Research IndicatorsGraph generated 11 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (8)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: CEACAM5 (cancer-related)
Zekri J, Al-Shehri A, Mahrous M, et al.Mutations in codons 12 and 13 of K-ras exon 2 in colorectal tumors of Saudi Arabian patients: frequency, clincopathological associations, and clinical outcomes.
Genet Mol Res. 2017; 16(1) [PubMed
] Related Publications
Mutations in codons 12/13 of K-ras exon 2 are associated with reduced benefit from anti-epidermal growth factor receptor antibody treatment for metastatic colorectal cancer (CRC). Here, we evaluated the frequency of K-ras mutations and their relationship with clinicopathological features and treatment outcomes in Saudi Arabian patients with CRC. The genetic status of K-ras was determined in 300 patients diagnosed with CRC. Clinical information was collected retrospectively. K-ras was wild-type in 58% and mutated in 42% of the tumors. Most mutations were at codon 12 (89%) and were associated with metastasis [odds ratio (OR) = 1.38 (95%CI = 1.14-1.67] and occurrence of >40 µg/L carcinoembryonic antigen (CEA) [OR = 1.33 (1.1-1.74)] during diagnosis. Patients in stages I-III of the disease with wild-type K-ras tumors had a median relapse free survival (RFS) of 29 months in contrast to 22 months for those with the mutated K-ras tumor (P = 0.0357). In multivariate analysis, only the stage of the disease significantly predicted RFS (P = 0.001). Patients in stage IV of CRC with the wild-type K-ras tumor did not reach the median overall survival (OS), whereas patients with the mutated K-ras tumor survived for 23.5 months (P = 0.044). CEA level >40 µg/L (P = 0.004) and status of K-ras (P = 0.044) were independent predictors of OS. This is the largest study investigating K-ras mutations in patients with CRC in the Middle East. Mutations were associated with advanced stage of CRC, higher serum CEA, shorter RFS and OS.
Hu HB, Jie HY, Zheng XXThree Circulating LncRNA Predict Early Progress of Esophageal Squamous Cell Carcinoma.
Cell Physiol Biochem. 2016; 40(1-2):117-125 [PubMed
] Related Publications
BACKGROUND/AIMS: Previous studies revealed that circulating (either from plasma or serum) long non-coding RNA may predict the occurrence or prognosis of multiple human malignant tumors. In this study, we mainly explored whether circulating lncRNAs can be utilized as biomarkers predicting the development of human esophageal squamous cell carcinoma (ESCC).
METHODS: LncRNA microarray was applied to screen the potential biomarkers for ESCC. Each group contained three individual plasma samples. A multi-stage validation and risk score formula detection were used for validation.
RESULTS: Eleven dysregulated lncRNAs were obtained after Venny analysis. Further validation in a larger cohort including 205 ESCC patients, 82 patients suffering from esophagus dysplasia and 210 healthy controls confirmed that increased Linc00152, CFLAR-AS1 and POU3F3 might be potential biomarkers for predicting the early progress with an area under curve (AUC) of 0.698, 0.651 and 0.584, respectively. The merged AUC of the three factors and merged with CEA was 0.765 and 0.955, respectively. We also revealed that circulating levels of three lncRNAs were associated with poor post-surgery prognosis of ESCC patients.
CONCLUSIONS: The three circulating lncRNAs might serve as potential biomarkers for predicting the early occurrence of ESCC.
Deng T, Yuan Y, Zhang C, et al.Identification of Circulating MiR-25 as a Potential Biomarker for Pancreatic Cancer Diagnosis.
Cell Physiol Biochem. 2016; 39(5):1716-1722 [PubMed
] Related Publications
BACKGROUND: The aim of this study was to identify novel microRNAs for potential use in the diagnosis of pancreatic cancer (PaC).
METHODS: A total of 1063 serum samples from 303 patients with PaC were collected, and the expression level of miR-25 was measured using quantitative real-time PCR (qRT-PCR).
RESULTS: We found that miR-25 had significant diagnostic value for the differential diagnosis of PaC in normal controls with an AUC (the area under the ROC curve) of 0.915 (95% CI: 0.893-0.937) that was significantly higher compared with an AUC of 0.725 for serum tumor marker carcinoembryonic antigen (CEA) and an AUC of 0.844 for CA19-9.
CONCLUSIONS: These data suggest that serum miR-25 has strong potential as a novel biomarker for the early detection of PaC.
Liang W, Lv T, Shi X, et al.Circulating long noncoding RNA GAS5 is a novel biomarker for the diagnosis of nonsmall cell lung cancer.
Medicine (Baltimore). 2016; 95(37):e4608 [PubMed
] Related Publications
The recently discovered long noncoding RNAs have the potential to regulate many biological processes, which are aberrantly expressed in many tumor types. Our previous study showed that the long noncoding RNA-growth arrest-specific transcript 5 (GAS5) was decreased in lung cancer tissue, which contributed to the proliferation and apoptosis of nonsmall cell lung cancer (NSCLC). GAS5 was also associated with the prognosis of lung cancer patients. These results suggest that GAS5 may represent a novel prognostic indicator and a target for gene therapy in NSCLC. However, the expression and diagnosis significance of GAS5 in the plasma of NSCLC patients was unknown. The plasma samples were more readily available than the tissue samples in clinical, so we designed the study to investigate the diagnosis value of GAS5 in blood samples. In our study, 90 patients with NSCLC and 33 healthy controls were included. Blood samples were collected before surgery and therapy. We extracted the free RNA in the plasma and analyzed the expression of GAS5 with quantitative reverse transcription PCR. Suitable statistics methods were used to compare the plasma GAS5 levels of preoperative and postoperative plasma samples between the NSCLC patients and healthy controls. Receiver-operating characteristic curve analysis was used to evaluate the diagnostic sensitivity and specificity of plasma GAS5 in NSCLC. The results showed that GAS5 was detectable and stable in the plasma of NSCLC patients. Furthermore, the plasma levels of GAS5 were significantly down-regulated in NSCLC patients compared with healthy controls (P = 0.000). Moreover, GAS5 levels increased markedly on the seventh day after surgery compared with preoperative GAS5 levels in NSCLC patients (P = 0.003). GAS5 expression levels could be used to distinguish NSCLC patients from control patients with an area under the curve of 0.832 (P < 0.0001; sensitivity, 82.2%; specificity, 72.7%). The combination of the GAS5 and carcinoembryonic antigen could produce an area of 0.909 under the receiver-operating characteristic curve in distinguishing NSCLC patients from control subjects (95% confidence interval 0.857-0.962, P = 0.000). We have demonstrated that GAS5 expression was decreased in NSCLC Plasma. Plasma samples were more accessible than tissue samples in clinical; therefore, GAS5 could be an ideal biomarker for the diagnosis of NSCLC.
