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Special Issue "Emerging Classes of Biomarkers for Molecular Diagnostics"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2015).

Special Issue Editor

Guest Editor
Prof. Dr. Camile S. Farah

Head, Oral Oncology Research Program, UQ Centre for Clinical Research, The University of Queensland, Royal Brisbane & Women’s Hospital, Herston, Qld 4029, Australia
Website | E-Mail
Interests: biomarkers of oral cancer and oral epithelial dysplasia; oral oncology; personalized medicine; next generation sequencing; immunohistochemistry; molecular diagnostics; molecular tumour stratification; microRNA; optical biopsy; molecular imaging

Special Issue Information

Dear Colleagues,

There has been an explosion of biomarker research in the last five years, and much interest in diagnostic, prognostic and predictive products utilised in the ever expanding field of personalized medicine. Biomarker research has become at once more sophisticated yet more profuse, and we currently have a plethora of biomarkers for a diverse range of diseases from heart failure to oral cancer. As we explore these biomarkers further, we must endeavour to learn about the underlying mechanisms of disease processes, as we move along the path to discovery of novel drugs and therapies that will increase our ability to offer personalized patient care into the future. With the migration of advanced high throughput technologies, such as Next Generation Sequencing from the research arena into clinical practice, biomarker research and discovery is poised to explode once again. Translation of novel biomarkers into clinical practice and diagnostic laboratories is coupled with regulatory and administrative requirements that must be met, while collaboration between research institutions, industry and the private sector drive further advancements in the field of biomarker discovery and application. This Special Issue explores the ever expanding field of emerging biomarkers for molecular diagnostics and their application in the clinical setting, and their potential utility in personalized patient care.

Prof. Dr. Camile S Farah
Guest Editor

Manuscript Submission Information

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Keywords

  • cancer biomarkers
  • cancer stem cells
  • clinical trials
  • circulating biomarkers
  • companion diagnostics
  • copy number variation
  • cytogenetics
  • diagnostic imaging
  • digital PCR
  • emerging biomarkers
  • epigenomics
  • exosomes
  • genome-wide association studies
  • genomic database
  • genomics
  • lab-on-a-chip diagnostics
  • liquid biopsy
  • massively parallel sequencing
  • metabolomics
  • methylation
  • microarray
  • microfluidics
  • microRNA
  • molecular diagnostics
  • molecular pathology
  • molecular imaging
  • nanofluidics next-generation sequencing
  • deep sequencing
  • non-coding RNAs
  • omics
  • personalized medicine
  • point-of-care diagnostics
  • precision medicine
  • predictive diagnostics
  • prognostic diagnostics
  • proteomics
  • single nucleotide polymorphism
  • single cell sequencing
  • targeted therapy
  • translational medicine

Published Papers (18 papers)

