Serum Biomarkers For Early Detection Research Articles

Discovery of a haptoglobin glycopeptides biomarker panel for early diagnosis of hepatocellular carcinoma.

There is a need for new serum biomarkers for early detection of hepatocellular carcinoma (HCC). Haptoglobin (Hp) N-glycosylation is altered in HCC, but the diagnostic value of site-specific Hp glycobiomarkers is rarely reported. We aimed to determine the site-specific glycosylation profile of Hp for early-stage HCC diagnosis. Hp glycosylation was analyzed in the plasma of patients with liver diseases (n=57; controls), early-stage HCC (n=50) and late-stage HCC (n=32). Hp phenotype was determined by immunoblotting. Hp was immunoisolated and digested into peptides. N-glycopeptides were identified and quantified using liquid chromatography-mass spectrometry. Cohort samples were compared using Wilcoxon rank-sum (Mann-Whitney U) tests. Diagnostic performance was assessed using receiver operating characteristic (ROC) curves and area under curve (AUC). Significantly higher fucosylation, branching and sialylation of Hp glycans, and expression of high-mannose glycans, was observed as disease progressed from cirrhosis to early- and late-stage HCC. Several glycopeptides demonstrated high values for early diagnosis of HCC, with an AUC of 93% (n=1), >80% (n=3), >75% (n=13) and >70% (n=11), compared with alpha-fetoprotein (AFP; AUC of 79%). The diagnostic performance of the identified biomarkers was only slightly affected by Hp phenotype. We identified a panel of Hp glycopeptides that are significantly differentially regulated in early- and late-stage HCC. Some glycobiomarkers exceeded the diagnostic value of AFP (the most commonly used biomarker for HCC diagnosis). Our findings provide evidence that glycobiomarkers can be effective in the diagnosis of early HCC - individually, as a panel of glycopeptides or combined with conventional serological biomarkers.

Early transcriptomic signatures and biomarkers of renal damage due to prolonged exposure to embedded metal.

Prolonged exposure to toxic heavy metals leads to deleterious health outcomes including kidney injury. Metal exposure occurs through both environmental pathways including contamination of drinking water sources and from occupational hazards, including the military-unique risks from battlefield injuries resulting in retained metal fragments from bullets and blast debris. One of the key challenges to mitigate health effects in these scenarios is to detect early insult to target organs, such as the kidney, before irreversible damage occurs. High-throughput transcriptomics (HTT) has been recently demonstrated to have high sensitivity and specificity as a rapid and cost-effective assay for detecting tissue toxicity. To better understand the molecular signature of early kidney damage, we performed RNA sequencing (RNA-seq) on renal tissue using a rat model of soft tissue-embedded metal exposure. We then performed small RNA-seq analysis on serum samples from the same animals to identify potential miRNA biomarkers of kidney damage. We found that metals, especially lead and depleted uranium, induce oxidative damage that mainly cause dysregulated mitochondrial gene expression. Utilizing publicly available single-cell RNA-seq datasets, we demonstrate that deep learning-based cell type decomposition effectively identified cells within the kidney that were affected by metal exposure. By combining random forest feature selection and statistical methods, we further identify miRNA-423 as a promising early systemic marker of kidney injury. Our data suggest that combining HTT and deep learning is a promising approach for identifying cell injury in kidney tissue. We propose miRNA-423 as a potential serum biomarker for early detection of kidney injury.

Diagnostic Performance of AFP, AFP-L3, or PIVKA-II for Hepatitis C Virus-Associated Hepatocellular Carcinoma: A Multicenter Analysis.

Background and Aim: Alpha-fetoprotein (AFP), a lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), is a protein that is induced by vitamin K deficiency or antagonist-II (PIVKA-II) that has been clinically used as a serum biomarker for early detection and diagnosis of hepatocellular carcinoma (HCC). Diagnostic performance of each serum biomarker alone, or their combinations for the detection of hepatitis C virus (HCV)-associated HCC were compared. Methods: Serum AFP, AFP-L3, and PIVKA-II levels were evaluated in patients with HCV-associated HCC, and those with chronic HCV infection without HCC (HCV-controls). The areas under the curve (AUC), sensitivity, and specificity were compared to identify the diagnostic performance of each serum HCC biomarker alone or in combination. Results: Overall, 172 HCV controls and 105 patients with HCV-associated HCC were enrolled. The AFP, AFP-L3, and PIVKA-II levels were significantly increased among patients with HCV-associated HCC when compared with HCV patients without HCC (p < 0.001). When these biomarkers were analyzed individually, PIVKA-II revealed the best predictive performance (AUC: PIVKA-II 0.90 vs. AFP 0.80 vs. AFP-L3 0.69, p < 0.001). In evaluating the combinations of any two biomarkers, the best predictive performance was found in PIVKA-II + AFP (0.93 vs. AFP + AFP-L3 0.78, p = 0.001; and PIVKA-II + AFP-L3 0.89, p < 0.001), which had no difference compared to the predictive performance of the combination of all three serum biomarkers (AFP + AFP-L3 + PIVKA-II 0.93, p = 0.277). Similar results were identified in the subgroups of patients with HCV-induced cirrhosis, and among patients with early-stage HCC defined by BCLC and TNM staging. Conclusions: The addition of the PIVKA-II test to routine AFP test maybe provide a more suitable biomarker approach to detect HCV-induced HCC in patients with HCV infection undergoing HCC surveillance.