Zhang K, Luo Z, Zhang Y, et al.Circulating lncRNA H19 in plasma as a novel biomarker for breast cancer.
Cancer Biomark. 2016; 17(2):187-94 [PubMed
] Related Publications
BACKGROUND: Long non-coding RNA (lncRNA) H19 has been well studied playing an important role in breast cancer (BC) progress and the expression of H19 may service as a diagnostic target for BC. However, it is unclear if circulating lncRNA H19 could as a potential biomarker for BC diagnosis and monitor.
OBJECTIVE: The objective of our study was to determine whether plasma lncRNA H19 could be used as biomarkers for the screening and early diagnosis of breast cancer.
METHODS: In this study, we carried out a quantitative real-time PCR (qRT-PCR) method to examine the expression levels of lncRNA H19 in 24 pairs of BC tissues and 20 pairs of BC plasma. The differentially expressed of plasma H19 was further validated in another 102 BC patients and 96 healthy controls. The potential correlations between plasma H19 levels and clinicopathological characteristics were analyzed. Receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic values of plasma H19 between 30 early stage BC patients and 30 healthy controls. 24 paired pre- and postoperative plasma samples were detected to assess the tumor monitoring values.
RESULTS: The results revealed that the expression of H19 was significantly increased in BC tissues and plasma compared with healthy controls (P< 0.05), and plasma H19 levels were significantly correlated with estrogen receptor (ER) (P= 0.008), progesterone receptor (PR) (P= 0.025), c-erbB-2 (P= 0.043) and lymph node metastasis (P= 0.006). The area under the ROC curve (AUC) of plasma H19 was 0.81(sensitivity, 56.7%; specificity, 86.7%; P< 0.0001), which was higher than the values of carcinoembryonic antigen (CEA) and carbohydrate antigen 153 (CA153). Furthermore, plasma H19 levels were significantly decreased in postoperative samples than preoperative samples (P= 0.0006).
CONCLUSION: Plasma H19 may serve as a potential biomarker for BC early screening and prognosis monitor.
Kim CW, Roh SA, Tak KH, et al.ZKSCAN3 Facilitates Liver Metastasis of Colorectal Cancer Associated with CEA-expressing Tumor.
Anticancer Res. 2016; 36(5):2397-406 [PubMed
] Related Publications
AIM: Zinc finger with KRAB and SCAN domain 3 (ZKSCAN3) is overexpressed in invasive colorectal cancer (CRC) cells and regulates the expression of several genes favoring tumor progression, including vascular endothelial growth factor (VEGF) and integrin β4. We evaluated the association of ZKSCAN3 and colorectal cancer liver metastasis (CLM) to determine whether it is related to invasive signaling pathways.
MATERIALS AND METHODS: The ratios of expression by primary tumor to normal tissue and metastatic tumor to normal tissue were compared between ZKSCAN3-overexpressing and underexpressing primary tumor groups.
RESULTS: In terms of CLM, the ZKSCAN3 overexpression was positively correlated with carcinoembryonic antigen (CEA), VEGF, and AKT expression. The protein-expression analysis showed that ZKSCAN-specific siRNA knockdown reduced CEA expression in LoVo and LS174T CRC cells. Matrigel invasion by ZKSCAN3-overexpressing HCT116 cells was increased when examined on CEA-coated filters compared with phosphate-buffered saline-treated controls. Additionally, matrix metalloproteinase 9 (MMP9) expression was greater in cells with reference allele (GG) than substitution allele (CC) for ZKSCAN3 rs733743 (p=0.032). ZKSCAN3 protein expression of the high serum CEA group was increased in hepatic metastatic tissue compared with the primary tumor tissue, while in the group with normal serum CEA it decreased or was similar. Reference ZKSCAN3 alleles were correlated with male dominance, a family history of malignancy, high serum CEA concentration and stage IV CRC in 450 patients with sporadic CRC. In conclusion, ZKSCAN3 appears to promote colorectal tumor progression and invasion. ZKSCAN3 may facilitate hepatic metastasis of CRC associated with CEA particularly in cases with CEA-producing tumor.
Yamauchi K, Kokuryo T, Yokoyama Y, et al.Prediction of Early Recurrence After Curative Resection of Colorectal Liver Metastasis and Subsequent S-1 Chemotherapy.
Anticancer Res. 2016; 36(5):2175-9 [PubMed
] Related Publications
BACKGROUND: S-1, an oral 5-fluorouracil (5-FU)-based medicine that combines tegafur, gimeracil and oteracil potassium is commonly used as an adjuvant chemotherapeutic drug for the treatment of colorectal cancer.
PATIENTS AND METHODS: We enrolled 53 patients who underwent curative resection for colorectal cancer and liver metastasis (synchronous, n=24; metachronous, n=29). The subsequent adjuvant chemotherapy with oral S-1 administration was initiated within 56 days after liver resection. Recurrence was evaluated by imaging studies, that were performed during the first year after liver resection. Of the 53 patients, 25 who did not recur within 1 year were defined as being in the no-recurrence (NREC) group and the remaining 18 patients were defined as being in the early-recurrence (EREC) group. There were no significant differences in gene expression profiling for drug resistance and metabolism between the NREC group and the EREC group.
RESULTS: In synchronous liver metastasis, there was no significant difference in early recurrence between serum carcinoembryonic antigen (CEA) ≤5 ng/ml and serum CEA >5 ng/ml (8/24 vs. 16/24, respectively). In metachronous liver metastasis, the early recurrence rate was significantly higher in patients with CEA >5 ng/ml compared to patients with CEA ≤5 ng/ml (15/29 vs. 14/29, p=0.05). The expression of cytochrome P450 2C19 (CYP2C19) and ATP-binding cassette, sub-family B member 1 (ABCB1) were significantly lower in the EREC group (6/15) compared to the NREC group (9/15) in colorectal cancer with metachronous liver metastasis and with serum CEA >5 ng/ml.
