FAM64A aggravates proliferation, invasion, lipid droplet formation, and chemoresistance in gastric cancer: A biomarker for aggressiveness and a gene therapy target.

FAM64A is a mitogen-induced regulator of the metaphase and anaphase transition. Here, we found that FAM64A messenger RNA (mRNA) and protein expression levels were higher in gastric cancer tissue than in normal mucosa (p < .05). FAM64A methylation was negatively correlated with FAM64A mRNA expression (p < .05). The differentially expressed genes of FAM64A were mainly involved in digestion, potassium transporting or exchanging ATPase, contractile fibers, endopeptidase, and pancreatic secretion (p < .05). The FAM64A-related genes were principally categorized into ubiquitin-mediated proteolysis, cell cycle, chromosome segregation and mitosis, microtubule binding and organization, metabolism of amino acids, cytokine receptors, lipid droplet, central nervous system, and collagen trimer (p < .05). FAM64A protein expression was lower in normal gastric mucosa than intestinal metaplasia, adenoma, and primary cancer (p < .05), negatively correlated with older age, T stage, lymphatic and venous invasion, tumor, node, metastasis stage, and dedifferentiation (p < .05), and associated with a favorable overall survival of gastric cancer patients. FAM64A overexpression promoted proliferation, antiapoptosis, migration, invasion, and epithelial-mesenchymal transition via the EGFR/Akt/mTOR/NF-κB, while the opposite effect was observed for FAM64A knockdown. FAM64A also induced chemoresistance directly or indirectly through lipid droplet formation via ING5. These results suggested that upregulation of FAM64A expression might induce aggressive phenotypes, leading to gastric carcinogenesis and its subsequent progression. Thus, FAM64A could be regarded as a prognosis biomarker and a target for gene therapy.

The effects of REG4 expression on chemoresistance of ovarian cancer.

Although ovarian cancer usually responds well to platinum- and taxane-based first-line chemotherapy, most patients develop recurrence and chemoresistance. Regenerating gene 4 (REG4) is a secretory protein involved in cell differentiation and proliferation. We found higher REG4 expression in ovarian cancer than in normal tissues (p < .05). Regenerating gene 4 expression was negatively associated with overall, progression-free or post-progression survival rates of patients with ovarian cancer receiving platinum or paclitaxel treatment (p < .05) according to a Kaplan-Meier plotter. Regenerating gene 4 overexpression resulted in either cisplatin or paclitaxel resistance, and apoptosis resistance in CAOV3 ovarian cancer cells (p < .05). REG4-transfected ovarian cancer cells showed stronger migration and invasion treated with cisplatin or paclitaxel (p < .05). Additionally, cisplatin or paclitaxel exposure led to the overexpression of phosphorylated phosphoinositide 3-kinase (p-PI3K), p-Akt, phosphorylated mammalian target of rapamycin (p-mTOR), glutathione S-transferase-π, survivin, and B-cell lymphoma 2 in REG4 transfectants compared with control cells (p < .05). These findings suggested that REG4 expression was up-regulated in ovarian cancer, and associated with poor survival and chemotherapy resistance. REG4 promoted the occurrence, development, and chemotherapy resistance of ovarian cancer by regulating cell proliferation, apoptosis, migration, and invasion, and PI3K/Akt/m-TOR signalling pathways. IMPACT STATEMENTWhat is already known on this subject? REG4 mRNA expression is up-regulated in many digestive cancers. High REG4 expression was associated with an adverse prognosis, high tumour and nodal stages, poor differentiation, and hepatic and peritoneal metastases of digestive cancers. REG4 expression conferred cancer cells with increased resistance to chemoradiotherapy, especially 5-FU-based treatment, by activating the MAPK/Erk/Bim signalling pathway.What do the results of this study add? REG4 was highly expressed in ovarian cancer. The expression of p-PI3K, p-AKT, p-mTOR, GST-π, survivin, and Bcl-2 was increased in REG4-overexpressing cells. High REG4 expression was significantly associated with inferior OS, PFS, and PPS rates in patients with ovarian cancer receiving platinum chemotherapy. REG4 mediated cisplatin and paclitaxel resistance in CAOV3 ovarian cancer cells. The percentage of apoptotic cells was markedly lower in REG4-transfected compared to mock-transfected cells after cisplatin or paclitaxel treatment.What are the implications of these findings for clinical practice and/or further research? This study aimed to evaluate the prognostic significance of REG4 expression in ovarian cancer treated with platinum and paclitaxel, to explore REG4 chemoresistance mechanisms to platinum and paclitaxel, and to provide a scientific experimental basis for the clinical treatment and outcome evaluation of ovarian cancer. In order to provide comprehensive clinical treatment of ovarian cancer, it is helpful to improve our understanding of multi-drug resistance and identify new cancer diagnostic biomarkers.

