Gene Summary

Gene:CRP; C-reactive protein
Aliases: PTX1
Summary:The protein encoded by this gene belongs to the pentaxin family. It is involved in several host defense related functions based on its ability to recognize foreign pathogens and damaged cells of the host and to initiate their elimination by interacting with humoral and cellular effector systems in the blood. Consequently, the level of this protein in plasma increases greatly during acute phase response to tissue injury, infection, or other inflammatory stimuli. [provided by RefSeq, Sep 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:C-reactive protein
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: CRP (cancer-related)

Zhou DJ, Bai FJ
The relationship between c-reactive protein gene +1444C/T, 3407T/C polymorphisms and colorectal cancer susceptibility.
Gene. 2019; 710:145-147 [PubMed] Related Publications
AIM: The present study was conducted to analyze the relationship between c-reactive protein (CRP) gene +1444C/T, 3407T/C (rs2808630) polymorphisms and colorectal cancer susceptibility.
METHODS: A total of 142 colorectal cancer patients and 127 healthy controls were recruited into this case-control study. The genotypes of CRP gene +1444C/T, rs2808630 polymorphisms were tested by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the genotypes distributions of polymorphisms in controls was assessed whether conformed to Hardy-Weinberg equilibrium (HWE). The calculation of odds ratio (OR) with its 95% confidence interval (95% CI) is used for evaluating the association strength of gene polymorphism and disease.
RESULTS: Through the testing of χ
CONCLUSION: CRP rs2808630 polymorphism was related to the decreased risk of colorectal cancer, but not +1444C/T polymorphism.

Petrera M, Paleari L, Clavarezza M, et al.
The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 × 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients.
BMC Cancer. 2018; 18(1):1210 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin can reduce colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin has also been associated with decreased colon adenoma recurrence in clinical trials and lower CRC incidence and mortality in epidemiological studies in diabetics. While both drugs have been tested as single agents, their combination has not been tested in cancer prevention trials.
METHODS/DESIGN: This is a randomized, placebo-controlled, double-blind, 2 × 2 biomarker trial of aspirin and metformin to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery, 160 patients with stage I-III CRC are randomly assigned in a four-arm trial to either aspirin (100 mg day), metformin (850 mg bis in die), their combination, or placebo for one year. The primary endpoint biomarker is the change of IHC expression of nuclear factor kappa-B (NFκB) in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the measurement of circulating IL-6, CRP and VEGF; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of genetic markers with treatment response as assessed by next generation sequencing of primary tumors; 4) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; and 5) the evaluation of adenoma occurrence at 1 year.
DISCUSSION: A favorable biomarker modulation by aspirin and metformin may provide important clues for a subsequent phase III adjuvant trial aimed at preventing second primary cancer, delaying recurrence and improving prognosis in patients with CRC.
TRIAL REGISTRATION: EudraCT Number: 2015-004824-77; Identifier: NCT03047837 . Registered on February 1, 2017.

Gráf L, Barabás L, Madaras B, et al.
High serum Hsp70 level predicts poor survival in colorectal cancer: Results obtained in an independent validation cohort.
Cancer Biomark. 2018; 23(4):539-547 [PubMed] Related Publications
BACKGROUND: Hsp70 plays important role in the development and progression of cancer. Previously we described the association between serum Hsp70 levels and mortality of colorectal cancer.
OBJECTIVE: In this new prospective study we aimed to confirm and extend our previous findings in a larger cohort of patients, based on a longer follow-up period.
METHODS: Two hundred and thirty-two patients diagnosed with colorectal cancer were enrolled in the study. Baseline serum Hsp70 level and classical biomarker levels were measured. Patients were treated according to stage of the tumor and follow-up lasted for a median 46.4 months.
RESULTS: We found that serum Hsp70 concentrations increase significantly with stage of the disease (1.79; 2.23 and 3.21 ng/ml in stage I+II, III and IV respectively, p= 0.012 and 0.002, Mann-Whitney test) and with other known biomarkers of the disease. We managed to confirm our previous findings that high baseline serum Hsp70 level (> 1.64 ng/ml) predicted poor 5-year survival (risk of death HR: 1.94 CI: 1.294-2.909; univariate; HR: 2.418 CI: 1.373-4.258; multivariate Cox regression analysis) in the whole patient population and also in subgroups of stage IV and stage III disease. The strongest association was observed in women under age of 70 (HR: 8.12, CI: 2.02-35.84; p= 0.004; multivariate Cox regression). The power of this colorectal cancer prognostic model could be amplified by combining Hsp70 levels and inflammatory markers. Patients with high Hsp70, CRP and high baseline WBC or platelet count had 5-times higher risk of death (HR: 5.07 CI: 2.74-9.39, p< 0.0001; and HR: 4.98 CI: 3.08-8.06, p< 0.0001 respectively).
CONCLUSIONS: These results confirm and validate our previous findings that serum Hsp70 is a useful biomarker of colorectal cancer.

She S, Jiang L, Zhang Z, et al.
Identification of the C-Reactive Protein Interaction Network Using a Bioinformatics Approach Provides Insights into the Molecular Pathogenesis of Hepatocellular Carcinoma.
Cell Physiol Biochem. 2018; 48(2):741-752 [PubMed] Related Publications
BACKGROUND/AIMS: C reactive protein (CRP) levels are elevated in many diseases, including malignant tumors and cardiovascular disorders. In this study, the protein interaction network for CRP was evaluated to determine the importance of CRP and its interacting proteins in the molecular pathogenesis of hepatocellular carcinoma (HCC).
METHODS: Isobaric tags for relative and absolute quantitation (iTRAQ) and mass spectrometry were used to identify CRP interacting proteins in SMMC7721 cells. Moreover, Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to evaluate enriched genes and pathways for differentially expressed genes using DAVID and WebGestalt. Co-immunoprecipitation and western blot analyses were employed to assess interactions between CRP and KRT8, ANXA2, ENO2, and HSP90B1.
RESULTS: In total, 52 proteins that interact with CRP were identified. A GO analysis suggested that most of the interacting proteins were involved in CRP complexes and regulated metabolic processes. A KEGG pathway analysis suggested that most CRP-interacting proteins contribute to the TRAIL signaling pathway, Class I PI3K/Akt signaling pathway, plasma membrane estrogen receptor signaling, Nectin adhesion pathway, and S1P1 pathway. Immunoprecipitation and western blot analyses revealed interactions between CRP and KRT8, ANXA2, ENO2, and HSP90B1.
CONCLUSIONS: iTRAQ based proteomic profiling revealed the network of CRP interacting proteins. This network may activate the PI3K/Akt signaling pathway, thereby contributing to the pathogenesis of HCC.