CONCLUSION: Although the exact reason for down-regulation of these genes in the group with poor prognosis is unknown, the information obtained in this study may be useful in clinical practice for colorectal cancer.
Wang Q, Zhang H, Shen X, Ju SSerum microRNA-135a-5p as an auxiliary diagnostic biomarker for colorectal cancer.
Ann Clin Biochem. 2017; 54(1):76-85 [PubMed
] Related Publications
Objective The purpose of this study was to explore serum miR-135a-5p expression in colorectal cancer and examine the potential usefulness of this molecule as a biomarker for diagnosis in colorectal cancer. Methods Serum samples were collected from 60 patients with primary colorectal cancer, 40 patients with colorectal polyps and 50 healthy controls. Serum miR-135a-5p expression levels were detected by reverse transcription quantitative real-time quantitative polymerase chain reaction. Serum carcinoembryonic antigen and carbohydrate antigen 199 concentrations were detected by MODULAR ANALYTICS E170. Results The relative expression level of serum miR-135a-5p in colorectal cancer patients, colorectal polyps patients and healthy controls was 2.451 (1.107, 4.413), 0.946 (0.401, 1.942) and 0.949 (0.194, 1.415), respectively, indicating that it was significantly higher in colorectal cancer patients than that in the other two groups ( U = 351.0, 313.0, both P < 0.001). Additionally, it was significantly correlated with different degrees of tumour differentiation ( U = 215.0, P = 0.029) and different tumour stages ( U = 202.0, P = 0.013). There was no significant correlation between the relative expression of serum miR-135a-5p and carcinoembryonic antigen ( r(2 )= 0.023, P = 0.293) or carbohydrate antigen 199 ( r(2 )= 0.067, P = 0.068) in colorectal cancer patients. Compared with colorectal polyps group, AUC(ROC) of serum miR-135a-5p in colorectal cancer group was 0.832 with 95% CI 0.73-0.93; compared with healthy control group, AUC(ROC) was 0.875 with 95% CI 0.80-0.95. Conclusion Serum miR-135a-5p expression in colorectal cancer patients was higher than that in patients with colorectal polyps and healthy controls, suggesting that serum miR-135a-5p may prove to be an important biomarker for auxiliary diagnosis of colorectal cancer.
Adjuvant oxaliplatin-based chemotherapy is widely used for stage III colorectal cancer (CRC) after curative surgery. CRC is a molecularly heterogeneous disease, and our current knowledge of therapeutic response-related genetic factors remains limited. N-acetylgalactosaminyltransferase 14 (GALNT14)-rs9679162 genotype is a prognostic predictor for chemotherapy response in advanced hepatocellular carcinoma. Here, we investigated whether this genotype was related to the therapeutic outcome of stage III CRC.A cohort of 300 stage III CRC patients receiving curative resection followed by oxaliplatin-based chemotherapy was retrospectively recruited. GALNT14 genotypes and the clinicopathological factors were correlated with posttherapeutic prognosis.Of these patients, 18% patients had GALNT14-rs9679162 "TT" and 82% had the "GT" + "GG" genotypes. The analysis showed that the "TT" genotype was associated with unfavorable overall survival (OS, P = 0.009) but not with recurrence-free survival (RFS, P = 0.700). The subgroup analysis showed that the "TT" genotype was associated with unfavorable OS in the following subgroups: age ≤65 years, men, left side CRC, N2 stage, carcinoembryonic antigen >5 ng/mL, and mucinous histology (P = 0.012, 0.011, 0.009, 0.025, 0.013, and 0.007, respectively). Within the latter 2 subgroups, the "TT" genotype was the only independent predictor for OS. Finally, the "TT" genotype was associated with the T4 tumor stage (P = 0.017) and in patients with T4 tumors, the "TT" genotype was the only independent predictor for unfavorable RFS (P = 0.007).GALNT14 "TT" genotype was associated with unfavorable OS in stage III CRC patients receiving curative surgery and adjuvant oxaliplatin-based chemotherapy.
Gallegos CE, Michelin S, Dubner D, Carosella EDImmunomodulation of classical and non-classical HLA molecules by ionizing radiation.
Cell Immunol. 2016; 303:16-23 [PubMed
] Related Publications
Radiotherapy has been employed for the treatment of oncological patients for nearly a century, and together with surgery and chemotherapy, radiation oncology constitutes one of the three pillars of cancer therapy. Ionizing radiation has complex effects on neoplastic cells and on tumor microenvironment: beyond its action as a direct cytotoxic agent, tumor irradiation triggers a series of alterations in tumoral cells, which includes the de novo synthesis of particular proteins and the up/down-regulation of cell surface molecules. Additionally, ionizing radiation may induce the release of "danger signals" which may, in turn lead to cellular and molecular responses by the immune system. This immunomodulatory action of ionizing radiation highlights the importance of the combined use (radiotherapy plus immunotherapy) for cancer healing. Major histocompatibility complex antigens (also called Human Leukocyte Antigens, HLA in humans) are one of those molecules whose expression is modulated after irradiation. This review summarizes the modulatory properties of ionizing radiation on the expression of HLA class I (classical and non-classical) and class II molecules, with special emphasis in non-classical HLA-I molecules.
Mutational processes and signatures that drive early tumorigenesis are centrally important for early cancer prevention. Yet, to date, biomarkers and risk factors for polyps (adenomas) that inordinately and rapidly develop into colon cancer remain poorly defined. Here, we describe surprisingly high mutational profiles through whole-genome sequence (WGS) analysis in 2 of 4 pairs of benign colorectal adenoma tissue samples. Unsupervised hierarchical clustered transcriptomic analysis of a further 7 pairs of adenomas reveals distinct mutational signatures regardless of adenoma size. Transitional single nucleotide substitutions of C:G>T:A predominate in the adenoma mutational spectrum. Strikingly, we observe mutations in the TGF-β pathway and CEA-associated genes in 4 out of 11 adenomas, overlapping with the Wnt pathway. Immunohistochemical labeling reveals a nearly 5-fold increase in CEA levels in 23% of adenoma samples with a concomitant loss of TGF-β signaling. We also define a functional role by which the CEA B3 domain interacts with TGFBR1, potentially inactivating the tumor suppressor function of TGF-β signaling. Our study uncovers diverse mutational processes underlying the transition from early adenoma to cancer. This has broad implications for biomarker-driven targeting of CEA/TGF-β in high-risk adenomas and may lead to early detection of aggressive adenoma to CRC progression.