LINC01140 inhibits nonsmall cell lung cancer progression and cisplatin resistance through the miR-4742-5p/TACC1 axis.

Recent studies show that lncRNAs participate in drug resistance and nonsmall cell lung cancer (NSCLC) progression. This study aimed to study the roles and mechanisms of long intergenic nonprotein coding RNA 01140 (LINC01140) in regulating NSCLC progression and drug resistance. Real-time quantitative polymerase chain reaction and western blot analysis were used to detect LINC01140, miR-4742-5p, and transforming acidic coiled-coil 1 (TACC1) expression in NSCLC cells. The interaction between two molecules was examined by luciferase reporter and/or RNA immunoprecipitation assays. Cell invasion, apoptosis, and cisplatin cytotoxicity were assessed by transwell invasion assay, flow cytometry analysis, and CCK-8 assay, respectively. LINC01140 was downregulated and miR-4742-5p was upregulated in NSCLC. LINC01140 inhibited miR-4742-5p expression by competitively binding to miR-4742-5p, while miR-4742-5p targeted TACC1 to inhibit TACC1 expression in NSCLC cells. LINC01140 enrichment repressed the invasive potential and cisplatin resistance and triggered apoptosis, which was reversed by miR-4742-5p overexpression. miR-4742-5p inhibition suppressed cell invasion and cisplatin resistance and accelerated apoptosis in NSCLC cells, while TACC1 silencing abolished these effects. Mechanistically, LINC01140 positively regulated TACC1 expression by sponging miR-4742-5p. In conclusion, LINC01140 inhibited NSCLC progression and cisplatin resistance via functioning as a ceRNA for miR-4742-5p to modulate TACC1.

Histone deacetylase 6-mediated downregulation of TMEM100 expedites the development and progression of non-small cell lung cancer.

The significance of epigenetic modulation, involving acetylation, methylation, as well as ubiquitination has been indicated in the regulation of gene expression and tumor progression. Here, we elucidated the role of histone deacetylase 6 (HDAC6) in regulating epithelial-mesenchymal transition (EMT)-mediated metastasis via mRNA in non-small cell lung cancer (NSCLC). Three microarrays associated with lung cancer metastasis or recurrence, GSE23361, GSE7880 and GSE162102, were downloaded from the GEO database. Transmembrane protein 100 (TMEM100) was revealed to be the only one mRNA that was significantly downregulated in three microarrays. TMEM100, poorly expressed in lung cancer tissues, was associated with poor prognosis of lung cancer patients. Moreover, TMEM100 transcription was regulated by HDAC6 which repressed TMEM100 expression by deacetylation modification on the TMEM100 promoter. Knockdown of HDAC6 or overexpression of TMEM100 in NSCLC cells significantly inhibited TGF-ß1-induced EMT and metastasis and suppressed the activation of Wnt/ß-catenin signaling pathway. Altogether, our study highlights HDAC6 as a lung cancer metastasis supporter through the suppression of TMEM100 and the induction of Wnt/ß-catenin signaling pathway.

Screening and identification of biomarkers associated with the diagnosis and prognosis of lung adenocarcinoma.