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Research

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Open AccessArticle
Gene Expression Signature in Endemic Osteoarthritis by Microarray Analysis
Int. J. Mol. Sci. 2015, 16(5), 11465-11481; https://doi.org/10.3390/ijms160511465
Received: 15 April 2015 / Revised: 3 May 2015 / Accepted: 5 May 2015 / Published: 19 May 2015
Cited by 3 | PDF Full-text (821 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Kashin-Beck Disease (KBD) is an endemic osteochondropathy with an unknown pathogenesis. Diagnosis of KBD is effective only in advanced cases, which eliminates the possibility of early treatment and leads to an inevitable exacerbation of symptoms. Therefore, we aim to identify an accurate blood-based [...] Read more.
Kashin-Beck Disease (KBD) is an endemic osteochondropathy with an unknown pathogenesis. Diagnosis of KBD is effective only in advanced cases, which eliminates the possibility of early treatment and leads to an inevitable exacerbation of symptoms. Therefore, we aim to identify an accurate blood-based gene signature for the detection of KBD. Previously published gene expression profile data on cartilage and peripheral blood mononuclear cells (PBMCs) from adults with KBD were compared to select potential target genes. Microarray analysis was conducted to evaluate the expression of the target genes in a cohort of 100 KBD patients and 100 healthy controls. A gene expression signature was identified using a training set, which was subsequently validated using an independent test set with a minimum redundancy maximum relevance (mRMR) algorithm and support vector machine (SVM) algorithm. Fifty unique genes were differentially expressed between KBD patients and healthy controls. A 20-gene signature was identified that distinguished between KBD patients and controls with 90% accuracy, 85% sensitivity, and 95% specificity. This study identified a 20-gene signature that accurately distinguishes between patients with KBD and controls using peripheral blood samples. These results promote the further development of blood-based genetic biomarkers for detection of KBD. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
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Open AccessArticle
Optimal Decision Rules for Biomarker-Based Subgroup Selection for a Targeted Therapy in Oncology
Int. J. Mol. Sci. 2015, 16(5), 10354-10375; https://doi.org/10.3390/ijms160510354
Received: 25 February 2015 / Revised: 16 April 2015 / Accepted: 29 April 2015 / Published: 7 May 2015
Cited by 5 | PDF Full-text (167 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Throughout recent years, there has been a rapidly increasing interest regarding the evaluation of so-called targeted therapies. These therapies are assumed to show a greater benefit in a pre-specified subgroup of patients—commonly identified by a predictive biomarker—as compared to the total patient population [...] Read more.
Throughout recent years, there has been a rapidly increasing interest regarding the evaluation of so-called targeted therapies. These therapies are assumed to show a greater benefit in a pre-specified subgroup of patients—commonly identified by a predictive biomarker—as compared to the total patient population of interest. This situation has led to the necessity to develop biostatistical methods allowing an efficient evaluation of such treatments. Among others, adaptive enrichment designs have been proposed as a solution. These designs allow the selection of the most promising patient population based on an efficacy analysis at interim and restricting recruitment to these patients afterwards. As has recently been shown, the performance of the applied interim decision rule in such a design plays a crucial role in ensuring a successful trial. In this work, we investigate the situation when the primary outcome of the trial is a binary variable. Optimal decision rules are derived which incorporate the uncertainty about the treatment effects. These optimal decision rules are evaluated with respect to their performance in an adaptive enrichment design in terms of correct selection probability and power, and are compared to proposed ad hoc decision rules. Our methods are illustrated by means of a clinical trial example. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
Open AccessArticle
An Exploratory Pilot Study of Genetic Marker for IgE-Mediated Allergic Diseases with Expressions of FcεR1α and Cε
Int. J. Mol. Sci. 2015, 16(5), 9504-9519; https://doi.org/10.3390/ijms16059504
Received: 11 December 2014 / Revised: 10 April 2015 / Accepted: 20 April 2015 / Published: 27 April 2015