Reynders K, Wauters E, Moisse M, et al.
RNA-sequencing in non-small cell lung cancer shows gene downregulation of therapeutic targets in tumor tissue compared to non-malignant lung tissue.
Radiat Oncol. 2018; 13(1):131 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gene expression of specific therapeutic targets in non-malignant lung tissue might play an important role in optimizing targeted therapies. This study aims to identify different expression patterns of fifteen genes important for targeted therapy in non-small cell lung cancer (NSCLC).
METHODS: We prospectively collected tissue of NSCLC and non-malignant lung tissue from 25 primary resected patients. RNA-sequencing and 450 K methylation array profiling was applied to both NSCLC and non-malignant lung tissue and data were analyzed for 14 target genes. We analyzed differential expression and methylation as well as expression according to patient characteristics like smoking status, histology, age, chronic obstructive pulmonary disease, C-reactive protein (CRP) and gender. TCGA data served as a validation set.
RESULTS: Nineteen men and 6 women were included. Important targets like PD-L2 (p = 0.035), VEGFR2 (p < 0.001) and VEGFR3 (p < 0.001) were downregulated (respective fold changes = 1.8, 3.1, 2.7, 3.5) in tumor compared to non-malignant lung tissue. The TCGA set confirmed these findings almost universally. PD-L1 (p < 0.001) became also significantly downregulated in the TCGA set. In NSCLC, MUC1 (p = 0.003) showed a higher expression in patients with a CRP < 5 mg/L compared to > 5 mg/L. In the TCGA data but not in our primary data, PD-L1 & 2 were both borderline more expressed in tumors of active smokers vs. tumors of ex-smokers (p = 0.044 and 0.052).
CONCLUSIONS: Our results suggest a lower PD-L1 & 2 and VEGFR expression in NSCLC vs. non-malignant lung tissue. Specific patient characteristics did not seem to change the overall expression differences as they were in line with the overall results. This information may contribute to the optimization of targeted treatments.

Berg J, Halvorsen AR, Bengtson MB, et al.
Levels and prognostic impact of circulating markers of inflammation, endothelial activation and extracellular matrix remodelling in patients with lung cancer and chronic obstructive pulmonary disease.
BMC Cancer. 2018; 18(1):739 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The development of both chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is influenced by smoking related chronic pulmonary inflammation caused by an excessive innate immune response to smoke exposure. In addition, the smoking induced formation of covalent bonds between the carcinogens and DNA and the accumulation of permanent somatic mutations in critical genes are important in the carcinogenic processes, and can also induce inflammatory responses. How chronic inflammation is mirrored by serum markers in COPD and LC and if these markers reflect prognosis in patients with LC is, however, largely unknown.
METHODS: Serum levels of 18 markers reflecting inflammation, endothelial activation and extracellular matrix remodelling were analysed in 207 patients with non-small lung carcinoma (NSCLC) before surgery and 42 COPD patients. 56% of the LC patients also suffered from COPD. The serum samples were analysed by enzyme immunoassays.
RESULTS: Serum levels of OPG, PTX3, AXL, ALCAM, sCD163, CD147, CatS and DLL1 were significantly higher in patients with COPD as compared to patients with LC. High sTNFR1 levels were associated with improved progression free survival (PFS) and overall survival (OS) in LC patients with (PFS hazard ratio (HR) 0.49, OS HR 0.33) and without COPD (OS HR 0.30). High levels of OPG were associated with improved PFS (HR 0.17) and OS (HR 0.14) for LC with COPD. CRP was significantly associated with overall survival regardless of COPD status.
CONCLUSION: Several markers reflecting inflammation, endothelial activation and extracellular matrix remodelling are elevated in serum from patients with COPD compared to LC patients. Presence of COPD might influence the levels of circulating biomarkers. Some of these markers are also associated with prognosis.

Amiri Dash Atan N, Koushki M, Rezaei Tavirani M, Ahmadi NA
Protein-Protein Interaction Network Analysis of Salivary Proteomic Data in Oral Cancer Cases
Asian Pac J Cancer Prev. 2018; 19(6):1639-1645 [PubMed] Free Access to Full Article Related Publications
Background: Oral cancer is a frequently encountered neoplasm of the head and neck region, being the eight most common type of human malignancy worldwide. Despite improvement in its control, morbidity and mortality rates have improved little in the past decades. Therefore, prevention and/or early detection are a high priority. Proteomics with network analysis have emerged as a powerful tool to identify important proteins associated with cancer development and progression that can be potential targets for early diagnosis. In the present study, network- based protein- protein interactions (PPI) for oral cancer were identified and then analyzed for use as key proteins/potential biomarkers. Material and Methods: Gene expression data in articles which focused on saliva proteomics of oral cancer were collected and 74 candidate genes or proteins were extracted. Related protein networks of differentially expressed proteins were explored and visualized using cytoscape software. Further PPI analysis was performed by Molecular Complex Detection (MCODE) and BiNGO methods. Results: Network analysis of genes/proteins related to oral cancer identified kininogen-1, angiotensinogen, annexin A1, IL-8, IgG heavy variable and constant chains, CRP, collagen alpha-1 and fibronectin as 9 hub-bottleneck proteins. In addition, based on clustering with the MCODE tool, vitronectin, collagen alpha-2, IL-8 and integrin alpha-v were established as 5 distinct seed proteins. Conclusion: A hub-bottleneck protein panel may offer a potential /candidate biomarker pattern for diagnosis and treatment of oral cancer disease. Further investigation and validation of these proteins are warranted.