BACKGROUND: In this study, we aimed to identify the pathogenesis and prognostic biomarkers of lung adenocarcinoma (LUAD). METHODS: Differentially expressed mRNAs (DEmRNAs) and single nucleotide polymorphism (SNP) mutant genes were screened. In addition, enrichment and protein-protein interaction (PPI) network analyses of the SNP-mutated genes were performed. Thereafter, the correlation between gene mutation and expression was analyzed. Finally, the mutated genes associated with LUAD prognosis were validated on the basis of The Cancer Genome Atlas (TCGA) database. RESULTS: A total of 2502 DEmRNAs were initially screened in this study. We identified 756 SNP-mutated genes from more than 30 cases. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the mutated genes involved in LUAD were mainly associated with the ECM-receptor interaction, focal adhesion, and calcium signaling pathways. Tumor protein p53 (TP53) and neurexin 1 (NRXN1) with the higher degree were chosen as the hub genes in the PPI network. In addition, the correlation analysis revealed six genes, including assembly factor for spindle microtubules (ASPM), centromere protein F (CENPF), contactin 3 (CNTN3), catenin delta 2 (CTNND2), PKHD1 like 1 (PKHD1L1), and semaphorin 6D (SEMA6D), and three SNP mutations at ASPM rs368020495, CENPF rs762653487, and PKHD1L1 rs768349010 sites that were found to be associated with LUAD prognosis. Further validation showed that among the aforementioned six mutated genes, CENPF was upregulated and SEMA6D was downregulated. CONCLUSION: CENPF, SEMA6D, TP53, and NRXN1 were found to be closely associated with the development of LUAD.

Overexpression of ECT2 is a strong poor prognostic factor in ER(+) breast cancer.

Epithelial cell transforming sequence 2 (ECT2) is a guanine nucleotide exchange factor encoded by the ECT2 gene, which is located on the 3q26.31 chromosomal region and is directly associated with the occurrence of cancers. The aim of the present study was to examine the expression and prognostic importance of ECT2 in various breast cancer subtypes using the online tools, Gene Expression Profiling Interactive Analysis, Kaplan-Meier-plotter and bc-GenExMiner. ECT2 mRNA expression was significantly different in oestrogen receptor ER(+) breast cancer; overexpression of ECT2 was associated with poor prognosis in ER+ breast cancer. The mRNA expression levels of ECT2 were increased in basal-like breast cancer and triple negative breast cancer, but were not significant for prognostic prediction. We identified ECT2-correlated genes and their corresponding Gene Ontology (GO) enrichment terms. The results revealed that GO: 0005524 (protein binding) had the greatest number of correlated genes and also contained ECT2. This suggested that overexpression of ECT2 may be a significant prognostic factor for poor outcome in ER+ breast cancer; however, the precise role of ECT2 in breast cancer requires further investigation.

Silencing ARHGAP9 correlates with the risk of breast cancer and inhibits the proliferation, migration, and invasion of breast cancer.

Breast cancer (BC) is one of the most common malignant tumors in women, and screening relevant genes and markers that are involved in BC tumor genesis and progression is of great value. We previously found that messenger RNA expression of ARHGAP9 was high in BC tissue, but it is unclear whether ARHGAP9 participates in the progression of human BC. In this study, we found that ARHGAP9 expression was correlated with poor patient survival, American Joint Committee on Cancer clinical staging, tumor size, and tumor differentiation. MCF-7 and MDA-MB-231 cells exhibited higher expression of ARHGAP9 than other human BC cell lines (HCC1937, MDA-MB-453, ZR-75-1, and Hs 578T). Knockdown of ARHGAP9 in human BC cells markedly reduced the cell proliferation, migration, and invasive ability of MCF-7 and MDA-MB-231 cells. Furthermore, small interfering RNA (siRNA) of ARHGAP9 also induced G0-G1 cell cycle arrest and apoptosis in MCF-7 and MDA-MB-231 cells. Expressions of cell cycle markers (CDK2 and CCNB1) and invasion-related protein (RhoC and MTA1) were downregulated in siRNA-ARHGAP9-transfected cells. siRNA of ARHGAP9 also inhibited the phosphorylation of mitogen-activated protein kinases in BC cells. In conclusion, the abnormal expression of ARHGAP9 may correlate with the genesis, development, and diagnosis of BC.