Cited by 2 | PDF Full-text (1550 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The high affinity immunoglobulin E (IgE) receptor-FcεR1 is mainly expressed on the surface of effector cells. Cross-linking of IgE Abs bound to FcεR1 by multi-valent antigens can induce the activation of these cells and the secretion of inflammatory mediators. Since FcεR1 plays a [...] Read more.
The high affinity immunoglobulin E (IgE) receptor-FcεR1 is mainly expressed on the surface of effector cells. Cross-linking of IgE Abs bound to FcεR1 by multi-valent antigens can induce the activation of these cells and the secretion of inflammatory mediators. Since FcεR1 plays a central role in the induction and maintenance of allergic responses, this study aimed to investigate the association of FcεR1 with the allergic phenotype of Cε expression and cytokine and histamine release from peripheral leukocytes. Peripheral leukocytes from 67 allergic and 50 non-allergic subjects were used for genotyping analysis. Peripheral mononuclear cells (PBMCs) were used for Cε expression and ELISpot analysis, while polymorphonuclear cells (PMNs) were used for histamine release. The association between genotype polymorphism of the FcεR1α promoter region (rs2427827 and rs2251746) and allergic features of Cε expression and histamine were analyzed, and their effects on leukocytes function were compared with wild type. The genotype polymorphisms of FcεR1α promoter region with CT and TT in rs2427827 and TC in rs2251746 were significantly higher in allergic patients than in non-allergic controls. Patients with single nucleotide polymorphism (SNP) of FcεR1α promoter region had high levels of total IgE, mite-specific Der p 2 (Group 2 allergen of Dermatophagoides pteronyssinus)-specific IgE and IgE secretion B cells. The mRNA expression of FcεR1α was significantly increased after Der p2 stimulation in PBMCs with SNPs of the FcεR1α promoter region. Despite the increased Cε mRNA expression in PBMCs and histamine release from PMNs and the up-regulated mRNA expression of interleukin (IL)-6 and IL-8 secretions after Der p2 stimulation, there was no statistically significant difference between SNPs of the FcεR1α promoter region and the wild type. SNPs of FcεR1α promoter region were associated with IgE expression, IgE producing B cells, and increased Der p2-induced FcεR1α mRNA expression. These SNPs may be used as a disease marker for IgE-mediated allergic inflammation caused by Dermatophagoides pteronyssinus. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
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Open AccessArticle
Genetic Polymorphisms in Estrogen-Related Genes and the Risk of Breast Cancer among Han Chinese Women
Int. J. Mol. Sci. 2015, 16(2), 4121-4135; https://doi.org/10.3390/ijms16024121
Received: 3 November 2014 / Revised: 21 January 2015 / Accepted: 4 February 2015 / Published: 13 February 2015
Cited by 8 | PDF Full-text (704 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Exposure to high levels of estrogen is considered an important risk factor for susceptibility to breast cancer. Common polymorphisms in genes that affect estrogen levels may be associated with breast cancer risk, but no comprehensive study has been performed among Han Chinese women. [...] Read more.
Exposure to high levels of estrogen is considered an important risk factor for susceptibility to breast cancer. Common polymorphisms in genes that affect estrogen levels may be associated with breast cancer risk, but no comprehensive study has been performed among Han Chinese women. In the present study, 32 single-nucleotide polymorphisms (SNPs) in estrogen-related genes were genotyped using the MassARRAY IPLEX platform in 1076 Han Chinese women. Genotypic and allelic frequencies were compared between case and control groups. Unconditional logistic regression was used to assess the effects of SNPs on breast cancer risk. Associations were also evaluated for breast cancer subtypes stratified by estrogen receptor (ER) and progesterone receptor (PR) status. Case-control analysis showed a significant relation between heterozygous genotypes of rs700519 and rs2069522 and breast cancer risk (OR = 0.723, 95% CI = 0.541–0.965, p = 0.028 and OR = 1.500, 95% CI = 1.078–2.087, p = 0.016, respectively). Subgroup comparisons revealed that rs2446405 and rs17268974 were related to ER status, and rs130021 was associated with PR status. Our findings suggest that rs700519 and rs2069522 are associated with susceptibility to breast cancer among the Han Chinese population and have a cumulative effect with three other identified SNPs. Further genetic and functional studies are needed to identify additional SNPs, and to elucidate the underlying molecular mechanisms. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
Open AccessArticle