Agizamhan S, Qu F, Liu N, et al.
Preoperative neutrophil-to-lymphocyte ratio predicts the surgical outcome of Xp11.2 translocation/TFE3 renal cell carcinoma patients.
BMC Urol. 2018; 18(1):60 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The preoperative neutrophil-to-lymphocyte ratio (NLR), C-reactive protein/albumin ratio (CRP/Alb ratio) and platelet-to-lymphocyte ratio (PLR) have been demonstrated to predict the clinical outcome of various human cancer, including renal cell carcinoma(RCC). The aim of our study was to explore the prognostic values of these ratios in patients with Xp11.2 translocation/TFE3 gene fusions renal cell carcinoma (Xp11.2 tRCC).
METHODS: A retrospective multicentre study was performed in 82 Xp11.2 tRCC patients who underwent radical or partial nephrectomy. The optimal cutoff values of the NLR, CRP/Alb ratio and PLR were determined by the receiver operating characteristic (ROC) analysis. The impact of the NLR, CRP/Alb ratio and PLR, as well as other clinicopathological characteristics, on disease-free survival (DFS) and overall survival (OS) were evaluated using the univariate and multivariate Cox regression analyses.
RESULTS: The optimal cutoff values of the NLR, CRP/Alb ratio and PLR were set at 2.45, 140 and 0.08, respectively, according to the ROC analysis. Univariate analyses showed that the NLR, CRP/Alb ratio and PLR all were associated with DFS of Xp11.2 tRCC patients (P < 0.001, P = 0.005 and P = 0.001, respectively) and OS of Xp11.2 tRCC patients (P = 0.016, P = 0.003 and P = 0.014, respectively). Multivariate analysis indicated that the NLR was independently associated with DFS of Xp11.2 tRCC patients (hazard ratio [HR]: 4.25; 95% confidence interval [95% CI]: 1.19-15.18; P = 0.026) along with age (P = 0.004), the pT status (P < 0.001) and the pN status (P < 0.019), and the NLR (HR: 26.26; 95% CI: 1.44-480.3; P = 0.028) also was independently associated with OS in patients with Xp11.2 tRCC, along with age (P = 0.016) and a tumour thrombus (P = 0.007).
CONCLUSION: Overall, relatively high NLRs, CRP/Alb ratios and PLRs were associated with a poor prognosis of Xp11.2 tRCC patients; among of them, only the NLR independently predicted the progression of Xp11.2 tRCC, and the NLR may help to identify patients with high metastasis or relapse risk.

Jamilian M, Samimi M, Mirhosseini N, et al.
The influences of vitamin D and omega-3 co-supplementation on clinical, metabolic and genetic parameters in women with polycystic ovary syndrome.
J Affect Disord. 2018; 238:32-38 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to evaluate the effect of the co-administration of vitamin D and omega-3 fatty acid on clinical, metabolic and genetic parameters in women with polycystic ovary syndrome (PCOS).
METHODS: This randomized, double-blinded, placebo-controlled clinical trial was conducted on 60 subjects, aged 18-40 years old with PCOS. Subjects were randomly allocated to take either 50,000 IU vitamin D every 2 weeks plus 2000 mg/day omega-3 fatty acid from fish oil (n = 30) or placebo (n = 30) for 12 weeks. Gene expression analysis of inflammatory cytokines was conducted on peripheral blood mononuclear cells (PBMCs) of PCOS women using RT-PCR method.
RESULTS: Vitamin D and omega -3 fatty acid co-supplementation significantly decreased serum total testosterone levels (-0.2 ± 0.5 vs. + 0.1 ± 0.4 ng/mL, P = 0.02) compared with the placebo. In addition, vitamin D and omega-3 fatty acid co-supplementation resulted in a significant improvement in beck depression inventory (-1.4 ± 1.6 vs. -0.5 ± 0.6, P = 0.01), general health questionnaire scores (-4.5 ± 4.3 vs. -1.9 ± 2.3, P = 0.005) and depression anxiety and stress scale scores (-5.0 ± 5.1 vs. -2.3 ± 3.5, P = 0.01) compared with the placebo. Additionally, vitamin D and omega-3 fatty acid co-administration significantly decreased serum high-sensitivity C-reactive protein (hs-CRP) (-1.2 ± 1.9 vs. + 0.1 ± 0.7 mg/L, P = 0.001) and malondialdehyde (MDA) levels (-0.4 ± 0.4 vs. + 0.2 ± 0.6 µmol/L, P < 0.001), and significantly increased plasma total antioxidant capacity (TAC) levels (+ 114.6 ± 122.2 vs. -2.4 ± 168.2 mmol/L, P = 0.003) compared with the placebo. Results of RT-PCR demonstrated that vitamin D and omega-3 fatty acid co-supplementation significantly downregulated gene expression of interleukin-1 (IL-1) (P = 0.03), and upregulated vascular endothelial growth factor (VEGF) (P = 0.004) in PBMCs of subjects with PCOS, when compared with placebo.
CONCLUSIONS: Overall, the co-administration of vitamin D and omega-3 fatty acid for 12 weeks had beneficial effects on mental health parameters, serum total testosterone, hs-CRP, plasma TAC and MDA levels, and gene expression of IL-1 and VEGF among women with PCOS.

Huang BZ, Tsilidis KK, Smith MW, et al.
Polymorphisms in genes related to inflammation and obesity and colorectal adenoma risk.
Mol Carcinog. 2018; 57(10):1278-1288 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
We previously investigated the association between single nucleotide polymorphisms (SNPs) in genes related to obesity and inflammation and colorectal cancer in the CLUE II cohort. However, the relationships between these SNPs and colorectal adenomas have not been well evaluated. In a nested case-control study of 135 incident adenoma cases and 269 matched controls in the CLUE II cohort (1989-2000), we genotyped 17 candidate SNPs in 12 genes (PPARG, TCF7L2, ADIPOQ, LEP, IL10, CRP, TLR4, IL6, IL1B, IL8, TNF, RNASEL) and 19 tagSNPs in three genes (IL10, CRP, and TLR4). Conditional logistic regression was used to calculate odds ratios (OR) for adenomas (overall and by size, histology, location, number). Polymorphisms in the inflammatory-related genes CRP, ADIPOQ, IL6, and TLR4 were observed to be associated with adenoma risk. At rs1205 in CRP, T (minor allele) carriers had a higher risk (OR 1.67, 95%CI 1.07-2.60; reference: CC) of adenomas overall and adenomas with aggressive characteristics. At rs1201299 in ADIPOQ, the AC genotype had a higher risk (OR 1.58, 95%CI 1.00-2.49) of adenomas, while the minor AA genotype had a borderline inverse association (OR 0.44, 95%CI 0.18-1.08; reference: CC). At rs1800797 in IL6, the AA genotype had a borderline inverse association (OR 0.53, 95%CI 0.27-1.05; reference: GG). Three TLR4 tagSNPs (rs10116253, rs1927911, rs7873784) were associated with adenomas among obese participants. None of these SNPs were associated with colorectal cancer in our prior study in CLUE II, possibly suggesting a different genetic etiology for early colorectal neoplasia.