Combination of platelet count and lymphocyte to monocyte ratio is a prognostic factor in patients undergoing surgery for non-small cell lung cancer.

The aim of this study was to investigate the usefulness of a novel inflammation-based prognostic system, called COP-LMR (combination of platelet count and lymphocyte to monocyte ratio), for predicting postoperative survival of patients with non-small cell lung cancer (NSCLC). COP-LMR was calculated on the basis of the obtained data. Patients with both an elevated platelet count (PLT) (>30 × 104mm-3) and a low LMR (<3.6) were assigned a score of 2, and patients with one or none of the parameters were assigned a score of 1 or 0, respectively. A total of 1120 patients who underwent complete resection were enrolled in this study. Multivariate analysis revealed that COP-LMR is an independent prognostic factor for disease-free survival (DFS) (P<0.001) and overall survival (OS) (P<0.001). Kaplan-Meier analysis and the log-rank test revealed that COP-LMR stratified the patients into 3 independent groups (P<0.001). In conclusion, COP-LMR is a potential prognostic biomarker in patients undergoing surgery for NSCLC.

Prognostic significance of subclassification of stage IIB lung cancer: a retrospective study of 226 patients.

We investigated the prognostic significance of subclassification of stage IIB lung cancer according to the eighth tumor-node-metastasis (TNM) classification. To this purpose, the prognostic outcomes of 226 stage IIB lung cancer patients who underwent surgery without adjuvant therapies between 2001 and 2010 were evaluated retrospectively based on the eighth TNM classification. Of the 226 patients, 23, 30, 118 and 55 had pT1b, pT1c, pT2a, and pT2b stage cancers, respectively. Their 5-year survival rates were 67%, 33%, 21%, and 27%, respectively. There was no significant difference in the 5-year survival between T1b and T1c, between T1c and T2a, and between T2a and T2b (p = 0.128, 0.105, and 0.403, respectively). There were significant differences in the 5-year survival between T1b and T2a, between T1b and T2b, and between T1c and T2b (p = 0.005, 0.002, and 0.042, respectively). The 5-year survival of patients with pleural invasion and vessel invasion was significantly worse than that of their counterparts (p = 0.009 and <0.001, respectively). Subclassification of stage IIB lung cancer is of prominent prognostic significance. It is recommended that the current stage be subclassified, in order to more accurately predict the prognosis of patients.

Association of single nucleotide polymorphisms in the MVP gene with platinum resistance and survival in patients with epithelial ovarian cancer.

The human major vault protein (MVP) has been linked to the development of multidrug resistance in cancer cells, and overexpression of MVP has been observed in ovarian cancer tissues. The aim of the present study was to investigate the association between single nucleotide polymorphisms (SNPs) in the MVP gene and the tumor response to platinum-based chemotherapy and survival of patients affected by epithelial ovarian cancer (EOC), in addition to confirm whether tetra-primer amplification-refractory mutation system (ARMS)-polymerase chain reaction (PCR) is an accurate genotyping method. For this purpose, two polymorphisms in the MVP gene, namely reference SNP (rs)1057451 and rs4788186, were selected from the data obtained by the International haplotype map (HapMap) Project regarding Chinese Han population, and were evaluated by tetra-primer ARMS-PCR. Upon validation by DNA sequencing, the association of these polymorphisms with platinum resistance, progression-free survival (PFS) and overall survival (OS) in patients with EOC was assessed. The results of tetra-primer ARMS-PCR were in agreement with those derived from DNA sequencing. No significant differences were observed between platinum-sensitive and platinum-resistant cohorts in terms of allele and genotype distribution of these two polymorphisms in the MVP gene, which were not associated with PFS or OS. However, a trend toward prolonged PFS was observed in patients carrying the heterozygous AG allele at the rs4788186 locus. These results suggest that rs1057451 and rs4788186 variants in the MVP gene are not associated with favorable therapeutic response to platinum or longer survival in Chinese Han patients affected by EOC. In addition, the data of the present study confirm that tetra-primer ARMS-PCR is a trustworthy and economical genotyping method.