Metastatic spread of colorectal cancer (CRC) to the peritoneal cavity is common and difficult to treat, with many patients dying from malignant bowel obstruction. Chimeric antigen receptor T cell (CAR-T) immunotherapy has shown great promise, and we previously reported murine and phase I clinical studies on regional intrahepatic CAR-T infusion for CRC liver metastases. We are now studying intraperitoneal (IP) delivery of CAR-Ts for peritoneal carcinomatosis. Regional IP infusion of CAR-T resulted in superior protection against carcinoembryonic antigen (CEA+) peritoneal tumors, when compared with systemically infused CAR-Ts. IP CAR-Ts also provided prolonged protection against IP tumor re-challenges and demonstrated an increase in effector memory phenotype over time. IP CAR-Ts provided protection against tumor growth at distant subcutaneous (SC) sites in association with increases in serum IFNγ levels. Given the challenges posed by immunoinhibitory pathways in solid tumors, we combined IP CAR-T treatment with suppressor cell targeting. High frequencies of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) were found within the IP tumors, with MDSC expressing high levels of immunosuppressive PD-L1. Combinatorial IP CAR-T treatment with depleting antibodies against MDSC and Treg further improved efficacy against peritoneal metastases. Our data support further development of combinatorial IP CAR-T immunotherapy for peritoneal malignancies.
Zhang R, Zhang X, Ma B, et al.Enhanced antitumor effect of combining TRAIL and MnSOD mediated by CEA-controlled oncolytic adenovirus in lung cancer.
Cancer Gene Ther. 2016; 23(6):168-77 [PubMed
] Related Publications
Lung cancer, especially adenocarcinoma, is one of the leading causes of death in the world. Carcinoembryonic antigen (CEA), a superb non-small-cell lung cancer marker candidate, showed a beneficial effect in cancer therapy with oncolytic adenovirus in recent studies. Cancer-targeting dual gene-virotherapy delivers two therapeutic genes, linked by a connexon, in the replication-deficient vector instead of one gene so that they can work in common. In this study, we constructed a tumor-specific oncolytic adenovirus, CD55-TRAIL-IETD-MnSOD. The virus has the fusion protein complementary DNAs for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and for manganese superoxide dismutase (MnSOD) complementary DNA linked through a 4-amino acid caspase-8 cleavage site (IETD), and uses a CEA promoter to control virus E1A express. This is the first work to use a CEA promoter-regulated oncolytic adenovirus carrying two therapeutic genes for cancer research. Its targeting and anticancer capacity was evaluated by in vitro and in vivo experiments. The results indicated that CD55-TRAIL-IETD-MnSOD caused more cell apoptosis than CD55-TRAIL or CD55-MnSOD alone, or their combination in vitro, with low cytotoxicity of normal cells. In the A549 tumor xenograft model in nude mice, data showed that CD55-TRAIL-IETD-MnSOD could effectively suppress tumor growth than single gene groups, with no histological damage in liver, spleen or kidney tissues. Thus, the CEA-regulated dual-gene oncolytic virus CD55-TRAIL-IETD-MnSOD may be a novel potential therapy for lung cancer.
Hu Q, Xiao P, Li J, Yu PA retrospective analysis of serum tumor markers found in non-small cell lung cancer.
J Cancer Res Ther. 2016 Jan-Mar; 12(1):117-20 [PubMed
] Related Publications
AIM: This paper discusses the retrospective analysis conducted to determine the significance of diagnostic biomarkers, carcinoembryonic antigens (CEA), cytokeratin fragment antigens 21-1 (CYFRA 21-1), neuron-specific enolases (NSE), and tumor-specific growth factors (TSGF) upon patients who suffered with non-small cell lung cancer (NSCLC).
MATERIALS AND METHODS: From June 2010 to December 2011, we analyzed the positive rates of biomarkers in 276 NSCLC patients. We assessed the relationship between biomarkers and clinical characteristics of sex, smoking history, and disease stage.
RESULTS: The median and positive rates of each serum biomarker were marked as 1.91-22.77 ng/ml and 35.86% (CEA), 2.0-6.77 ng/ml and 50% (CYFRA 21-1), 13.91-23.78 ng/ml and 62.31% (NSE), and 56-67 μ/ml and 10.14% (TSGF). The level of CEA in peripheral (2.43-23.76 ng/ml) was significantly higher than the level at central position (1.97-3.63 ng/ml) (P < 0.05).
CONCLUSION: Although the positive CEA, CYFRA 21-1, NSE, and TSGF rates were observed at low values during the NSLCLC serum diagnosis, they still played an important role in diagnosing lung cancer. Significant levels of CEA, CYFRA 21-1, NSE, and TSGF were detected in the serum. The amounts found were useful for diagnosing NSCLC patients who depended on the currently limited biomarker development.
BACKGROUND: Circulating hypermethylated RASSF1A could be a novel and potential useful marker for monitoring patients with metastatic breast cancer. Technical obstacles include fragmentation of the circulating DNA, fluctuations in the concentration, low concentrations of circulating tumor DNA, and different locations of methylation in the RASSF1A gene among patients. One common method for detection of hypermethylated genes is sodium bisulfite conversion of non-methylated cytosine to uracil, followed by detection with PCR. However, the method relies on full conversion of all non-methylated cytosines, cause strand breaks, and loss of DNA. Alternatively, methylation-sensitive restriction enzymes have been used to digest genomic DNA, as well as sodium bisulfite-treated DNA. By flanking different regions of the RASSF1A with different PCR primer pairs, we analyzed for methylated genomic regions resistant to cleavage by the methylation-sensitive restriction enzymes HpaII and BstUI. The goal was to find region(s) in RASSF1A with high sensitivity and specificity that could be used for monitoring.