Castellano-Castillo D, Morcillo S, Clemente-Postigo M, et al.
Adipose tissue inflammation and
Clin Epigenetics. 2018; 10:60 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Background: Lack of vitamin D (VD) has been associated with colorectal cancer (CRC). VD has anti-inflammatory effects and regulates several cellular pathways by means of its receptor, including epigenetic modifications. Adipose tissue dysfunction has been related to low-grade inflammation, which is related to diseases like cancer. The aim of this study was to explore the relationship between serum 25-hydroxyvitamin D (25(OH)D), adipose tissue gene expression of VD receptor (VDR), pro-inflammatory markers, and the epigenetic factor DNA methyltransferase 3a (DNMT3A) as well as VDR promoter methylation in CRC.
Methods: Blood and visceral adipose tissue from 57 CRC and 50 healthy control subjects were collected. CRC subjects had lower serum 25(OH)D levels and higher VDR gene expression, and these were negatively correlated in the CRC group.
Results: Adipose tissue
Conclusion: Our results suggest that adipose tissue may be a key factor in CRC development. The low 25(OH)D levels and high adipose tissue

Alyoussef A, Al-Gayyar MMH
Cytotoxic and partial hepatoprotective activity of sodium ascorbate against hepatocellular carcinoma through inhibition of sulfatase-2 in vivo and in vitro.
Biomed Pharmacother. 2018; 103:362-372 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is characterized by elevation in the activity of sulfatase-2, an extracellular enzyme that catalyzes removal of 6-O-sulfate groups from heparan sulfate. Therefore, we conducted this study to investigate the cytotoxic activity of the strong water-soluble antioxidant, sodium ascorbate, against HCC both in vivo and in vitro. Sodium ascorbate enhanced animal survival in vivo and reduced HepG2 cells survival. The protein levels of heparan sulfate proteoglycans (HSPGs), insulin like growth factor (IGF)-2, sulfatase-2 and glypican-3 were assessed. Inflammation was evaluated by measuring the gene and protein expression of NFκB, TNF-α, IL-1β, IL-4, IL-6 and IL-10. We found that sodium ascorbate blocked HCC-induced activation of sulfatase-2 leading to restoration of HSPGs receptors associated with reduction in IGF-2 and glypican-3. Sodium ascorbate exerts anti-inflammatory activity by reducing the expression of NFκB, CRP, TNF-α, IL-1β and IL-6 associated with enhanced expression of the anti-inflammatory cytokines, IL-4 and IL-10. In conclusion, cytotoxic effects of sodium ascorbate against HCC can be partially explained by inhibition of sulfatase-2, restoration of HSPGs receptors and deactivation of the inflammatory pathway.

Mei QX, Huang CL, Luo SZ, et al.
Characterization of the duodenal bacterial microbiota in patients with pancreatic head cancer vs. healthy controls.
Pancreatology. 2018; 18(4):438-445 [PubMed] Related Publications
An increasing number of reports have demonstrated that there is an association between the presence of pathogenic microorganisms and pancreatic cancer. However, the role of the duodenal microbiota in pancreatic carcinogenesis remains unknown. In this study, duodenal mucosal microbiota was analyzed in 14 patients with pancreatic head cancer and 14 healthy controls using 16S rRNA gene pyrosequencing methods. Plasma endotoxin activity and the concentrations of the proinflammatory cytokine IL-6 and C-reactive protein (CRP) were measured in blood samples. The urea breath test was used to detect Helicobacter pylori infections. Endoscopic duodenal mucosal biopsies were evaluated by histological examinations. Statistical comparisons of inflammatory factors revealed significantly higher levels of CRP and IL-6 in the pancreatic cancer group as compared to healthy controls. Patients with pancreatic cancer also had a higher incidence of H. pylori infections and showed mucosal changes, including villous abnormalities and diffuse inflammatory cell infiltration in the lamina propria. The sequences analysis showed that based on linear discriminant analysis effect size (LEfSe) analysis at the genus level, Acinetobacter, Aquabacterium, Oceanobacillus, Rahnella, Massilia, Delftia, Deinococcus, and Sphingobium were more abundant in the duodenal mucosa of pancreatic cancer patients, whereas the duodenal microbiotas of healthy controls were enriched with Porphyromonas, Paenibacillus, Enhydrobacter, Escherichia, Shigella, and Pseudomonas. These results reveal a picture of duodenal microbiota in pancreatic head cancer patients that could be useful in future trials investigating the role of gut microbiota in pancreatic cancer.

Tvedt THA, Hovland R, Tsykunova G, et al.
A pilot study of single nucleotide polymorphisms in the interleukin-6 receptor and their effects on pre- and post-transplant serum mediator level and outcome after allogeneic stem cell transplantation.
Clin Exp Immunol. 2018; 193(1):130-141 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Interleukin (IL)-6 is an important regulator of immunity and inflammation in many diseases. Single nucleotide polymorphisms (SNPs) in the IL-6 gene influence outcome after allogeneic stem cell transplantation (ASCT), but the possible importance of SNPs in the IL-6 receptor has not been examined. We therefore investigated whether SNPs in the IL-6R gene influenced biochemical characteristics and clinical outcomes after ASCT. We examined the IL-6 promoter variant rs1800975 and the IL-6R SNPs rs4453032, rs2228145, rs4129267, rs4845374, rs4329505, rs4845617, rs12083537, rs4845618, rs6698040 and rs4379670 in a 101 population-based cohort of allotransplant recipients and their family donors. Patients being homozygous for the major alleles of the IL-6R SNPs rs2228145 and rs4845618 showed high pretransplant CRP serum levels together with decreased sIL-6R levels; the decreased IL-6R levels persisted 6 months post-transplant. In contrast, patients being homozygous for the minor allele of the IL-6R SNP rs4379670 showed decreased pretransplant CRP levels. Furthermore, the IL-6R rs4845618 donor genotype showed an association with severe acute graft-versus-host disease (GVHD), whereas the donor genotype of the IL-6 SNP rs1800795 was associated with decreased survival 100 days post-transplant. Finally, the recipient genotype of the IL-6R SNP rs4329505 showed a strong association with 2-years non-relapse mortality, and this effect was also highly significant in multivariate analysis. IL-6 and IL-6R SNPs influence the clinical outcome after allogeneic stem cell transplantation.