Hypermethylation of the 16q23.1 Tumor Suppressor Gene ADAMTS18 in Clear Cell Renal Cell Carcinoma
Int. J. Mol. Sci. 2015, 16(1), 1051-1065; https://doi.org/10.3390/ijms16011051
Received: 14 September 2014 / Accepted: 23 December 2014 / Published: 5 January 2015
Cited by 10 | PDF Full-text (2004 KB) | HTML Full-text | XML Full-text
Abstract
To identify tumor suppressor genes (TSGs) silenced by hypermethylation and discover new epigenetic biomarkers for early cancer detection. ADAMTS18, located at 16q23.1, has been reported to be a critical TSG in multiple primary tumors; however, this has not yet been verified in [...] Read more.
To identify tumor suppressor genes (TSGs) silenced by hypermethylation and discover new epigenetic biomarkers for early cancer detection. ADAMTS18, located at 16q23.1, has been reported to be a critical TSG in multiple primary tumors; however, this has not yet been verified in clear cell renal cell carcinoma (ccRCC). We explored epigenetic alterations in this gene in ccRCC and analyzed possible clinicopathological associations. We examined ADAMTS18 gene expression and methylation by semi-quantitative reverse transcription PCR (RT-PCR) and methylation-specific polymerase chain reaction (MSP) in 5 ccRCC-derived cell lines before and after treatment with 5-aza-2'-deoxycytidine (5-AzaC). MSP was further performed for 101 ccRCC primary tumors and 20 adjacent normal tissues. Some cell lines and specimens were examined by subsequent bisulfite genomic sequencing (BGS) and real-time PCR. Further, we analyzed the relationship between the ADAMTS18 gene methylation and clinicopathological features, including short-term disease-free survival (DFS), in patients with ccRCC. ADAMTS18 down-regulation and hypermethylation were detected in the ccRCC-derived cell lines using RT-PCR and MSP. Treatment with 5-AzaC reversed the hypermethylation of the ADAMTS18 gene and restored its expression. Hypermethylation was further detected in 44 of 101 (43.6%) primary tumors and 3 of 20 (15.0%) adjacent normal tissues. However, a significant difference between both groups was observed (p = 0.02). BGS analysis and real-time PCR were subsequently performed to confirm the results of RT-PCR and MSP. Furthermore, the methylation status of ADAMTS18 was not significantly associated with gender, age, location, tumor diameter, pathological stage, nuclear grade or short-term DFS in patients with ccRCC (p > 0.05). The ADAMTS18 gene is often down-regulated by hypermethylation in ccRCC-derived cell lines and primary tumors, indicating its critical role as a TSG in ccRCC. We conclude that ADAMTS18 gene hypermethylation may be involved in the tumorigenesis of ccRCC and may serve as a novel biomarker for this disease. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
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Open AccessArticle
Zinc-α-2-Glycoprotein: A Candidate Biomarker for Colon Cancer Diagnosis in Chinese Population
Int. J. Mol. Sci. 2015, 16(1), 691-703; https://doi.org/10.3390/ijms16010691
Received: 12 November 2014 / Accepted: 17 December 2014 / Published: 30 December 2014
Cited by 13 | PDF Full-text (4042 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Zinc-α-2-glycoprotein (AZGP1) is a 41-kDa secreted glycoprotein, which has been detected in several malignancies. The diagnostic value of AZGP1 in serum of prostate and breast cancer patients has been reported. Analyzing “The Cancer Genome Atlas” data, we found that in colon cancer AZGP1 [...] Read more.
Zinc-α-2-glycoprotein (AZGP1) is a 41-kDa secreted glycoprotein, which has been detected in several malignancies. The diagnostic value of AZGP1 in serum of prostate and breast cancer patients has been reported. Analyzing “The Cancer Genome Atlas” data, we found that in colon cancer AZGP1 gene expression was upregulated at transcriptional level. We hypothesized that AZGP1 could be used as a diagnostic marker of colon cancer. First, we confirmed AZGP1 expression was higher in a set of 28 tumor tissues than in normal colonic mucosa tissues by real-time quantitative PCR and western blot in a Chinese population. We verified that serum concentration of AZGP1 was higher in 120 colon cancer patients compared with 40 healthy controls by ELISA (p < 0.001). Then receiver-operating characteristic (ROC) curve analysis was used to evaluate the predictive diagnostic value of AZGP1 in serum. The area under the curve (AUC) of AZGP1 was 0.742 (p < 0.001, 95% confidence interval (CI) = 0.656–0.827) in between the AUC of carcinoembryonic antigen (CEA) and the AUC of CA19-9, suggesting that predictive diagnostic value of AZGP1 is between CEA and Carbohydrate 19-9 (CA19-9). The combination of AZGP1 with traditional serum biomarkers, CEA and