate and severe squamous dysplasia, respectively; 0.19 and 0.08% showed squamous carcinoma in situ and invasive ESCC. Using deep well (depth >100 meters) as water source (odds ratio=0.72, 95% confidence interval: 0.54–0.96) was negatively associated with ESCC and its precursors, whereas tobacco and alcohol use were not significantly associated with ESCC.
Conclusions:
Water source and other factors in this region need further evaluation by longitudinal studies.
doi:10.1038/sj.bjc.6605843
PMCID: PMC2965859  PMID: 20700119
prevalence; risk factor; esophageal cancer; precursor lesion; China
15.  Common genetic variability in ESR1 and EGF in relation to endometrial cancer risk and survival 
British Journal of Cancer  2009;100(8):1358-1364.
We investigated common genetic variation in the entire ESR1 and EGF genes in relation to endometrial cancer risk, myometrial invasion and endometrial cancer survival. We genotyped a dense set of single-nucleotide polymorphisms (SNPs) in both genes and selected haplotype tagging SNPs (tagSNPs). The tagSNPs were genotyped in 713 Swedish endometrial cancer cases and 1567 population controls and the results incorporated into logistic regression and Cox proportional hazards models. We found five adjacent tagSNPs covering a region of 15 kb at the 5′ end of ESR1 that decreased the endometrial cancer risk. The ESR1 variants did not, however, seem to affect myometrial invasion or endometrial cancer survival. For the EGF gene, no association emerged between common genetic variants and endometrial cancer risk or myometrial invasion, but we found a five-tagSNP region that covered 51 kb at the 5′ end of the gene where all five tagSNPs seemed to decrease the risk of dying from endometrial cancer. One of the five tagSNPs in this region was in strong linkage disequilibrium (LD) with the untranslated A61G (rs4444903) EGF variant, earlier shown to be associated with risk for other forms of cancer.
doi:10.1038/sj.bjc.6604984
PMCID: PMC2676544  PMID: 19319135
ESR1; EGF; polymorphism; endometrial cancer; survival
16.  ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen 
Wei, J | Zou, Z | Qian, X | Ding, Y | Xie, L | Sanchez, J J | Zhao, Y | Feng, J | Ling, Y | Liu, Y | Yu, L | Rosell, R | Liu, B
British Journal of Cancer  2008;98(8):1398-1402.
Molecular markers involved in DNA repair can help to predict survival in gastric cancer patients treated with 5-FU plus platinum chemotherapy. Excision repair cross-complementing 1 (ERCC1) and thymidylate synthase (TS) mRNA expression levels were assessed in advanced gastric cancer tumour samples using real-time quantitative PCR in 76 patients treated with a modified FOLFOX (biweekly oxaliplatin plus 5-FU and folinic acid) regimen. Median survival time in patients with low ERCC1 levels was significantly longer than in those with high levels (15.8 vs 6.2 months; P<0.0001). Patients with high TS levels had longer survival than those with low levels (12.2 vs 10.1 months; P=0.01). Forty-eight patients with low ERCC1 and high TS levels had a median survival of 16.1 months (P<0.0001). The hazard ratio for patients with high ERCC1 expression was 9.4 (P<0.0001). In patients with high mRNA levels of ERCC1, alternative chemotherapy regimens should be considered.
doi:10.1038/sj.bjc.6604317
PMCID: PMC2361707  PMID: 18362936
ERCC1; TS; advanced gastric cancer; FOLFOX
17.  Risk of cervical cancer is not increased in Chinese carrying homozygous arginine at codon 72 of p53 
British Journal of Cancer  1999;80(11):1828-1829.