Serum DSG2 as a potential biomarker for diagnosis of esophageal squamous cell carcinoma and esophagogastric junction adenocarcinoma.

Background: Exploration of serum biomarkers for early detection of upper gastrointestinal cancer is required. Here, we aimed to evaluate the diagnostic potential of serum desmoglein-2 (DSG2) in patients with esophageal squamous cell carcinoma (ESCC) and esophagogastric junction adenocarcinoma (EJA).Methods: Serum DSG2 levels were measured by enzyme-linked immunosorbent assay (ELISA) in 459 participants including 151 patients with ESCC, 96 with EJA, and 212 healthy controls. Receiver operating characteristic (ROC) curves were used to evaluate diagnostic accuracy.Results: Levels of serum DSG2 were significantly higher in patients with ESCC and EJA than those in healthy controls (P<0.001). Detection of serum DSG2 demonstrated an area under the ROC curve (AUC) value of 0.724, sensitivity of 38.1%, and specificity of 84.8% for the diagnosis of ESCC in the training cohort, and AUC 0.736, sensitivity 58.2%, and specificity 84.7% in the validation cohort. For diagnosis of EJA, measurement of DSG2 provided a sensitivity of 29.2%, a specificity of 90.2%, and AUC of 0.698. Similar results were observed for the diagnosis of early-stage ESCC (AUC 0.715 and 0.722, sensitivity 36.3 and 50%, and specificity 84.8 and 84.7%, for training and validation cohorts, respectively) and early-stage EJA (AUC 0.704, sensitivity 44.4%, and specificity 86.9%). Analysis of clinical data indicated that DSG2 levels were significantly associated with patient age and histological grade in ESCC (P<0.05).Conclusion: Serum DSG2 may be a diagnostic biomarker for ESCC and EJA.

Alterations of gut microbiota-derived metabolites in gestational diabetes mellitus and clinical significance.

BackgroundThe change in the characteristics of the gut microbiota is linked to gestational diabetes mellitus (GDM). However, whether and how the gut microbiota‐derived metabolites change in GDM is uncertain. Here, we aimed to determine associations between the gut microbiota‐derived metabolites and GDM.MethodsUsing targeted metabolomics approaches, 7 types of short‐chain fatty acids (SCFAs), 38 types of bile acids (BAs), and 5 types of trimethylamine N‐oxide (TMAO), and its derivatives of serum samples were obtained from pregnant women with GDM (n = 24), and healthy pregnant controls (HC, n = 28) were detected to identify the metabolic signature of GDM to investigate the potential biomarkers. Moreover, we assessed the associations between gut microbiota‐derived metabolites and clinical parameters.ResultsIn our study, the gut microbiota‐derived metabolites signatures were significantly different between GDM and HC. Quantitative results showed the levels of isobutyric acid, isovaleric acid, valeric acid, caproic acid, GUDCA, THDCA + TUDCA, and LCA‐3S were significantly higher in GDM, but the level of TMAO and its derivatives did not change significantly. Some altered gut microbiota‐derived metabolites were significantly correlated with glucose and lipid levels. Receiver‐operating characteristic (ROC) analysis of generalized linear models showed that gut microbiota‐derived metabolites may be potential biomarkers of GDM.ConclusionThis study highlights gut microbiota‐derived metabolites alterations in GDM and correlation of the clinical indicators, which provides a new direction for future studies aiming to novel serum biomarker for early detection or target of drug therapy of GDM.