CA19-9, could result in better diagnostic results. To further validate the diagnostic value of AZGP1, a tissue microarray containing 190 samples of primary colon cancer tissue paired with normal colonic tissue was analysed and the result showed that AZGP1 was significantly upregulated in 68.4% (130 of 190) of the primary cancer lesions. In contrast, there was a weakly positive staining in 29.5% (56 of 190) of the normal colonic tissue samples (p < 0.001). Leave-one-out cross-validation was performed on the serum data, and showed that the diagnostic value of AZGP1 had 63.3% sensitivity and 65.0% specificity. Combination of AZGP1, CEA and CA19-9 had improved diagnosis value accuracy with 74.2% sensitivity and 72.5% specificity. These results suggest that AZGP1 is a useful diagnostic biomarker in tissues and serum from a Chinese population. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
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Open AccessArticle
Reduced 5-Methylcytosine Level as a Potential Progression Predictor in Patients with T1 or Non-Invasive Urothelial Carcinoma
Int. J. Mol. Sci. 2015, 16(1), 677-690; https://doi.org/10.3390/ijms16010677
Received: 30 October 2014 / Accepted: 17 December 2014 / Published: 30 December 2014
Cited by 5 | PDF Full-text (6810 KB) | HTML Full-text | XML Full-text
Abstract
This study aims to elucidate the level of DNA methylation in urothelial carcinomas (UCs) using 5-methylcytosine (5-MeC) immunohistochemistry (IHC). We examined the relationship among 5-MeC levels, DNA (cytosine-5)-methyltransferase 1 (DNMT1) immunostaining levels, and clinicopathologic features. Tissue samples included 23 normal urothelia and 150 [...] Read more.
This study aims to elucidate the level of DNA methylation in urothelial carcinomas (UCs) using 5-methylcytosine (5-MeC) immunohistochemistry (IHC). We examined the relationship among 5-MeC levels, DNA (cytosine-5)-methyltransferase 1 (DNMT1) immunostaining levels, and clinicopathologic features. Tissue samples included 23 normal urothelia and 150 urothelial neoplasia, which comprised 40 non-invasive and 110 invasive UCs. The levels of 5-MeC and DNMT1 were assessed based on their immunoreactivities and then divided into low and high levels. In addition, we collected information on clinical variables, pathologic features, and recurrent status from patient questionnaires and medical records. Chi-square test and multivariate logistic regression model were used for analyses. Results showed that 5-MeC levels were positively associated with DNMT1 levels in UC (p = 0.0288). Both 5-MeC and DNMT1 were low in approximately 50% (76/150) of UC. The percentage of low 5-MeC levels was higher in invasive UC (65/110; 59%) than in normal urothelia (2/23; 13%) and non-invasive UC (18/40; 45%). Clinical factors were independently associated with low 5-MeC levels after adjusting for age and sex, including cancer stages II–IV, presence of UC in situ, and marked inflammation. Low 5-MeC levels in stage I invasive UC were not significantly different from those of non-invasive tumors (p = 0.8478). Low DNMT1 levels were only associated with UC with squamous differentiation (p = 0.0365). Neither 5-MeC nor DNMT1 levels were associated with UC recurrence. In conclusion, a low 5-MeC level could predict the progression of UC invasion into muscle. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
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Open AccessArticle
Serum Calreticulin Is a Negative Biomarker in Patients with Alzheimer’s Disease
Int. J. Mol. Sci. 2014, 15(12), 21740-21753; https://doi.org/10.3390/ijms151221740
Received: 9 October 2014 / Revised: 3 November 2014 / Accepted: 10 November 2014 / Published: 25 November 2014
Cited by 10 | PDF Full-text (364 KB) | HTML Full-text | XML Full-text
Abstract
Calreticulin is down-regulated in the cortical neurons of patients with Alzheimer’s disease (AD) and may be a potential biomarker for the diagnosis of AD. A total of 128 AD patients were randomly recruited from May 2012 to July 2013. The mRNA levels of [...] Read more.
Calreticulin is down-regulated in the cortical neurons of patients with Alzheimer’s disease (AD) and may be a potential biomarker for the diagnosis of AD. A total of 128 AD patients were randomly recruited from May 2012 to July 2013. The mRNA levels of calreticulin were measured from the serum of tested subjects using real-time quantitative reverse transcriptase-PCR (real-time qRT-PCR). Serum levels of calreticulin were determined by ELISA and Western Blot. Serum levels of calreticulin in AD patients were significantly lower than those from a healthy group (p < 0.01). The baseline characters indicated that sample size, gender, mean age, diabetes and BMI (body mass index) were not major sources of heterogeneity. The serum levels of mRNA and protein of calreticulin were lower in AD patients than those from a healthy group, and negatively associated with the progression of AD according to CDR scores (p < 0.01). Thus, there is a trend toward decreased serum levels of calreticulin in the patients with progression of AD. Serum levels of calreticulin can be a negative biomarker for the diagnosis of AD patients. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