Nojima M, Iwasaki M, Kasuga Y, et al.
Correlation between global methylation level of peripheral blood leukocytes and serum C reactive protein level modified by MTHFR polymorphism: a cross-sectional study.
BMC Cancer. 2018; 18(1):184 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Chronic inflammatory conditions are associated with higher tumor incidence through epigenetic and genetic alterations. Here, we focused on an association between an inflammation marker, C-reactive-protein (CRP), and global DNA methylation levels of peripheral blood leukocytes.
METHODS: The subjects were 384 healthy Japanese women enrolled as the control group of a case-control study for breast cancer conducted from 2001 to 2005. Global DNA methylation was quantified by Luminometric Methylation Assay (LUMA).
RESULTS: With adjustment for lifestyle-related factors, including folate intake, the global DNA methylation level of peripheral blood leukocytes was significantly but weakly increased by 0.43% per quartile category for CRP (P for trend = 0.010). Estimated methylation levels stratified by CRP quartile were 70.0%, 70.8%, 71.4%, and 71.3%, respectively. In addition, interaction between polymorphism of MTHFR (rs1801133, known as C677T) and CRP was significant (P for interaction = 0.046); the global methylation level was significantly increased by 0.61% per quartile category for CRP in the CT/TT group (those with the minor allele T, P for trend = 0.001), whereas no association was observed in the CC group (wild type).
CONCLUSIONS: Our study suggests that CRP concentration is weakly associated with global DNA methylation level. However, this association was observed more clearly in individuals with the minor allele of the MTHFR missense SNP rs1801133. By elucidating the complex mechanism of the regulation of DNA methylation by both acquired and genetic factors, our results may be important for cancer prevention.

Caputi FF, Acquas E, Kasture S, et al.
The standardized Withania somnifera Dunal root extract alters basal and morphine-induced opioid receptor gene expression changes in neuroblastoma cells.
BMC Complement Altern Med. 2018; 18(1):9 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Behavioral studies demonstrated that the administration of Withania somnifera Dunal roots extract (WSE), prolongs morphine-elicited analgesia and reduces the development of tolerance to the morphine's analgesic effect; however, little is known about the underpinning molecular mechanism(s). In order to shed light on this issue in the present paper we explored whether WSE promotes alterations of μ (MOP) and nociceptin (NOP) opioid receptors gene expression in neuroblastoma SH-SY5Y cells.
METHODS: A range of WSE concentrations was preliminarily tested to evaluate their effects on cell viability. Subsequently, the effects of 5 h exposure to WSE (0.25, 0.50 and 1.00 mg/ml), applied alone and in combination with morphine or naloxone, on MOP and NOP mRNA levels were investigated.
RESULTS: Data analysis revealed that morphine decreased MOP and NOP receptor gene expression, whereas naloxone elicited their up-regulation. In addition, pre-treatment with naloxone prevented the morphine-elicited gene expression alterations. Interestingly, WSE was able to: a) alter MOP but not NOP gene expression; b) counteract, at its highest concentration, morphine-induced MOP down-regulation, and c) hamper naloxone-induced MOP and NOP up-regulation.
CONCLUSION: Present in-vitro data disclose novel evidence about the ability of WSE to influence MOP and NOP opioid receptors gene expression in SH-SY5Y cells. Moreover, our findings suggest that the in-vivo modulation of morphine-mediated analgesia by WSE could be related to the hindering of morphine-elicited opioid receptors down-regulation here observed following WSE pre-treatment at its highest concentration.

Li JK, Wang C, Gong HD, Li HZ
Coagulation in hindbrain membrane meningioma patients treated with different injections using acute hypervolemic hemodilution.
J Biol Regul Homeost Agents. 2017 Oct-Dec; 31(4):991-996 [PubMed] Related Publications
The aim of this study was to analyze the changes in coagulation in meningioma patients treated with different injections using the method of acute hypervolemic hemodilution (AHH). One hundred fifty hindbrain membrane meningioma patients were randomly divided into 5 groups, 30 per group. The first group were injected 40ml/time with Danhong after anesthesia induction; the second group were injected with 40ml~60ml/time Kangai and combined with interventional chemotherapy and embolization procedure; the third group of AHH were injected with polygeline 15ml/kg; the fourth group were injected with hydroxyethyl starch (130/0.4) sodium chloride in doses of 15ml/kg; the control group underwent basic treatment for lowering blood pressure and lowering blood fat. The changes of coagulation index were recorded before and after surgery and before and after the injection of different medications. Compared to the control group, for the first group of AHH, after being treated for 10 days and 30 days, the concentrations of bone specific alkaline phosphatase (BALP), bone Gla protein (BGP) and pro-collagen carboxy-terminal propeptide (PICP) were higher than that of the control group, the levels of endotoxin (ET) and C-reactive protein (CRP) were decreased compared to the control group (p less than 0.05); for the second group of AHH, after being treated for 10 days, the index of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fg) were not significantly changed, but the related level of vascular endothelial growth factor (VEGF) significantly decreased (p less than 0.05). Comparing the coagulation function index after surgery in the third and fourth groups, there were no significant changes in mean arterial pressure (MAP) level, heart rate (HR) value presented a low decrease, central venous pressure (CVP) level increased and the level of interleukin IL-6 showed a steady state after increasing. Analyzing the levels of interleukin IL-8 and tumor necrosis factor-α (TNF-α) after surgery, it was seen that in the third group they increased and in the fourth group they decreased (p less than 0.05). Danhong injection improved the coagulation function and microcirculation of patients, Kangai injection and interventional chemotherapy and embolization restrained the appearance of tumor angiogenesis, AHH operation with polygeline injection and hydroxyethyl starch (130/0.4) sodium chloride kept blood flow in normal parameters.