Role of BCL2-associated athanogene in resistance to platinum-based chemotherapy in non-small-cell lung cancer.

The present study aimed to address the pharmacogenetic role of BAG1 in platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC) and in cultured human lung adenocarcinoma A549 cells. A total of 108 NSCLC patients (stages I-IIIA) were treated with a standard chemotherapy regimen of cisplatin plus vinorelbine. Additionally, in vitro cultured A549 cells were treated with cisplatin in the presence or absence of tunicamycin. Cell proliferation was determined by MTT assay and protein levels were assessed via western blot analysis. Patients with BAG1-positive expression were revealed to have a prolonged survival time (progression-free survival, 24.0 months) compared with that of patients without BAG1 expression (21.6 months; χ2=18.018, P<0.05). Treatment of A549 cells with tunicamycin followed by cisplatin resulted in elevated BAG1 levels. In addition, tunicamycin was found to significantly enhance cisplatin-induced growth inhibition and apoptosis in A549 cells. The results indicate that BAG1 is important in cisplatin-induced cell death in lung adenocarcinoma, suggesting that endoplasmic reticulum stress may promote the sensitivity of NSCLC patients to chemotherapy.

Clinical significance of GRHL3 expression in diffuse large B cell lymphoma.

In the present study, we assessed the GRHL3 expression in 967 patients with diffuse large B cell lymphomas to identify the potential prognostic value and the development of specific therapeutic strategies. All patients enrolled were from a previous study by Hao Zhang et al. (BMC Cancer 14:333, 2014). GRHL3 expression status was evaluated by immunohistochemical analysis. Survival analysis using the Kaplan-Meier method and multivariate analysis were conducted to adjust the effect of GRHL3 expression as a potential independent prognostic factor. In the enrolled 967 patients, GRHL3 expression was detected in 398 (41.16 %) patients under immunohistochemical analysis. The 5-year survival rate in patients with GRHL3 expression was significantly lower than that in those without GRHL3 expression (37.8 vs 52.8 %, P < 0.001). Multivariate analysis identified GRHL3 expression as an independent predictor of poor survival. The sensitivity and specificity of GRHL3 for the diagnosis of germinal center B cell (GCB)/non-GCB was 89.2 % (182/204) and 82.1 % (174/212), respectively. GRHL3 expression may be useful as a prognostic factor and for the diagnosis GCB/non-GCB of diffuse large B cell lymphoma.

Association between polymorphisms of BAG-1 and XPD and chemotherapy sensitivity in advanced non-small-cell lung cancer patients treated with vinorelbine combined cisplatin regimen.