RESULTS: The serum was spiked with non-human control DNA. By tracing the spiking control, the isolation procedure of the rare circulating tumor DNA was initially optimized. By analysis of production of PCR amplicons from HpaII- or BstUI-treated DNA isolated from 24 patients with metastatic breast cancer, we located four regions resulting in sensitivities from 63 to 83 %. When examining samples from 24 control subjects, these four regions gave a specificity of 100 %. Among these four regions, the primer pair with the highest PCR efficacy was selected to monitor the RASSF1A concentration in 31 collected serum samples. The spiked DNA was then used to calculate the tumor RASSF1A concentrations independent of fluctuations in circulating non-tumor DNA. As a proof of principle, there was concordance in the kinetics of the RASSF1A and the serological cancer biomarkers CA 15-3, CEA, and TPA.
CONCLUSIONS: Methylation-sensitive restriction enzymes may be a useful methodological approach for monitoring circulating hypermethylated RASSF1A among patients with metastatic breast cancer.
OBJECTIVES: Recent investigations have suggested that upregulated levels of inflammatory biomarkers, such as chemokines, may be associated with development of many malignancies, including esophageal cancer (EC). Based on our knowledge, this study is the first to assess the serum concentration of chemokine CXCL12 and its specific receptor CXCR4 in the diagnosis of EC patients.
MATERIAL AND METHODS: The present study included 79 subjects: 49 patients with EC and 30 healthy volunteers. The serum concentrations of CXCL12 and CXCR4 and classical tumor markers such as carcinoembryonal antigen (CEA) and squamous cell cancer antigen (SCC-Ag) were measured using immunoenzyme assays, while C-reactive protein (CRP) levels were assessed by immunoturbidimetric method. Moreover, diagnostic criteria of all proteins tested and the survival of EC patients were assessed.
RESULTS: The serum concentrations of CXCL12 were significantly higher, while those of its receptor CXCR4 were significantly lower in EC patients compared to healthy controls. The diagnostic sensitivity, negative predictive value, and accuracy of CXCR4 were the highest among all analyzed proteins and increased for combined analysis with classical tumor markers and CRP levels.
CONCLUSION: Our findings suggest that serum CXCR4 may improve the diagnosis of EC patients, especially in combination with classical tumor markers.
BACKGROUND: Cancer is a disease driven by the accumulation of genomic alterations, including the integration of exogenous DNA into the human somatic genome. We previously identified in silico evidence of DNA fragments from a Pseudomonas-like bacteria integrating into the 5'-UTR of four proto-oncogenes in stomach cancer sequencing data. The functional and biological consequences of these bacterial DNA integrations remain unknown.
RESULTS: Modeling of these integrations suggests that the previously identified sequences cover most of the sequence flanking the junction between the bacterial and human DNA. Further examination of these reads reveals that these integrations are rich in guanine nucleotides and the integrated bacterial DNA may have complex transcript secondary structures.
CONCLUSIONS: The models presented here lay the foundation for future experiments to test if bacterial DNA integrations alter the transcription of the human genes.
BACKGROUND: Accurately distinguishing serosal invasion in patients with gastric cancer (GC) prior to surgery can be difficult. Molecular analysis of peritoneal fluid (MAPF) for free cancer cells with higher sensitivity than other methods; however, its prognostic value for GC remains controversial, precluding its application in clinical practice.
METHODS: PubMed, EMBASE and other databases were systematically searched. Thirty-one studies were eligible for the meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled for overall survival (OS), disease-free survival (DFS) and peritoneal recurrence-free survival (PRF).
RESULTS: The current meta-analysis focused on patients with GC and negative cytological diagnoses. The results showed that positive MAPF status (MAPF+) led to poorer prognoses for OS (HR 2.59, 95% CI 1.99-3.37), DFS (HR 4.92, 95% CI 3.28-7.37) and PRF (HR 2.81, 95% CI 2.12-3.72) compared with negative MAPF status (MAPF-). Moreover, among the patients with GC who received curative treatment, the MAPF+ patients had poorer prognoses for OS (HR 3.27, 95% CI 2.49-4.29), DFS (HR 3.90, 95% CI 2.74-5.57) and PRF (HR 5.45, 95% CI 3.70-8.03). A meta-analysis of multivariate-adjusted HRs demonstrated that MAPF+ status was an independent prognostic factor for patients with GC who underwent curative treatment (OS: HR 2.19, 95% CI 1.47-3.28; PRF: HR 3.44, 95% CI 2.01-5.87). Using the identical target genes (CEA, CEA/CK20) as molecular markers, the patients with GC who were MAPF+ had significantly worse prognoses for OS (CEA: HR 3.03, 95% CI 2.29-4.01; CEA/CK20: HR 4.24, 95% CI 2.42-7.40), DFS (CEA: HR 3.99, 95% CI 2.24-7.12; CEA/CK20: HR 4.31, 95% CI 1.49-2.48) and PRF (CEA: HR 4.45, 95% CI 2.72-7.31; CEA/CK20: HR 6.46, 95% CI 3.62-11.55) than the patients who were MAPF-.
CONCLUSION/SIGNIFICANCE: The above results demonstrate that MAPF could be a prognostic indicator for patients with GC who have a negative cytological diagnosis and/or are receiving curative treatment. MAPF could provide clinicians with additional prognostic information that could aid in developing individualized treatment plans prior to surgery. The widely used target genes CEA, CEA/CK20 were confirmed to be valuable MAPF markers for predicting the prognosis of GC.
BACKGROUND: A large number of epigenetic alterations has been found to be implicated in the etiology of gastric cancer. We have studied the DNA methylation status of 27 500 gene promoter regions in 24 gastric adenocarcinomas from a Norwegian cohort, and aimed at identifying the hypermethylated regions. We have compared our findings to the gene expression in the same tissue, and linked our results to prognosis and survival.
METHODS: Biopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 24 patients following surgical resection of the tumor. Genome-wide DNA methylation profiling of the tumor and matched non-cancerous mucosa was performed. The results were compared to whole transcriptome cDNA microarray analysis of the same material.