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Open AccessArticle
WISP1 Polymorphisms Contribute to Platinum-Based Chemotherapy Toxicity in Lung Cancer Patients
Int. J. Mol. Sci. 2014, 15(11), 21011-21027; https://doi.org/10.3390/ijms151121011
Received: 2 September 2014 / Revised: 28 October 2014 / Accepted: 30 October 2014 / Published: 14 November 2014
Cited by 12 | PDF Full-text (2010 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Platinum-based chemotherapy toxicity is always one of the serious problems from which lung cancer patients suffer. The genetic polymorphism of WISP1 was revealed to be associated with susceptibility and platinum-based chemotherapy response in our previous studies. In this study, we aimed to investigate [...] Read more.
Platinum-based chemotherapy toxicity is always one of the serious problems from which lung cancer patients suffer. The genetic polymorphism of WISP1 was revealed to be associated with susceptibility and platinum-based chemotherapy response in our previous studies. In this study, we aimed to investigate the relationship of WISP1 genetic polymorphisms with platinum-based chemotherapy toxicity in lung cancer patients. A total of 412 lung cancer patients were enrolled in this study, and 28 polymorphisms of the WISP1 gene were genotyped by SequenomMassARRAY. We found that WISP1 polymorphisms (rs2929965, rs2929969, rs2929970, rs2929973 and rs754958) were related to the overall chemotherapy toxicity of lung cancer in subgroup analyses. Rs16904853, rs2929970, rs2977549 and rs2977551 (p = 0.021, 0.028, 0.024, 0.048, respectively) polymorphisms were significantly associated with hematologic toxicity. Rs2929946, rs2929970, rs2977519, rs2977536, rs3739262 and rs754958 (p = 0.031, 0.046, 0.029, 0.016, 0.042, 0.035, respectively) polymorphisms were significantly associated with the gastrointestinal toxicity of lung cancer. Genotypes of WISP1 may be novel and useful biomarkers for predicting platinum-based chemotherapy toxicity in lung cancer patients. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
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Open AccessArticle
Association of CDKN2BAS Polymorphism rs4977574 with Coronary Heart Disease: A Case-Control Study and a Meta-Analysis
Int. J. Mol. Sci. 2014, 15(10), 17478-17492; https://doi.org/10.3390/ijms151017478
Received: 22 July 2014 / Accepted: 17 September 2014 / Published: 29 September 2014
Cited by 27 | PDF Full-text (862 KB) | HTML Full-text | XML Full-text
Abstract
The goal of our study was to explore the significant association between a non-protein coding single nucleotide polymorphism (SNP) rs4977574 of CDKN2BAS gene and coronary heart disease (CHD). A total of 590 CHD cases and 482 non-CHD controls were involved in the present [...] Read more.
The goal of our study was to explore the significant association between a non-protein coding single nucleotide polymorphism (SNP) rs4977574 of CDKN2BAS gene and coronary heart disease (CHD). A total of 590 CHD cases and 482 non-CHD controls were involved in the present association study. A strong association of rs4977574 with CHD was observed in females (genotype: p = 0.002; allele: p = 0.002, odd ratio (OR) = 1.57, 95% confidential interval (CI) = 1.18–2.08). Moreover, rs4977574 was more likely to be a risk variant of CHD under the recessive model in females (χ2 = 10.29, p = 0.003, OR = 2.14, 95% CI = 1.31–2.77). A breakdown analysis by age had shown that there was an 87% increased risk of CHD for females younger than 65 years (genotype: χ2 = 14.64, degrees of freedom (df) = 2, p = 0.0002; allele: χ2 = 11.31, df = 1, p = 0.0008, OR = 1.87, 95% CI = 1.30–2.70). Similar observation was also found in males younger than 65 years (genotype: χ2 = 8.63, df = 2, p = 0.04; allele: χ2 = 7.55, df = 1, p = 0.006, OR = 1.45, 95% CI = 1.11–1.90). p values were adjusted by age, sex, smoking, high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C). Meta-analysis of 23 studies among 36,452 cases and 39,781 controls showed a strong association between rs4977574 and the risk of CHD (p < 0.0001, OR = 1.27, 95% CI = 1.22–1.31). Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
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Review