BCL-2 Associated athanogene 1 (BAG-1) and Xeroderma pigmentosum group D (XPD) are involved in the nucleotide excision repair pathway and DNA repair. We aimed to investigate whether polymorphisms in BAG-1 and XPD have effects on chemotherapy sensitivity and survival in patients with advanced non-small-cell lung cancer (NSCLC) treated with vinorelbine combined cisplatin (NP) regimen. A total of 142 patients with diagnosed advanced NSCLC were recruited in the current study. NP regimen was applied for all eligible patients. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for BAG-1 (codon 324) and XPD (codons 312 and 751) genotyping. The treatment response was evaluated according to the RECIST guidelines. Progression-free survival (PFS) and overall survival (OS) were record as median and end point, respectively. As for BAG-1 codon 324, the chemotherapy sensitivity in NSCLC patients with CT genotype was 0.383 times of those with CC genotype (P < 0.05). With respect to XPD codon 751, the chemotherapy sensitivity in NSCLC patients with Lys/Gln genotype was 0.400 times of those with Lys/Lys genotype (P < 0.05). In addition, NSCLC patients carrying combined C/C genotype at codon 324 in BAG-1, Asp/Asp of XPD codon 312, and Lys/Lys of XPD codon 751 produced a higher efficacy of NP chemotherapy compared to those carrying mutation genotypes (all P < 0.05). Further, there were significant differences in PFS between patients with combined C/C genotype of BAG-1 codon 324, Lys/Lys genotype of XPD codon 751, and Asp/Asp genotype of XPD codon 312 and patients carrying BAG-1 codon 324 C/T genotype, XPD codon751 Lys/Gln genotype, and XPD codon312 Asp/Asn genotype (P < 0.05). Multivariate Cox regression analysis indicated that the combined wild-type of codon 324 XPD, codon 751 XPD, and codon 312 BAG-1 is the protective factor for OS and PFS, and clinical stages is the risk factor for OS and PFS. In conclusion, our research demonstrated the combined effects of BAG-1 and XPD polymorphisms on chemotherapy sensitivity and survival in patients with advanced NSCLC, which might be the important predictive markers for platinum-based chemotherapy efficacy.

Effect of the -2081G/A polymorphism of the TLR4 gene and its interaction with Helicobacter pylori infection on the risk of gastric cancer in Chinese individuals.

AIMS: Toll-like receptor 4 (TLR4) plays an important role in gastric carcinoma. Using a case-control study, we analyzed the genotypic distribution of TLR4 rs10983755 (-2081G/A) and rs11536878 in a Chinese population and investigated the effect of their interactions with Helicobacter pylori infection on susceptibility to gastric cancer (GC) and atrophic gastritis (AG). METHODS: In this study, 409 and 581 cases of GC and AG, respectively, were selected for analyses along with an equal number of matched controls. The TLR4 polymorphisms were genotyped using Sequenom MassARRAY. Serum levels of anti-H. pylori IgG were determined by enzyme-linked immunosorbent assay. RESULTS: The TLR4-2081G/A polymorphism was negatively associated with GC (AG+AA vs. GG: odds ratio [OR]=0.70, 95% confidence interval [CI]=0.53-0.93, p=0.012). A decreased risk of GC was observed in H. pylori negative and TLR4-2081(AG+AA) genotype subjects [H. pylori(-)/AG+AA vs. H. pylori(+)/GG: OR=0.16, 95% CI=0.09-0.27, p<0.001]. The rs11536878 polymorphism was not associated with GC or AG. CONCLUSIONS: The TLR4-2081G/A polymorphism seems to affect the risk of gastric carcinogenesis and may to some degree play a protective role against H. pylori infection.

Elevated pretreatment serum concentration of YKL-40: an independent prognostic biomarker for poor survival in patients with colorectal cancer.

Serum YKL-40 levels have been associated with a poor prognosis in patients with several cancer types. However, the role of YKL-40 and its relationship with colorectal cancer are poorly understood. Pretreatment serum levels of YKL-40 were determined in 86 patients with colorectal cancer and from 20 healthy controls. The serum YKL-40 levels in colorectal cancer patients were compared with those in healthy controls, and we retrospectively assessed the association between serum YKL-40 levels and clinicopathological findings and progression-free survival. Colorectal patients had a median serum YKL-40 level of 216 ng/mL (range 22.3-1, 253.2 ng/mL). Expression of serum YKL-40 levels was significantly higher in colorectal cancer patients compared with healthy controls, and the median serum values were 216 and 62.5 ng/mL, respectively (p < 0.01). No correlation was observed between progression-free survival and the type of chemotherapy regimen used tumor stage, sex, or histologic types. Patients with high serum YKL-40 levels [greater than the median level for all patients (216 ng/mL)] had a significantly shorter survival than patients with serum YKL-40 levels below the median (median progression-free survival, 36 vs. 50 months; p = 0.003). In multivariate analysis, the serum YKL-40 level, and the presence of distant metastasis were independent, statistically significant prognostic factors. The pretreatment serum YKL-40 level was identified as a new, independent prognostic biomarker in patients with colorectal cancer and may help to determine the individual prognosis of these patients.