RESULTS: Most of the gene promoter regions in both types of tissue showed a low degree of methylation, however there was a small, but significant hypermethylation of the tumors. Hierarchical clustering showed separate grouping of the tumor and normal tissue. Hypermethylation of the promoter region of the GFRA3 gene showed a strong correlation to post-operative survival and several of the clinicopathological parameters, however no difference was found between the two main histological types of gastric cancer. There was only a modest correlation between the DNA methylation status and gene expression.
CONCLUSIONS: The different DNA methylation clusters of the tumors and normal tissue indicate that aberrant DNA methylation is a distinct feature of gastric cancer, although there is little difference in the overall, and low, methylation levels between the two tissue types. The GFRA3 promoter region showed marked hypermethylation in almost all tumors, and its correlation with survival and other clinicopathological parameters may have important prognostic significance.
BACKGROUND: EGFR mutation-induced cell proliferation causes changes in tumor biology and tumor metabolism, which may reflect tumor marker concentration and 18F-FDG uptake on PET/CT. Direct aspirates of primary lung tumors contain different concentrations of tumor markers than serum tumor markers, and may correlate better with EGFR mutation than serum tumor markers. The purpose of this study is to investigate an association between cytologic tumor markers and FDG uptake with EGFR mutation status in non-small cell lung cancer (NSCLC).
METHODS: We prospectively collected tumor aspirates of 61 patients who underwent EGFR mutation analysis. Serum and cytologic CYFRA 21-1, CEA, and SCCA levels were measured and correlated with EGFR gene mutations. FDG PET/CT was performed on 58 patients for NSCLC staging, and SUV was correlated with EGFR mutation status.
RESULTS: Thirty (50%) patients had EGFR mutation and 57 patients had adenocarcinoma subtype. Univariate analysis showed that female gender, never smoker, high levels of cytologic CYFRA 21-1 (c-CYFRA) and lower maximum standard uptake value (SUVmax) were correlated with EGFR mutations. ROC generated cut-off values of 20.8 ng/ml for c-CYFRA and SUVmax of 9.6 showed highest sensitivity for EGFR mutation detection. Multivariate analysis revealed that female gender [hazard ratio (HR): 18.15, p = 0.025], higher levels of c-CYFRA (HR: 7.58, and lower SUVmax (HR: 0.08, p = 0.005) were predictive of harboring EGFR mutation.
CONCLUSIONS: The cytologic tumor marker c-CYFRA was positively associated with EGFR mutations in NSCLC. EGFR mutation-positive NSCLCs have relatively lower glycolysis compared with NSCLCs without EGFR mutation.
Shen ZY, Fang Y, Zhen L, et al.Analysis of the predictive efficiency of S100P on adverse prognosis and the pathogenesis of S100P-mediated invasion and metastasis of colon adenocarcinoma.
Cancer Genet. 2016; 209(4):143-53 [PubMed
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Elevated expression of S100P has been detected in several tumor types. To analyze the potential use of S100P for the prediction of colorectal cancer (CRC) metastasis and prognosis, S100P expression was detected in 125 patients with colon adenocarcinoma by immunohistochemistry, followed by correlation and survival analysis. High S100P expression was correlated with metastasis, as demonstrated by clinically relevant data, and predicted poor survival more effectively than preoperative serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels in colon adenocarcinoma. Stable S100P knockdown CRC cell lines were established to elucidate the relationship between S100P expression and tumor progression in vitro and in vivo. S100P knockdown resulted in reductions in the invasiveness and metastasis of CRC cells. Xenograft growth in nude mice also demonstrated that down-regulated S100P dramatically inhibited peritoneal metastasis of CRC cells. S100P promoted the invasion and metastasis of CRC by activating RAGE/ERK signaling and promoting the epithelial-mesenchymal transition (EMT). RAGE was found to be crucial for S100P-mediated EMT in colon cancer. Knockdown of RAGE in S100P-overexpressing colon cancer cells dramatically suppressed EMT process. Our results indicate that overexpression of S100P is related with an invasive and metastatic phenotype of CRC which is EMT-involved and RAGE dependent.
Abdelgawad IA, Radwan NH, Hassanein HRKIAA0101 mRNA expression in the peripheral blood of hepatocellular carcinoma patients: Association with some clinicopathological features.
Clin Biochem. 2016; 49(10-11):787-91 [PubMed
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OBJECTIVES: The development of hepatocellular carcinoma (HCC) is multi-factorial, multi-step and involving many genes. Recent studies have revealed the involvement of KIAA0101 in HCC development and progression. KIAA0101 is involved in the regulation of DNA repair, cell cycle progression, and cell proliferation. This study aims to elucidate the clinicopathological significance of KIAA0101 mRNA expression in the whole blood of HCC patients.
DESIGN AND METHODS: This study was conducted on 77 patients with proven HCC who presented to the outpatient clinic at the National Cancer Institute - Cairo University over a period of 8 consecutive months. Thirty patients with cirrhosis and forty apparently healthy volunteers were included as control groups. Detection of KIAA0101 mRNA was done on whole blood collected on EDTA for all patients and control subjects using real-time PCR.
RESULTS: KIAA0101 mRNA was over-expressed in the HCC group compared to the control groups. Overexpression of KIAA0101 mRNA was significantly associated with distant metastasis, advanced stage, high serum alkaline phosphatase and low serum albumin levels. Both sensitivity and specificity of KIAA0101 mRNA were higher than those of AFP and CEA.
CONCLUSION: Being associated with some of the prognostic factors of HCC which reflect tumor progression; as advanced stage, distant metastasis, hypoalbuminemia and elevated serum alkaline phosphatase, together with its relatively high diagnostic performance; KIAA0101 mRNA might be nominated to play a probable role in the diagnosis and prognosis prediction of HCC. Further studies on a wider scale are recommended to confirm these results.
Huberfeld G, Vecht CJSeizures and gliomas--towards a single therapeutic approach.