Jump to: Research

Open AccessReview
Circulating Cell-Free Tumour DNA in the Management of Cancer
Int. J. Mol. Sci. 2015, 16(6), 14122-14142; https://doi.org/10.3390/ijms160614122
Received: 22 February 2015 / Revised: 23 April 2015 / Accepted: 26 May 2015 / Published: 19 June 2015
Cited by 52 | PDF Full-text (737 KB) | HTML Full-text | XML Full-text
Abstract
With the development of new sensitive molecular techniques, circulating cell-free tumour DNA containing mutations can be identified in the plasma of cancer patients. The applications of this technology may result in significant changes to the care and management of cancer patients. Whilst, currently, [...] Read more.
With the development of new sensitive molecular techniques, circulating cell-free tumour DNA containing mutations can be identified in the plasma of cancer patients. The applications of this technology may result in significant changes to the care and management of cancer patients. Whilst, currently, these “liquid biopsies” are used to supplement the histological diagnosis of cancer and metastatic disease, in the future these assays may replace the need for invasive procedures. Applications include the monitoring of tumour burden, the monitoring of minimal residual disease, monitoring of tumour heterogeneity, monitoring of molecular resistance and early diagnosis of tumours and metastatic disease. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
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Open AccessReview
Undetected Toxicity Risk in Pharmacogenetic Testing for Dihydropyrimidine Dehydrogenase
Int. J. Mol. Sci. 2015, 16(4), 8884-8895; https://doi.org/10.3390/ijms16048884
Received: 26 February 2015 / Revised: 30 March 2015 / Accepted: 13 April 2015 / Published: 21 April 2015
Cited by 9 | PDF Full-text (671 KB) | HTML Full-text | XML Full-text
Abstract
Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%–30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in [...] Read more.
Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%–30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients’ homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies’ results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
Open AccessReview
Non-Coding RNAs in Saliva: Emerging Biomarkers for Molecular Diagnostics
Int. J. Mol. Sci. 2015, 16(4), 8676-8698; https://doi.org/10.3390/ijms16048676
Received: 23 February 2015 / Revised: 2 April 2015 / Accepted: 8 April 2015 / Published: 17 April 2015
Cited by 31 | PDF Full-text (1061 KB) | HTML Full-text | XML Full-text
Abstract
Saliva is a complex body fluid that comprises secretions from the major and minor salivary glands, which are extensively supplied by blood. Therefore, molecules such as proteins, DNA, RNA, etc., present in plasma could be also present in saliva. Many studies have [...] Read more.
Saliva is a complex body fluid that comprises secretions from the major and minor salivary glands, which are extensively supplied by blood. Therefore, molecules such as proteins, DNA, RNA, etc., present in plasma could be also present in saliva. Many studies have reported that saliva body fluid can be useful for discriminating several oral diseases, but also systemic diseases including cancer. Most of these studies revealed messenger RNA (mRNA) and proteomic biomarker signatures rather than specific non-coding RNA (ncRNA) profiles. NcRNAs are emerging as new regulators of diverse biological functions, playing an important role in oncogenesis and tumor progression. Indeed, the small size of these molecules makes them very stable in different body fluids and not as susceptible as mRNAs to degradation by ribonucleases (RNases). Therefore, the development of a non-invasive salivary test, based on ncRNAs profiles, could have a significant applicability to clinical practice, not only by reducing the cost of the health system, but also by benefitting the patient. Here, we summarize the current status and clinical implications of the ncRNAs present in human saliva as a source of biological information. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
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Open AccessReview
Detection of miRNA as Non-Invasive Biomarkers of Colorectal Cancer
Int. J. Mol. Sci. 2015, 16(2), 2810-2823; https://doi.org/10.3390/ijms16022810
Received: 3 November 2014 / Accepted: 15 January 2015 / Published: 27 January 2015
Cited by 36 | PDF Full-text (676 KB) | HTML Full-text | XML Full-text
Abstract
Colorectal Cancer (CRC) is one of the deadliest cancers—ranking as the fourth most common cause of cancer-related deaths in the world. It is such a deadly disease because it is largely asymptomatic until the latter stages—oftentimes when the cancer has metastasized. Thus, a [...] Read more.
Colorectal Cancer (CRC) is one of the deadliest cancers—ranking as the fourth most common cause of cancer-related deaths in the world. It is such a deadly disease because it is largely asymptomatic until the latter stages—oftentimes when the cancer has metastasized. Thus, a huge emphasis of cancer treatment is placed on early detection. Currently, there is a lack of a noninvasive, reliable, and cost-effective screening method for CRC. In recent years, microRNA (miRNA) diagnostic markers have been suggested as a viable new screening method for CRC. miRNAs play an important role in carcinogenesis, and has been observed to be dysregulated in many cancers including CRC. This review examines the diagnostic potential of circulatory and fecal miRNA markers in relation to CRC, as well as current techniques to detect them. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
Open AccessReview
Promoter Hypermethylation of Tumour Suppressor Genes as Potential Biomarkers in Colorectal Cancer
Int. J. Mol. Sci. 2015, 16(2), 2472-2496; https://doi.org/10.3390/ijms16022472
Received: 30 October 2014 / Revised: 2 December 2014 / Accepted: 14 January 2015 / Published: 22 January 2015
Cited by 64 | PDF Full-text (731 KB) | HTML Full-text | XML Full-text
Abstract
Colorectal cancer (CRC) is a common malignancy and the fourth leading cause of cancer deaths worldwide. It results from the accumulation of multiple genetic and epigenetic changes leading to the transformation of colon epithelial cells into invasive adenocarcinomas. In CRC, epigenetic changes, in [...] Read more.