Effects of MTHFR genetic polymorphisms on toxicity and clinical response of irinotecan-based chemotherapy in patients with colorectal cancer.

AIMS: This meta-analysis aims to evaluate the effects of common polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene on the toxicity and clinical responses of irinotecan-based chemotherapy in patients with colorectal cancer (CRC). METHODS: The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched from their inception through November 1st, 2013 without language restrictions. Meta-analysis was conducted with the use of the STATA 12.0 software. Crude odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated. Seven clinical cohort studies with a total of 815 CRC patients met the inclusion criteria. Two common polymorphisms (677 C>T and 1298 A>C) in the MTHFR gene were assessed. RESULTS: The results from our meta-analysis suggested that MTHFR genetic polymorphisms might significantly decrease the rate of grade 3/4 toxicity of irinotecan-based chemotherapy in CRC patients (OR=0.53, 95% CI: 0.32-0.89, p=0.015). Furthermore, we also demonstrated that MTHFR genetic polymorphisms strongly correlated with good clinical responses (complete response+partial response) to irinotecan-based chemotherapy in CRC patients (OR=1.47, 95% CI: 1.05-2.04, p=0.024). CONCLUSIONS: Our findings provide empirical evidence that MTHFR genetic polymorphisms may decrease the toxicity of irinotecan-based chemotherapy and increase the clinical benefits for CRC patients. Thus, MTHFR genetic polymorphisms may be screened to predict the clinical responses to irinotecan-based chemotherapy in CRC patients.

Role of MDM2 T309G polymorphism in susceptibility and prognosis of nonsmall cell lung cancer: a meta-analysis.

AIMS: This meta-analysis was performed to evaluate the relationships of a common polymorphism (T309G, rs2279744 T>G) in the murine double minute 2 (MDM2) gene with susceptibility and prognosis of nonsmall cell lung cancer (NSCLC). METHODS: The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before November 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude odds ratios (ORs) or hazard risk (HR) with their 95% confidence intervals (95% CI) were calculated. Seven clinical studies with a total 3732 NSCLC patients and 1472 healthy controls met the inclusion criteria. RESULTS: The results of our meta-analysis suggested that MDM2 T309G polymorphism might be strongly correlated with an increased risk of NSCLC (G allele vs. T allele: OR=1.63, 95% CI: 1.42-1.89, p<0.001; TG+GG vs. TT: OR=1.54, 95% CI: 1.31-1.80, p<0.001; respectively). Furthermore, we observed significant associations of MDM2 T309G polymorphism with poor overall survival (TT vs. GT: HR=1.22, 95% CI: 101-1.43, p<0.001; TT vs. GG: HR=1.31, 95% CI: 1.04-1.59, p<0.001; TT vs. GT+GG: HR=1.44, 95% CI: 1.13-1.76, p<0.001; respectively) and progression-free survival (TT vs. GT+GG: HR=1.26, 95% CI: 0.82-1.69, p<0.001) of NSCLC patients. CONCLUSIONS: Our findings provide convincing evidence that the MDM2 T309G polymorphism may contribute to individual differences in NSCLC susceptibility and prognosis. Thus, the MDM2 T309G polymorphism may be a promising potential biomarker for NSCLC diagnosis and prognosis.

Association of thymidylate synthase gene 3'-untranslated region polymorphism with sensitivity of non-small cell lung cancer to pemetrexed treatment: TS gene polymorphism and pemetrexed sensitivity in NSCLC.