Nat Rev Neurol. 2016; 12(4):204-16 [PubMed
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Epilepsy often develops in patients with glioma, and the two conditions share common pathogenic mechanisms. Altered expression of glutamate transporters, including the cystine-glutamate transporter (xCT) system, increases concentrations of extracellular glutamate, which contribute to epileptic discharge, tumour proliferation and peripheral excitotoxicity. Furthermore, mutation of the isocitrate dehydrogenase 1 gene in low-grade gliomas causes production of D-2-hydroxyglutarate, a steric analogue of glutamate. Dysregulation of intracellular chloride promotes glioma cell mitosis and migration, and γ-aminobutyric acid (GABA) signalling suppresses proliferation. In neurons, however, chloride accumulation leads to aberrant depolarization on GABA receptor activation, thereby promoting epileptic activity. The molecular target of rapamycin (mTOR) pathway and epigenetic abnormalities are also involved in the development of tumours and seizures. Antitumour therapy can contribute to seizure control, and antiepileptic drugs might have beneficial effects on tumours. Symptomatic treatment with antiepileptic drugs carries risks of adverse effects and drug interactions. In this Review, we discuss the potential for single therapeutic agents, such as the xCT blocker sulfasalazine, the chloride regulator bumetanide, and the histone deacetylase inhibitor valproic acid, to manage both gliomas and associated epilepsy. We also provide guidance on the evidence-based use of antiepileptic drugs in brain tumours. The development of solo therapies to treat both aspects of gliomas promises to yield more-effective treatment with fewer risks of toxicity and drug interactions.
Xue WJ, Feng Y, Wang F, et al.The value of serum RASSF10 hypermethylation as a diagnostic and prognostic tool for gastric cancer.
Tumour Biol. 2016; 37(8):11249-57 [PubMed
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The tumor-suppressing role of Ras-association domain family 10 (RASSF10) has been described in several types of cancers. Here, we evaluated the potential use of the hypermethylation status of the RASSF10 promoter in serum as a new diagnostic and prognostic tool in gastric cancer (GC). We used bisulfite sequencing polymerase chain reaction to examine RASSF10 methylation levels in serum and/or tumor samples from 82 GC, 45 chronic atrophic gastritis (CAG), and 50 healthy control patients. In the serum of GC patients, the median level of RASSF10 methylation was higher at 47.84 % than those in the serum of CAG and healthy control patients at 11.89 and 11.35 %, respectively. The median level of RASSF10 methylation in GC tumor tissue was similarly high at 62.70 %. Furthermore, RASSF10 methylation levels were highly correlated between paired serum and tumor samples from GC patients. We performed receiver-operating characteristic curve analyses to verify that serum RASSF10 methylation levels could effectively distinguish GC from control patients. Moreover, multivariate analyses showed that high serum RASSF10 methylation levels in GC patients were associated with large tumors, lymph node metastasis, and high carcinoembryonic antigen (CEA) levels. Survival analyses showed that GC patients with high serum RASSF10 methylation levels had shorter overall and disease-free survival after D2 lymphadenectomy than those with low levels. High serum RASSF10 methylation levels were also an independent predictor of tumor recurrence and GC patient survival. In conclusion, serum RASSF10 promoter methylation levels can serve as a valuable indicator for the diagnosis and prognosis of GC in the clinic.
Pregnancy-specific glycoproteins (PSGs) are immunoglobulin superfamily members related to the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family and are encoded by 10 genes in the human. They are secreted at high levels by placental syncytiotrophoblast into maternal blood during pregnancy, and are implicated in immunoregulation, thromboregulation, and angiogenesis. To determine whether PSGs are expressed in tumors, we characterized 16 novel monoclonal antibodies to human PSG1 and used 2 that do not cross-react with CEACAMs to study PSG expression in tumors and in the gastrointestinal (GI) tract using tissue arrays and immunohistochemistry. Staining was frequently observed in primary squamous cell carcinomas and colonic adenocarcinomas and was correlated with the degree of tumor differentiation, being largely absent from metastatic samples. Staining was also observed in normal oesophageal and colonic epithelium. PSG expression in the human and mouse GI tract was confirmed using quantitative RT-PCR. However, mRNA expression was several orders of magnitude lower in the GI tract compared to placenta. Our results identify a non-placental site of PSG expression in the gut and associated tumors, with implications for determining whether PSGs have a role in tumor progression, and utility as tumor biomarkers.
Liang L, Zheng W, Liu J, Liang SXAssessment of the Utility of PAX8 Immunohistochemical Stain in Diagnosing Endocervical Glandular Lesions.
Arch Pathol Lab Med. 2016; 140(2):148-52 [PubMed
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CONTEXT: PAX8, a member of the paired-box family of genes, is expressed in many tumors of Müllerian origin. However, it is unclear whether PAX8 is a useful marker in diagnosing endocervical glandular lesions because of limited data.
OBJECTIVE: To study the expression of PAX8 in endocervical glandular lesions.
DESIGN: We first studied a cohort of 29 cervical cone biopsies, followed by a second cohort of 17 cases of endocervical adenocarcinoma and 20 cases of uterine endometrioid adenocarcinoma.
RESULTS: In the first cohort, we found that PAX8 was expressed in 23 of 23 (100%) benign endocervical glandular epithelium, 15 of 16 (94%) adenocarcinoma in situ, and 21 of 26 (81%) invasive endocervical adenocarcinoma specimens. In the second cohort, endocervical adenocarcinomas were positive for PAX8 in 14 of 17 (82%), strongly and diffusely positive for p16 in 14 of 17 (82%), positive for carcinoembryonic antigen in 12 of 17 (71%), positive for vimentin in 2 of 17 (12%), and positive for estrogen receptor in 7 of 17 cases (41%). Uterine endometrioid cancer was positive for PAX8 in 20 of 20 (100%), weakly and/or patchy positive for p16 in 17 of 20 (85%), positive for carcinoembryonic antigen in 2 of 20 (10%), positive for vimentin in 19 of 20 (95%), and positive for estrogen receptor in 20 of 20 cases (100%).
CONCLUSIONS: PAX8 is expressed in the majority of benign, premalignant, and malignant endocervical glandular lesions. The usefulness of PAX8 in differentiating endocervical from endometrial lesions is limited.