Chen W, Pilling D, Gomer RH
C-reactive protein (CRP) but not the related pentraxins serum amyloid P and PTX3 inhibits the proliferation and induces apoptosis of the leukemia cell line Mono Mac 6.
BMC Immunol. 2017; 18(1):47 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Pentraxins are a family of highly conserved secreted proteins that regulate the innate immune system, including monocytes and macrophages. C-reactive protein (CRP) is a plasma protein whose levels can rise to 1000 μg/ml from the normal <3 μg/ ml during inflammation.
RESULTS: We find that CRP inhibits proliferation of the human myeloid leukemia cell line Mono Mac 6 with an IC50 of 75 μg/ ml by inducing apoptosis of these cells. The related proteins serum amyloid P (SAP) and pentraxin 3 (PTX3) do not inhibit Mono Mac 6 proliferation. CRP has no significant effect on the proliferation of other leukemia cell lines such as HL-60, Mono Mac 1, K562, U937, or THP-1, or the survival of normal peripheral blood cells. The effect of CRP appears to be dependent on the CRP receptor FcγRI, and is negatively regulated by a phosphatidylinositol -3-kinase pathway.
CONCLUSION: These data reveal differential signaling by pentraxins on immune cells, and suggest that CRP can regulate the proliferation of some myeloid leukemia cells.

Baran M, Canoz O, Altuntas H, et al.
Immunohistochemical investigation of P16, P53 and Ki-67's prognostic values in diffuse large B-Cell lymphomas.
Bratisl Lek Listy. 2017; 118(10):602-608 [PubMed] Related Publications
AIM: The aim of this study is to determine the immunohistochemical properties of Ki-67, P53 expression and loss of P16, and to assess their relationship with both clinical parameters and patient survival in DLBCL.
METHOD: Forty patients, diagnosed at the Pathology Department of our institute with nodal DLBCL were selected as the study group. The relationship between P16, P53, Ki-67 expressions and clinical and laboratory parameters like age, gender, performance status, Eastern Cooperative Oncology Group (ECOG), clinical stage, presence of B-symptoms, bone marrow involvement, International Prognostic Index (IPI) score, lactate dehydrogenase (LDH) level, extranodal extension, relapse, C-reactive protein (CRP), sedimentation, number of leukocytes in patients and patient survival were then statistically evaluated.
RESULTS: Our results display no statistically significant correlation between P53 expression and loss of P16, Ki-67 proliferation index and clinical parameters and overall survival (p > 0.05). The only statistically significant relationship was between loss of P16 and stage (p 0.05).
CONCLUSION: According to the results of our study, the loss of P16, P53 gene expression and Ki-67 proliferation index have no effect on life expectancy of patients with DLBCL (Tab. 2, Fig. 2, Ref. 29).

Afshar Ebrahimi F, Foroozanfard F, Aghadavod E, et al.
The Effects of Magnesium and Zinc Co-Supplementation on Biomarkers of Inflammation and Oxidative Stress, and Gene Expression Related to Inflammation in Polycystic Ovary Syndrome: a Randomized Controlled Clinical Trial.
Biol Trace Elem Res. 2018; 184(2):300-307 [PubMed] Related Publications
Magnesium and zinc are known to exert multiple beneficial effects including anti-inflammatory and antioxidant actions. To our knowledge, data on the effects of magnesium and zinc co-supplementation on biomarkers of inflammation and oxidative stress and gene expression related to inflammation in subjects of polycystic ovary syndrome (PCOS) are scarce. This study was conducted to evaluate the effects of magnesium and zinc co-supplementation on biomarkers of inflammation and oxidative stress and gene expression related to inflammation in subjects with PCOS. This randomized double-blind, placebo-controlled trial was conducted among 60 subjects with PCOS diagnosed according to the Rotterdam criteria, aged 18-40 years old. Participants were randomly assigned into two groups to take either 250 mg of magnesium oxide plus 220 mg of zinc sulfate (containing 50 mg zinc) supplements (n = 30) or placebo (n = 30) twice a day for 12 weeks. Biomarkers of inflammation and oxidative stress were assessed at baseline and at end of treatment. Gene expression related to inflammatory cytokines was assessed in peripheral blood mononuclear cells (PBMCs) of PCOS women with RT-PCR method. After the 12-week intervention, compared with the placebo, magnesium and zinc co-supplementation significantly decreased serum high-sensitivity C-reactive protein (hs-CRP) (- 1.6 ± 2.4 vs. + 0.1 ± 0.7 mg/L, P = 0.001) and protein carbonyl (PCO) (- 0.14 ± 0.28 vs. + 0.02 ± 0.07 mmol/mg protein, P = 0.002) and significantly increased plasma total antioxidant capacity (TAC) levels (+ 60.7 ± 69.4 vs. - 1.5 ± 141.5 mmol/L, P = 0.03). Results of RT-PCR demonstrated that compared with the placebo, magnesium and zinc co-supplementation downregulated gene expression of interleukin-1 (IL-1) (P = 0.007) and tumor necrosis factor alpha (TNF-α) (P = 0.03) in PBMCs of subjects with PCOS. Overall, magnesium and zinc co-supplementation, compared with the placebo, for 12 weeks among PCOS women had beneficial effects on serum hs-CRP, plasma PCO, TAC, and gene expression of IL-1 and TNF-α.

Yeh YC, Lei HJ, Chen MH, et al.
C-Reactive Protein (CRP) is a Promising Diagnostic Immunohistochemical Marker for Intrahepatic Cholangiocarcinoma and is Associated With Better Prognosis.
Am J Surg Pathol. 2017; 41(12):1630-1641 [PubMed] Related Publications
Differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) from its histologic mimickers, especially metastatic adenocarcinomas of gastric and pancreatic origin, is a great challenge for pathologists. In this study, through bioinformatics analysis of data from The Cancer Genome Atlas and Gene Expression Omnibus, we identified C-reactive protein (CRP) as a candidate marker to differentiate iCCA from other adenocarcinomas and validated its diagnostic performance by immunohistochemistry in a large cohort of clinical samples including 103 iCCAs, 384 other adenocarcinomas, and 34 liver metastases of various origins. The sensitivity and specificity of CRP expression in the diagnosis of iCCA were 75.7% and 91.1% when using tissue microarrays and 93.3% and 88.2% when using whole tissue sections, respectively. We also compared the diagnostic performance of CRP with N-cadherin, a previously reported marker for iCCA. The sensitivity and specificity of N-cadherin were 54.4% and 92.2% when using tissue microarrays and 80.0% and 88.2% when using whole tissue sections, respectively. The sensitivity of CRP was higher than that of N-cadherin, whereas their specificity was similar. CRP expression was associated with mass-forming gross type (P<0.001), absence of perineural invasion (P=0.002), and N-cadherin expression (P<0.001). CRP expression was also associated with better overall survival (P=0.002) and longer recurrence-free time (P=0.032) after surgery. Our study suggests that CRP is a promising immunohistochemical marker to differentiate iCCA from other adenocarcinomas. Compared with N-cadherin, CRP showed higher sensitivity and similar specificity. CRP expression was associated with better prognosis in iCCA.