BACKGROUND: Thymidylate synthase (TS) is a key enzyme responsible for DNA synthesis and repair. Altered expression of TS protein or TS gene polymorphisms has been associated with cancer progression and treatment response. This study investigated the expressions of TS and its gene SNPs in non-small cell lung cancer (NSCLC), and then its association with sensitivity to pemetrexed treatment. Immunohistochemistry and qRT-PCR were performed on 160 resected NSCLC specimens and corresponding normal tissues to assess the expressions of TS protein and TS mRNA, and for associations with clinicopathological data. Blood samples of 106 lung adenocarcinoma patients were examined for polymorphisms of the TS gene 3'-UTR 1494del 6 bp, which was then investigated for associations with responses of the patients to pemetrexed treatment and survival. RESULTS: Expression of both TS protein and its mRNA was elevated in NSCLC tissues compared with matched normal tissues, and significantly higher in lung squamous cell carcinoma than in lung adenocarcinoma. TS expression was associated with poor tumor differentiation. Furthermore, the genotyping data showed that 56% of lung adenocarcinoma patients had the TS gene 3'-UTR 1494 bp (-6 bp/-6 bp) genotype and the rest had TS gene 3'-UTR 1494 bp (-6 bp/+6 bp). There was no TS 3'-UTR 1494 bp (+6 bp/+6 bp) genotype in any patients. Statistical analysis revealed that gender, tumor stage, and TS 3'-UTR 1494del 6 bp polymorphism were significant prognostic factors after short-term pemetrexed treatment. Log-rank analysis revealed that patients with the (-6 bp/-6 bp) genotype had significantly better progression-free and overall survival than patients with (-6 bp/+6 bp). CONCLUSIONS: This study showed that TS protein is highly expressed in NSCLC and that polymorphisms of TS 3'-UTR 1494del 6 bp are associated with sensitivity of lung adenocarcinoma patients to pemetrexed treatment. This suggests that TS gene polymorphisms should be further evaluated as prognostic markers for personalized therapy in lung adenocarcinoma.

The role of expression and polymorphism of the BAG-1 gene in response to platinum-based chemotherapeutics in NSCLC.

We investigated the correlation between BAG-1 expression and sensitivity to platinum-based chemotherapeutics in patients with non-small cell lung cancer (NSCLC). mRNA and protein expression of BAG-1 in lung tissue of NSCLC postoperative patients (I-IIIA stage) or healthy subjects were detected using reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. Cox regression analysis was used to quantify the association of prognostic factors with survival in NSCLC patients. Venous blood samples from patients newly diagnosed with advanced NSCLC (IIIB-IV stage) were collected before chemotherapy to analyze allelic frequency and gene polymorphisms. Compared to healthy controls (11.67%, 14 cases), levels of mRNA and protein of BAG-1 in lung tissues was significantly higher in NSCLC patients (61.67%, 74 cases) (χ²=5.601, P<0.05). Moreover, BAG-1 expression was identified as an independent prognostic factor for survival in NSCLC patients. As time to progression and survival rate was dramatically increased, patients with a positive expression of BAG-1 exhibited a prolonged survival period (TTP, 49.3 months; 5-year survival rat, 16.21%) compared with those without BAG-1 expression (χ²=7.243, P<0.05). Two BAG-1 digestion patterns (CC and CT) were identified and confirmed. patients (77.46%) had a C/C genotype at BAG-1 codon 324, while 22.54% had the C/T genotype. The T/T genotype was not present in these patients. The progression risk of patients carrying the C/C genotype at Bag-1 codon 324 was 1.87 times higher than that of patients carrying the C/T genotype (P<0.001). Follow-up examination showed that the chemotherapeutic sensitivity of patients carrying the C/C genotype was 2.852 times higher than that of patients carrying the C/T genotype (95% CI, 1.133-7.182; P=0.026). Significant differences were found in the median progression-free survival (PFS) and overall survival (OS) of these two cohorts of patients. Compared to patients carrying the C/T genotype of BAG-1, patients carrying the C/C genotype at Bag-1 codon 324 exhibited better responses to platinum-based chemotherapy. Hence, the expression of BAG-1 was closely associated with the sensitivity to platinum-based chemotherapeutics in NSCLC patients.