Colorectal cancer (CRC) is a common malignancy and the fourth leading cause of cancer deaths worldwide. It results from the accumulation of multiple genetic and epigenetic changes leading to the transformation of colon epithelial cells into invasive adenocarcinomas. In CRC, epigenetic changes, in particular promoter CpG island methylation, occur more frequently than genetic mutations. Hypermethylation contributes to carcinogenesis by inducing transcriptional silencing or downregulation of tumour suppressor genes and currently, over 600 candidate hypermethylated genes have been identified. Over the past decade, a deeper understanding of epigenetics coupled with technological advances have hinted at the potential of translating benchtop research into biomarkers for clinical use. DNA methylation represents one of the largest bodies of literature in epigenetics, and hence has the highest potential for minimally invasive biomarker development. Most progress has been made in the development of diagnostic markers and there are currently two, one stool-based and one blood-based, biomarkers that are commercially available for diagnostics. Prognostic and predictive methylation markers are still at their infantile stages. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
Open AccessReview
The Promise of Novel Molecular Markers in Bladder Cancer
Int. J. Mol. Sci. 2014, 15(12), 23897-23908; https://doi.org/10.3390/ijms151223897
Received: 18 September 2014 / Revised: 25 November 2014 / Accepted: 11 December 2014 / Published: 22 December 2014
Cited by 18 | PDF Full-text (677 KB) | HTML Full-text | XML Full-text
Abstract
Bladder cancer is the fourth most common malignancy in the US and is associated with the highest cost per patient. A high likelihood of recurrence, mandating stringent surveillance protocols, has made the development of urinary markers a focus of intense pursuit with the [...] Read more.
Bladder cancer is the fourth most common malignancy in the US and is associated with the highest cost per patient. A high likelihood of recurrence, mandating stringent surveillance protocols, has made the development of urinary markers a focus of intense pursuit with the hope of decreasing the burden this disease places on patients and the healthcare system. To date, routine use of markers is not recommended for screening or diagnosis. Interests include the development of a single urinary marker that can be used in place of or as an adjunct to current screening and surveillance techniques, as well identifying a molecular signature for an individual’s disease that can help predict progression, prognosis, and potential therapeutic response. Markers have shown potential value in improving diagnostic accuracy when used as an adjunct to current modalities, risk-stratification of patients that could aid the clinician in determining aggressiveness of surveillance, and allowing for a decrease in invasive surveillance procedures. This review discusses the current understanding of emerging biomarkers, including miRNAs, gene signatures and detection of circulating tumor cells in the blood, and their potential clinical value in bladder cancer diagnosis, as prognostic indicators, and surveillance tools, as well as limitations to their incorporation into medical practice. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
Open AccessReview
Emerging Biomarkers in Heart Failure and Cardiac Cachexia
Int. J. Mol. Sci. 2014, 15(12), 23878-23896; https://doi.org/10.3390/ijms151223878
Received: 8 November 2014 / Revised: 11 December 2014 / Accepted: 11 December 2014 / Published: 22 December 2014
Cited by 20 | PDF Full-text (748 KB) | HTML Full-text | XML Full-text
Abstract
Biomarkers are objective tools with an important role for diagnosis, prognosis and therapy optimization in patients with heart failure (HF). To date, natriuretic peptides are closest to optimal biomarker standards for clinical implications in HF. Therefore, the efforts to identify and test new [...] Read more.
Biomarkers are objective tools with an important role for diagnosis, prognosis and therapy optimization in patients with heart failure (HF). To date, natriuretic peptides are closest to optimal biomarker standards for clinical implications in HF. Therefore, the efforts to identify and test new biomarkers in HF are reasonable and justified. Along the natural history of HF, cardiac cachexia may develop, and once at this stage, patient performance and prognosis is particularly poor. For these reasons, numerous biomarkers reflecting hormonal, inflammatory and oxidative stress pathways have been investigated, but only a few convey relevant information. The complex pathophysiology of HF appears far too complex to be embraced by a single biomarker; thus, a combined approach appears reasonable. With these considerations, we have reviewed the recent developments in the field to highlight key candidates with diagnostic, prognostic and therapy optimization properties, either alone or in combination. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
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Open AccessReview
Circulating RNA Molecules as Biomarkers in Liver Disease
Int. J. Mol. Sci. 2014, 15(10), 17644-17666; https://doi.org/10.3390/ijms151017644
Received: 23 August 2014 / Revised: 4 September 2014 / Accepted: 17 September 2014 / Published: 30 September 2014
Cited by 24 | PDF Full-text (707 KB) | HTML Full-text | XML Full-text
Abstract
Liver disease is a major cause of morbidity and mortality worldwide. As in other fields of medicine, there is a stringent need for non-invasive markers to improve patient diagnostics, monitoring and prognostic ability in liver pathology. Cell-free circulating RNA molecules have been recently [...] Read more.
Liver disease is a major cause of morbidity and mortality worldwide. As in other fields of medicine, there is a stringent need for non-invasive markers to improve patient diagnostics, monitoring and prognostic ability in liver pathology. Cell-free circulating RNA molecules have been recently acknowledged as an important source of potential medical biomarkers. However, many aspects related to the biology of these molecules remain to be elucidated. In this review, we summarize current concepts related to the origin, transportation and possible functions of cell-free RNA. We outline current development of extracellular RNA-based biomarkers in the main forms of non-inherited liver disease: chronic viral hepatitis, hepatocellular carcinoma, non-alcoholic fatty liver, hepato-toxicity, and liver transplantation. Despite recent technological advances, the lack of standardization in the assessment of these markers makes their adoption into clinical practice difficult. We thus finally review the main factors influencing quantification of circulating RNA. These factors should be considered in the reporting and interpretation of current findings, as well as in the proper planning of future studies, to improve reliability and reproducibility of results. Full article
(This article belongs to the Special Issue Emerging Classes of Biomarkers for Molecular Diagnostics)
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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