Homozygous arginine at codon 72 (HA72) of p53 was found in 22% of normal cervices and 30.0% of cervical cancers and no significant difference was detected between normal and cervical cancer with or without HPV 16/18. There was no correlation between HA72 and risk of cervical cancer in Chinese. © 1999 Cancer Research Campaign
doi:10.1038/sj.bjc.6690606
PMCID: PMC2374271  PMID: 10468305
p53 codon 72 polymorphism; cervical cancer; Chinese
18.  Metadherin regulates proliferation and metastasis via actin cytoskeletal remodelling in non-small cell lung cancer 
Yao, Y | Gu, X | Liu, H | Wu, G | Yuan, D | Yang, X | Song, Y
British Journal of Cancer  2014;111(2):355-364.
Background:
Metaderin (MTDH) protein is a novel component part of tight junction complex. The aim of this study was to investigate the correlation between MTDH and prognosis of patients and to explore the role of MTDH on NSCLC development and metastasis.
Methods:
Relative mRNA expression was evaluated by quantitative real-time PCR, and protein expression was detected using immunohistochemistry staining. The role of MTDH in cancer cell proliferation, migration and invasion was studied by modulation of MTDH expression in NSCLC cell lines. These functions of MTDH were further confirmed in vivo.
Results:
In NSCLC, low MTDH protein expression was correlated with lymph node metastasis, TNM stage and decreased OS (P=0.001, 0.011 and 0.013, respectively). Overexpression of MTDH reduced anchorage-independent and -dependent growth through arresting cell cycle, inhibited migration and invasion in vitro and further suppressed tumorigenesis, tumour growth and metastasis in vivo. Knockdown of MTDH expression increased cell invasiveness. MTDH overexpression reversed pro-metastatic actin cytoskeleton remodelling and inhibited EMT, supporting that MTDH has a key role on cancer proliferation and metastasis.
Conclusions:
MTDH has an important role in NSCLC proliferation and metastasis and provides potential in predicting metastasis and prognosis for patients with NSCLC.
doi:10.1038/bjc.2014.267
PMCID: PMC4102939  PMID: 24918821
non-small cell lung cancer; metadherin; epithelial–mesenchymal transition; metastasis; proliferation
19.  Dietary patterns and oesophageal squamous cell carcinoma: a systematic review and meta-analysis 
British Journal of Cancer  2014;110(11):2785-2795.
Background/Objective:
Dietary patterns, which represent a complex integration of food and nutrients, have been used to explore the association between dietary factors and the risk of oesophageal cancer. However, the association remains unclear. This systematic review was performed to evaluate the relationship between dietary patterns and oesophageal squamous cell carcinoma (ESCC) by pooling available data from existing studies.
Methods:
Pertinent articles published up to the end of 2013 were systematically searched and retrieved. The most common dietary patterns with high loadings of foods/nutrients were selected. Adjusted odds ratios (ORs) were derived by comparing the highest with the lowest categories of dietary pattern scores and by using a random-effect model. Heterogeneity was tested using I2 statistic.
Results:
From nine available case–control studies, in which smoking and other confounding factors were considered, three most common dietary patterns were selected: western pattern, healthy pattern, and drinker/alcohol pattern. Healthy pattern was significantly associated with a decreased risk of ESCC (OR=0.36, 95% confidence interval (CI): 0.23, 0.49); drinker/alcohol pattern was related to a significantly increased risk (OR=2.34, 95% CI: 1.22, 3.45), while no significant association with western pattern was observed (OR=1.29, 95% CI: 0.83, 1.75).
Conclusions:
Based on available studies, though limited in number, this meta-analysis suggests that some dietary patterns may be associated with the risk of ESCC.
doi:10.1038/bjc.2014.172
PMCID: PMC4037820  PMID: 24714753
dietary pattern; oesophageal squamous cell carcinoma; systematic review; meta-analysis
20.  Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: a comprehensive mutation profiling from 5125 Chinese cohorts 
Li, S | Li, L | Zhu, Y | Huang, C | Qin, Y | Liu, H | Ren-Heidenreich, L | Shi, B | Ren, H | Chu, X | Kang, J | Wang, W | Xu, J | Tang, K | Yang, H | Zheng, Y | He, J | Yu, G | Liang, N
British Journal of Cancer  2014;110(11):2812-2820.