Ma Z, Qi Z, Shan Z, et al.
The role of
Biosci Rep. 2017; 37(6) [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The purpose of the study is to investigate the correlation between the expression of C-reactive protein (

Wang G, Zhang DM, Zhuang HY, et al.
Roles of Loss of Chromosome 14q Allele in the Prognosis of Renal Cell Carcinoma with C-reactive Protein Abnormity.
Chin Med J (Engl). 2017; 130(18):2176-2182 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Background:: Renal cell carcinoma (RCC) is frequently associated with paraneoplastic inflammatory syndrome (PIS). This study aimed at exploring the connections between the survival rate and specific gene alterations and the potential mechanism.
Methods:: We retrospectively studied 69 surgical RCC cases from August 2014 to February 2016, including 18 cases of clear cell RCC (ccRCC) demonstrating elevated pretreatment serum C-reactive protein (CRP, Group A). Twelve of the 18 cases were symptomized with febrile episode. We also selected 49 cases of ccRCC with normal pretreatment CRP (Group B). Using 22 microsatellite markers, we compared the incidence of loss of heterozygosity (LOH) between Group A and Group B. All statistical tests are two-sided.
Results:: The 3p LOH was common in both Group A (89%) and Group B (92%). The frequency of 14q LOH in Group A (16 of 18) was higher than Group B (4 of 49, χ
Conclusions:: The results imply that the disruption of a 14q gene(s) might result in not only the inflammatory manifestations in the tumor host but also the poor survival rate as well. The isolation of the gene(s) on 14q might be a vital goal in the treatment of PIS-associated RCC.

Kim ES, Kim SY, Koh M, et al.
C-reactive protein binds to integrin α2 and Fcγ receptor I, leading to breast cell adhesion and breast cancer progression.
Oncogene. 2018; 37(1):28-38 [PubMed] Related Publications
C-reactive protein (CRP) is an acute phase protein synthesized upon the inflammatory responses, associated with breast cancer. The process of tumor cell invasion and metastasis involves the adherence of cells to the extracellular matrix via integrin as a receptor for matrix molecules. The present study investigated the role of CRP in the adhesive phenotype of breast cells and the underlying mechanisms. Here, we first showed that CRP induces adhesion of MCF10A human breast epithelial cells through the activation of integrin α2 signaling. Expression of integrin α2 was induced by CRP in which transcription factors c-fos and SP1 may be involved. Binding of CRP with integrin α2 leads to the activation of focal adhesion kinase (FAK), paxillin and ERKs. CRP also binds to an Fcγ receptor Fcγ receptor I (FcγRI), and induces activation of paxillin, FAK and ERKs. Integrin α2 and FAK have crucial roles in the adhesive and invasive phenotypes as well as MMP-9 upregulation induced by CRP in MCF10A cells. Treatment with an inflammatory lipid sphingosine-1-phosphate induced CRP, which may be secreted and exert an autocrine effect by binding to FcγRI and integrin α2. Involvement of CRP in adhesion, invasion, anchorage-independent growth and upregulation of integrin α2, paxillin and FAK was observed in MDA-MB-231 triple-negative human breast cancer (TNBC) cells. Using an in vivo invasion model and an orthotopic mouse tumor model with MDA-MB-231 cells, we showed that CRP has an important role in intravasation and tumor growth in vivo, demonstrating the in vivo relevance of our in vitro results. The present study elucidates a critical molecular basis between CRP, integrin α2 and FcγRI pathways in MCF10A breast cells and MDA-MB-231 TNBC cells, thereby providing useful information on CRP-induced aggressiveness of breast cells in the inflammatory microenvironment.

Victor M, Evgeniy H, Gergana T, et al.
Serum Hepcidin Levels in Multiple Myeloma.
Clin Lab. 2017; 63(7):1273-1277 [PubMed] Related Publications
BACKGROUND: Multiple myeloma (MM) is a malignant disease with a 10% frequency among all haematology neoplasms. It is characterized by clone proliferation of plasmatic cells in bone marrow, monoclonal gammopathy, and anemia, hypercalcemia, and kidney failure and bone lesions. IL-6 is an inflammatory cytokine, potential growth factor for myeloma cells, as elevated serum levels are connected with poor disease prognosis. IL-6 modulates many gene transcriptions, encoding synthesis of acute phase proteins, including C-reactive protein (CRP) and hepcidin.
METHODS: We evaluated 21 patients newly diagnosed with multiple myeloma at the Department of Haematology at "Aleksandrovska" Hospital; average age 51 ± 5.2. Their results were compared to 21 age matched controls. Included patients were enrolled before treatment onset. In the included groups, we measured CBC, serum iron and total iron binding capacity, ferritin, soluble transferrin receptors, IL-6, and hepcidin.
RESULTS: We established elevated serum hepcidin levels in MM patients compared to the control group: 99.4 ± 10.5 µg/L to 19.9 ± 2.8 µg/L (p < 0.001). Serum IL-6 and CRP concentrations were elevated in MM cases compared to controls (p < 0.005). In patients with MM we found strong negative correlation between serum hepcidin and inflammation markers, IL-6 and CRP. IL-6 shows r = -0.894, and CRP - r = -0.916; p < 0.001. Soluble transferrin receptors correlate negatively to hepcidin: r = -0.831, p < 0.001. Transferrin concentration correlated highly positive to hepcidin: r = 0.580; p < 0.001.
CONCLUSIONS: Our results show an important role of hepcidin in the evaluation of iron homeostasis disorders. Quantification of the peptide's concentration shows increased concentration in multiple myeloma patients. Treatment of anemia associated with multiple myeloma is still a serious challenge for clinicians.