Deguelin, the main components from Mundulea sericea, was reported to suppress the growth of various cancer cells. However, the effect of Deguelin on tumor cell invasion and metastasis and its mechanism still unclear so far. In this study, we investigated the effects of Deguelin on the cell invasion in human lung cancer A549 and H460 cells. Our results demonstrate that Deguelin can significantly inhibited cell proliferation, cell migration and cell invasion. Moreover, Deguelin could also affected reorganization of the actin cytoskeleton and decreased filopodia and lamellipodia formation. Furthermore, deguelin-treated tumors showed decreased the tumor metastasis related genes such as CD44, MMP2 and MMP9 at protein and mRNA levels and the content of CEA, SCC, NSE, CYFAR21-1. In addition, Deguelin down-regulated protein expression of Rac1 and Rock1, which are impotent in actin cytoskeleton rearrangements and cell motility. Together, our results suggest that Deguelin inhibit tumor growth and metastasis of lung cancer cells and might be a candidate compound for curing lung cancer.
Gataullina S, Lemaire E, Wendling F, et al.Epilepsy in young Tsc1(+/-) mice exhibits age-dependent expression that mimics that of human tuberous sclerosis complex.
Epilepsia. 2016; 57(4):648-59 [PubMed
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OBJECTIVE: To describe the epileptic phenotype of Tsc1(+/-) mice pups in comparison with age-related seizures in human tuberous sclerosis complex (TSC).
METHODS: Tsc1(+/-) and control mice underwent intracranial electroencephalography (EEG) recording at postnatal ages (P)8 to P33, with linear silicon probe implanted in the somatosensory cortex of one or both hemispheres for 8-24 h. Ictal events were classified visually by independent analyzers; distinct EEG patterns were related to age and analyzed to quantify field potential characteristics and signal dynamics between hemispheres. We collected retrospectively 20 infants with prenatally diagnosed TSC and EEG before seizure onset, and analyzed the electroclinical course of epilepsy, taking into account a first-line treatment by vigabatrin.
RESULTS: Spontaneous seizures were disclosed in 55% of Tsc1(+/-) mice at P9-18. Three ictal patterns were identified: from P9 to P12 "spike clusters" consisted of recurring large spikes without clinical correlate; "spasm-like" discharges dominated from P13 to P16 consisting of high amplitude large field potential superimposed with or followed by fast activity repeated every 2-10 s for at least 20 s, accompanied by rhythmic limb contractions; from P14 to P18 a "tonic-clonic like" pattern comprised rhythmic spikes of increasing amplitude with tonic-clonic movements. Early onset "spike clusters" were mainly unilateral, whereas "spasm-like" and "tonic-clonic like" patterns were bilateral. Interhemispheric propagation was significantly faster for "tonic-clonic like" than for "spasm-like" events. In infants diagnosed prenatally with TSC, clusters of sharp waves or spikes preceded the first seizure, and vigabatrin prevented the development of seizures. Patients treated after seizure onset developed spasms or focal seizures that were pharmacoresistant in 66.7% of cases.
SIGNIFICANCE: Tsc1(+/-) mice pups exhibit an age-dependent seizure pattern sequence mimicking early human TSC epilepsy features. Spike clusters before seizure onset in TSC should be considered as a first stage of epilepsy reinforcing the concept of preventive antiepileptic therapy.
BACKGROUND: Sub-lethal doses of ionizing radiation (IR) can alter the phenotype of target tissue by modulating genes that influence effector T cell activity. Previous studies indicate that cancer cells respond to radiation by up-regulating surface expression of death receptors, cell adhesion molecules and tumor-associated antigens (TAA). However, there is limited information available regarding how T cells themselves are altered following these interactions with irradiated tumor cells.
METHODS: Here, several human colorectal tumor cell lines were exposed to radiation (0-10 Gy) in vitro and changes in the expression of molecules costimulatory to effector T cells (4-1BBL, OX-40L, CD70, ICOSL) were examined by flow cytometry. T cell effector function was assessed to determine if changes in these proteins were directly related to the changes in T cell function.
RESULTS: We found OX-40L and 4-1BBL to be the most consistently upregulated proteins on the surface of colorectal tumor cells post-IR while ICOSL and CD70 remained largely unaltered. Expression of these gene products correlated with enhanced killing of irradiated human colorectal tumor cells by TAA-specific T-cells. Importantly, blocking of both OX-40L and 4-1BBL reversed radiation-enhanced T-cell killing of human tumor targets as well as T-cell survival and activation.
CONCLUSIONS: Overall, results of this study suggest that, beyond simply rendering tumor cells more sensitive to immune attack, radiation can be used to specifically modulate expression of genes that directly stimulate effector T cell activity.
Gameiro SR, Malamas AS, Tsang KY, et al.Inhibitors of histone deacetylase 1 reverse the immune evasion phenotype to enhance T-cell mediated lysis of prostate and breast carcinoma cells.
Oncotarget. 2016; 7(7):7390-402 [PubMed
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The clinical promise of cancer immunotherapy relies on the premise that the immune system can recognize and eliminate tumor cells identified as non-self. However, tumors can evade host immune surveillance through multiple mechanisms, including epigenetic silencing of genes involved in antigen processing and immune recognition. Hence, there is an unmet clinical need to develop effective therapeutic strategies that can restore tumor immune recognition when combined with immunotherapy, such as immune checkpoint blockade and therapeutic cancer vaccines. We sought to examine the potential of clinically relevant exposure of prostate and breast human carcinoma cells to histone deacetylase (HDAC) inhibitors to reverse tumor immune escape to T-cell mediated lysis. Here we demonstrate that prostate (LNCAP) and breast (MDA-MB-231) carcinoma cells are more sensitive to T-cell mediated lysis in vitro after clinically relevant exposure to epigenetic therapy with either the pan-HDAC inhibitor vorinostat or the class I HDAC inhibitor entinostat. This pattern of immunogenic modulation was observed against a broad range of tumor-associated antigens, such as CEA, MUC1, PSA, and brachyury, and associated with augmented expression of multiple proteins involved in antigen processing and tumor immune recognition. Genetic and pharmacological inhibition studies identified HDAC1 as a key determinant in the reversal of carcinoma immune escape. Further, our findings suggest that the observed reversal of tumor immune evasion is driven by a response to cellular stress through activation of the unfolded protein response. This offers the rationale for combining HDAC inhibitors with immunotherapy, including therapeutic cancer vaccines.