Background:
Determining the somatic mutations of epidermal growth factor receptor (EGFR)-pathway networks is the key to effective treatment for non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors (TKIs).The somatic mutation frequencies and their association with gender, smoking history and histology was analysed and reported in this study.
Methods:
Five thousand one hundred and twenty-five NSCLC patients' pathology samples were collected, and EGFR, KRAS, BRAF and PIK3CA mutations were detected by multiplex testing. The mutation status of EGFR, KRAS, BRAF and PIK3CA and their association with gender, age, smoking history and histological type were evaluated by appropriate statistical analysis.
Results:
EGFR, KRAS, BRAF and PIK3CA mutation rates revealed 36.2%, 8.4%, 0.5% and 3.3%, respectively, across the 5125 pathology samples. For the first time, evidence of KRAS mutations were detected in two female, non-smoking patients, age 5 and 14, with NSCLC. Furthermore, we identified 153 double and coexisting mutations and 7 triple mutations. Interestingly, the second drug-resistant mutations, T790M or E545K, were found in 44 samples from patients who had never received TKI treatments.
Conclusions:
EGFR exons 19, 20 and 21, and BRAF mutations tend to happen in females and non-smokers, whereas KRAS mutations were more inclined to males and smokers. Activating and resistant mutations to EGFR-TKI drugs can coexist and ‘second drug-resistant mutations', T790M or E545K, may be primary mutations in some patients. These results will help oncologists to decide candidates for mutation testing and EGFR-TKI treatment.
doi:10.1038/bjc.2014.210
PMCID: PMC4037826  PMID: 24743704
non-small cell lung cancer; somatic mutations; double and triple mutations; multiplex testing; liquid chip technology
21.  Differential effect of MMSET mRNA levels on survival to first-line FOLFOX and second-line docetaxel in gastric cancer 
British Journal of Cancer  2014;110(11):2662-2668.
Background:
Breast cancer susceptibility gene 1 (BRCA1) expression differentially affects outcome to platinum- and taxane-based chemotherapy. Mediator of DNA damage checkpoint protein 1 (MDC1), p53-binding protein 1 (53BP1), multiple myeloma SET domain (MMSET) and ubiquitin-conjugating enzyme 9 (UBC9) are involved in DNA repair and could modify the BRCA1 predictive model.
Methods:
Mediator of DNA damage checkpoint protein 1, 53BP1, MMSET and UBC9 mRNA were assessed in gastric tumours from patients in whom BRCA1 levels had previously been determined.
Results:
In vitro chemosensitivity assay, MMSET levels were higher in docetaxel-sensitive samples. In a separate cohort, survival was longer in those with low MMSET (12.3 vs 8.8 months; P=0.04) or UBC9 (12.4 vs 8.8 months; P=0.01) in patients receiving only folinic acid, fluorouracil (5-FU) and oxaliplatin (FOLFOX). Conversely, among patients receiving second-line docetaxel, longer survival was associated with high MMSET (19.1 vs 13.9 months; P=0.003). Patients with high MMSET and BRCA1 attained a median survival of 36.6 months, compared with 13.9 months for those with high BRCA1 and low MMSET (P=0.003). In the multivariate analyses, low MMSET (hazard ratio (HR), 0.59; P=0.04) and low UBC9 (HR, 0.52; P=0.01) levels were markers of longer survival to first-line FOLFOX, whereas palliative surgery (HR, 2.47; P=0.005), low BRCA1 (HR, 3.17; P=0.001) and low MMSET (HR, 2.52; P=0.004) levels were markers of shorter survival to second-line docetaxel.