Fang D, Ye Y
Biosci Rep. 2017; 37(4) [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The relationship between

Fan S, Zhong JL, Chen WX, et al.
Postoperative immune response and surgical stress in selective neck dissection: Comparison between endoscopically assisted dissection and open techniques in cT1-2N0 oral squamous cell carcinoma.
J Craniomaxillofac Surg. 2017; 45(8):1112-1116 [PubMed] Related Publications
BACKGROUND: Endoscopically assisted selective neck dissection (SND) has recently been applied in clinical N0 cases of oral squamous cell carcinoma (OSCC). However, nothing is known of the immune response after surgery.
METHODS: A total of 60 patients with cT1-2N0 OSCC randomly underwent endoscopically assisted SND and open operations. The serum levels of IL-6, IL-8, IL-10, IL-1b, TNF-a, CRP, cortisol, ACTH, and growth hormone were analyzed before the start of the surgery (T0) and at 2 (T1), 6 (T2), 24 (T3), and 72 h (T4) after surgery.
RESULTS: A total of 31 patients were randomized for endoscopic SND, whereas 29 underwent open procedures. The release of IL-6, IL-10 and CRP was significantly lower in the endoscopic group than in the open surgery group (p < 0.05), and cortisol levels were also lower in the endoscopic group (p < 0.05).
CONCLUSIONS: Endoscopic SND could effectively provide lower inflammatory responses and surgical stress, reducing peri-operative trauma and accelerating recovery.

Normando AGC, Rocha CL, de Toledo IP, et al.
Biomarkers in the assessment of oral mucositis in head and neck cancer patients: a systematic review and meta-analysis.
Support Care Cancer. 2017; 25(9):2969-2988 [PubMed] Related Publications
PURPOSE: The aim of this study was to evaluate the capability of biomarkers to predict the risk of oral mucositis in head and neck cancer patients, as well as to assess the correlation between these biomarkers and the severity of mucositis.
METHODS: The search was performed at LILACS, PubMed, Science Direct, Scopus, and Web of Science. A search of the gray literature was performed on Google Scholar, OpenGrey, and ProQuest. The methodological quality of the included studies was assessed using the Meta-Analysis of Statistics Assessment and Review Instrument (MAStARI) tool, and the evidence quality was assessed by the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system.
RESULTS: After a two-step selection process, 26 studies met the eligibility criteria. In total, 27 biomarkers were evaluated, and the most frequent were the epidermal growth factor (EGF), C-reactive protein (CRP), genetic polymorphisms, tumor necrosis factor alpha (TNF-α), and erythrocyte sedimentation rate (ESR). The meta-analysis showed an expression of polymorphisms in XRCC1 (32.66%), XRCC3 (31.00%), and RAD51 (39.16%) genes, as well as an expression of protein biomarkers (39.57%), in patients with an increased risk of developing oral mucositis.
CONCLUSIONS: Dosing biomarkers before starting radiation therapy may be a promising method to predict the risk of developing mucositis and allow radiosensitive patients to have a customized treatment. Although there is currently limited evidence to confirm the putative implementation of serum and salivary biomarkers to assess the correlation between them and the severity of mucositis, this current review provides new research directions.

Saldarriaga J, Bisig B, Couchy G, et al.
Focal β-catenin mutation identified on formalin-fixed and paraffin-embedded inflammatory hepatocellular adenomas.
Histopathology. 2017; 71(6):989-993 [PubMed] Related Publications
The identification of hepatocellular adenoma (HCA) with mutation in exon 3 of the CTNNB1 gene encoding for β-catenin is clinically relevant due to a higher risk of malignant transformation. Inflammatory HCA (IHCA) can exhibit β-catenin activation (β-IHCA). We report two cases with multiple IHCA in which focal β-catenin activation has been found in one of the IHCA. In both cases, the diagnosis of IHCA was confirmed on the resected nodules by routine stains, immunohistochemical detection of C-reactive protein (CRP) and molecular biology on frozen material. An additional molecular analysis was performed on formalin-fixed paraffin-embedded (FFPE) material that showed focal glutamine synthetase (GS) staining, the surrogate marker of β-catenin activation. In case 1, it was a 1.8-cm area within the 7.5 cm IHCA, and in case 2 a small 0.3-cm area within a 1.8 cm resected IHCA located close to a larger IHCA, negative for GS. In both cases, nuclear β-catenin expression and decreased reticulin network were observed in the GS expressing foci, together with cholestasis and diffuse CD34 expression in case 1. Molecular analysis by pyrosequencing on FFPE material using the GS-stained slides as reference to select areas with/without positive staining revealed a CTNNB1 exon 3 mutation restricted to the areas exhibiting both positive GS and CRP expression, whereas wild-type CTNNB1 was found in areas showing only CRP staining. These two cases illustrate focal β-catenin activation that can occur within IHCAs. Additional data are needed to determine if β-catenin mutation is a secondary event in IHCA.

Rhee H, Ko JE, Chung T, et al.
Transcriptomic and histopathological analysis of cholangiolocellular differentiation trait in intrahepatic cholangiocarcinoma.
Liver Int. 2018; 38(1):113-124 [PubMed] Related Publications
BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) is a heterogeneous entity with diverse aetiologies, morphologies and clinical outcomes. Recently, histopathological distinction of cholangiolocellular differentiation (CD) of iCCA has been suggested. However, its genome-wide molecular features and clinical significance remain unclear.
METHODS: Based on CD status, we stratified iCCAs into iCCA with CD (n=20) and iCCA without CD (n=102), and performed an integrative analysis using transcriptomic and clinicopathological profiles.
RESULTS: iCCA with CD revealed less aggressive histopathological features compared to iCCA without CD, and iCCA with CD showed favourable clinical outcomes of overall survival and time to recurrence than iCCA without CD (P<.05 for all). Transcriptomic profiling revealed that iCCA with CD resembled an inflammation-related subtype, while iCCA without CD resembled a proliferation subtype. In addition, we identified a CD signature that can predict prognostic outcomes of iCCA (CD_UP, n=486 and CD_DOWN, n=308). iCCAs were subgrouped into G1 (positivity for CRP and CDH2, 7%), G3 (positivity for S100P and TFF1, 32%) and G2 (the others, 61%). Prognostic outcomes for overall survival (P=.001) and time to recurrence (P=.017) were the most favourable in G1-iCCAs, intermediate in G2-iCCAs and the worst in G3-iCCAs. Similar result was confirmed in the iCCA set from GSE26566 (n=68).
CONCLUSIONS: CD signature was identified to predict the prognosis of iCCA. The combined evaluation of histology of CD and protein expression status of CRP, CDH2, TFF1 and S100P might help subtyping and predicting clinical outcomes of iCCA.

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