Conclusions:
Breast cancer susceptibility gene 1, MMSET and UBC9 can be useful for customising chemotherapy in gastric cancer patients.
doi:10.1038/bjc.2014.231
PMCID: PMC4037835  PMID: 24809779
gene expression; MMSET; FOLFOX; second-line docetaxel; gastric cancer
22.  Comparison of radiological and clinical features of temporal lobe necrosis in nasopharyngeal carcinoma patients treated with 2D radiotherapy or intensity-modulated radiotherapy 
British Journal of Cancer  2014;110(11):2633-2639.
Background:
To compare the imaging and clinical features of temporal lobe necrosis (TLN) in nasopharyngeal carcinoma (NPC) patients treated with two-dimensional radiotherapy (2D-RT) or those with intensity-modulated radiotherapy (IMRT).
Methods:
We retrospectively analysed NPC patients who underwent 2D-RT (72 patients, 128 temporal lobes) or IMRT (36 patients, 50 lobes) and developed radiation-induced, MRI-confirmed TLN.
Results:
White-matter lesions (WMLs), contrast-enhanced lesions, cysts and local mass effects were present in 128 out of 128 vs 48 out of 50 (P=0.078), 123 out of 128 vs 47 out of 50 (P=0.688), 10 out of 128 vs 1 out of 50 (P=0.185) and 57 out of 128 vs 13 out of 50 (P=0.023) temporal lobes, respectively, in the 2D-RT and IMRT groups. The WMLs were more extensive in the 2D-RT group (P<0.001). The maximum diameter of contrast-enhanced lesions was greater in the 2D-RT group (P<0.001), and these lesions tended to extend far away from the nasopharynx. The WMLs and enhancement had no impact on cyst development (both P=1). Local mass effects were always accompanied with contrast-enhanced lesions (P=0.024) but were not correlated with WMLs or cysts (P=0.523 and 0.341, respectively). There were no between-group differences in clinical features (all P-values>0.05), whereas the difference in the incidence of severe debility was of marginal significance (18.1% vs 5.6%, P=0.077).
Conclusions:
The IMRT-induced TLN was less extensive and milder than 2D-RT-induced TLN, but both had similar clinical features.
doi:10.1038/bjc.2014.243
PMCID: PMC4037838  PMID: 24809780
temporal lobe necrosis; nasopharyngeal carcinoma; radiotherapy; radiological features; clinical features
23.  Tumour-infiltrating CD4+ and CD8+ lymphocytes as predictors of clinical outcome in glioma 
Han, S | Zhang, C | Li, Q | Dong, J | Liu, Y | Huang, Y | Jiang, T | Wu, A
British Journal of Cancer  2014;110(10):2560-2568.
Background:
T lymphocyte infiltration has been detected in glioma, although its significance remains unclear. The purpose of the present study was to explore the prognostic value of CD4+ and CD8+ tumour-infiltrating lymphocytes (TILs) in glioma, and the prognostic value of infiltrating Forkhead box protein 3 (FoxP3+) regulatory T cells were also investigated.
Methods:
CD4+, FoxP3+ and CD8+ TILs were assessed by immunohistochemical staining of tissue microarray cores from 284 gliomas. Kaplan–Meier analysis and Cox proportional hazards models were used to examine the survival function of these TILs in 90 glioblastoma patients.
Results:
The number of CD8+ TILs was inversely correlated with tumour grade (P=0.025), whereas the number of CD4+ TILs was positively correlated with tumour grade (P=0.002). FoxP3+ TILs were only observed in glioblastomas, but not in low-grade astrocytomas or oligodendroglial tumours. Among patients with glioblastoma, none of CD4+ TILs, FoxP3+ TILs and CD8+ TILs alone was significantly associated with patient prognosis. However, the presence of high CD4+ and low CD8+ TIL levels was an independent predictor of poor progress-free survival (multivariate hazard ratio (HR) 1.618, 95% confidence interval (CI) 1.245–2.101, P<0.001) and poor overall survival (multivariate HR 1.508, 95% CI 1.162–1.956, P=0.002). Moreover, pseudoprogression was more often found in patients with high CD4+ TILs and high CD8+ TILs.
Conclusions:
The combination of CD4+ and CD8+ TILs is a predictor of clinical outcome in glioblastoma patients, and a high level of CD4+ TILs combined with low CD8+ TILs was associated with unfavourable prognosis.
doi:10.1038/bjc.2014.162
PMCID: PMC4021514  PMID: 24691423
glioma; tumour-infiltrating lymphocytes; prognosis
24.  Potent anti-tumour activity of a novel conditionally replicating adenovirus for melanoma via inhibition of migration and invasion 
British Journal of Cancer  2014;110(10):2496-2505.
Background:
Conditionally replicating adenoviruses (CRAds) represent a novel class of oncological therapeutic agents. One strategy to ensure tumour targeting is to place the essential viral genes under the control of tumour-specific promoters. Ki67 has been selected as a cancer gene therapy target, as it is expressed in most malignant cells but is barely detectable in most normal cells. This study aimed to investigate the effects of a Ki67 promoter-controlled CRAd (Ki67-ZD55-IL-24) on the proliferation and apoptosis of melanoma cells.
Methods:
Melanoma cells were independently treated with Ki67-ZD55-IL-24, ZD55-IL-24, Ki67-ZD55, and ZD55-EGFP. The cytotoxic potential of each treatment was assessed using cell viability measurements. Cell migration and invasion were assayed using cell migration and invasion assays. Apoptosis was assayed using the annexin V-FITC assay, western blotting, reverse transcriptase PCR (RT–PCR), haematoxylin and eosin (H&E) staining, and the TUNEL assay.
Results:
Our results showed that Ki67-ZD55-IL-24 had significantly enhanced anti-tumour activity as it more effectively induced apoptosis in melanoma cells than the other agents. Ki67-ZD55-IL-24 also caused the most significant inhibition of cell migration and invasion of melanoma cells. Furthermore, apoptosis was induced more effectively in melanoma xenografts in nude mice.
Conclusions:
This strategy holds promising potential for the further development of an effective approach to treat malignant melanoma.
doi:10.1038/bjc.2014.177
PMCID: PMC4021521  PMID: 24714752
melanoma; cancer therapy; conditionally replicating adenoviruses; Ki67 promoter; interleukin-24
25.  Efficacy and toxicity of external-beam radiation therapy for localised prostate cancer: a network meta-analysis 
Zhu, Z | Zhang, J | Liu, Y | Chen, M | Guo, P | Li, K
British Journal of Cancer  2014;110(10):2396-2404.
Background:
Many radiation regimens for treating prostate cancer have been used over the years, but which regimen is optimal for localised or locally advanced prostate cancer lacks consensus. We performed a network meta-analysis to identify the optimal radiation regimen.
Methods:
We systematically reviewed data from 27 randomised controlled trials and could group seven radiation regimens as follows: low- and high-dose radiation therapy (LDRT and HDRT), LDRT+ short- or long-term androgen deprivation therapy (LDRT+SADT and LDRT+LADT), HDRT+SADT, hypofractionated radiotherapy (HFRT), and HFRT+SADT. The main outcomes were overall mortality (OM), prostate-specific antigen (PSA) failure, cancer-specific mortality, and adverse events.
Results:
For the network meta-analysis of 27 trials, LDRT+LADT and LDRT+SADT were associated with decreased risk of OM as compared with LDRT alone as was LDRT+LADT compared with HDRT. Apart from HFRT, all other treatments were associated with decreased risk of PSA failure as compared with LDRT. HFRT+SADT was associated with decreased risk of cancer-specific mortality as compared with HFRT, LDRT+SADT, HDRT, and LDRT.
Conclusions:
HFRT+SADT therapy might be the most efficacious treatment but with worst toxicity for localised or locally advanced prostate cancer, and HDRT showed excellent efficacy but more adverse events.
doi:10.1038/bjc.2014.197
PMCID: PMC4021530  PMID: 24736585
EBRT; prostate cancer; network meta-analysis

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