Integrated Analysis of Super-Enhancer and Secretome Identifies EFNA1 and MMP13 as Potential Serum Biomarkers for Early Detection of Esophageal Squamous Cell Carcinoma

Integrated Analysis of Super-Enhancer and Secretome Identifies EFNA1 and MMP13 as Potential Serum Biomarkers for Early Detection of Esophageal Squamous Cell Carcinoma

Serum Biomarkers for the Prediction of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of global cancer death. Major etiologies of HCC relate to chronic viral infections as well as metabolic conditions. The survival rate of people with HCC is very low and has been attributed to late diagnosis with limited treatment options. Combining ultrasound and the biomarker alpha-fetoprotein (AFP) is currently one of the most widely used screening combinations for HCC. However, the clinical utility of AFP is controversial, and the frequency and operator-dependence of ultrasound lead to a variable degree of sensitivity and specificity across the globe. In this review, we summarize recent developments in the search for non-invasive serum biomarkers for early detection of HCC to improve prognosis and outcome for patients. We focus on tumor-associated protein markers, immune mediators (cytokines and chemokines), and micro-RNAs in serum or circulating extracellular vesicles and examine their potential for clinical application.

Serum angiogenin as a potential biomarker for early detection of colorectal adenomas and colorectal cancer.

Although colorectal cancer (CRC) is one of the most common causes of cancer mortality, early-stage detection dramatically improves survival rate. To explore the feasibility of serum angiogenin (ANG) as a biomarker for early detection of colorectal neoplasia, we collected serum samples from 781 participants, including 369 patients with CRC, 133 with colorectal adenoma and 279 healthy controls. We examined the levels of serum ANG by ELISA, calculated the diagnostic accuracy of ANG by plotted receiver operating characteristic curves (ROCs), and compared it with those obtained by carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). We also analyzed the relationship between serum ANG level and TNM stage in CRC patients. The results showed that ANG serum levels were significantly elevated in patients with colorectal adenomas and CRC (P < 0.01). The area under the ROC curve (AUC) for ANG in distinguishing CRC patients from healthy controls was 0.740 [95% confidence interval (CI): 0.705-0.744], comparable to that of CEA (0.770; 95% CI: 0.735-0.802; P = 0.26) but significantly higher than that of CA19-9 (0.636; 95% CI: 0.598-0.674, P < 0.01), with much higher sensitivity (67.75%) than CEA (36.86%) or CA19-9 (12.20%). We observed no significant differences in ANG serum levels among CRCs at different TNM stages. Furthermore, sensitivity and specificity of ANG for distinguishing colorectal adenomas patients from healthy controls were 66.20% and 64.90%, respectively. ANG has the potential to serve as a serum biomarker for early detection of colorectal neoplasia.

Circulating Levels of L1-cell Adhesion Molecule as a Serum Biomarker for Early Detection of Gastric Cancer and Esophagogastric Junction Adenocarcinoma.

Background: Low serum L1 cell adhesion molecule (L1CAM) has been found in several malignant tumors. Here, we aimed to evaluate the diagnostic potential for serum L1CAM in patients with gastric cancers (GC) and esophagogastric junction adenocarcinoma (EJA).Methods: Enzyme-linked immunosorbent assay (ELISA) was carried out to detect L1CAM level in sera of 148 GC patients, 59 EJA patients and 148 healthy controls. Receiver operating characteristics (ROC) was employed to evaluate diagnostic accuracy.Results: The concentrations of serum L1CAM were significantly lower in GC and EJA than those in healthy controls (P<0.001). Detection of L1CAM provided a sensitivity of 83.1%, a specificity of 62.2%, and an area under the curve (AUC) of 0.769 (95% CI: 0.715-0.823) in diagnosing GC, and a sensitivity of 66.1%, a specificity of 62.2%, and an AUC of 0.672 (95% CI: 0.590-0.755) in diagnosing EJA. Similar results were observed in the diagnosis of early-stage GC (0.681 (95%CI: 0.596-0.766)) and early-stage EJA (0.674 (95%CI: 0.528-0.820)). Analysis of clinical data showed that the levels of L1CAM were significantly associated with lymph node metastasis in GC (P<0.05).Conclusions: Our study showed that serum L1CAM might be a diagnostic biomarker for GC and EJA.

An Efficient Diagnostic Model Combined with Novel Serum Biomarkers for Early Detection of Steroid-Induced Osteonecrosis of the Femoral Head

Steroid-induced osteonecrosis of the femoral head (SONFH) is difficult to be diagnosed at the early stages when it can be administrated effectively. Yet, to date no study has been performed to identify diagnostic biomarkers and to develop diagnostic models for SONFH. In the current study, a total of 60 SONFH patients with Association Research Circulation Osseous (ARCO) stages I-IV, and 20 controls were enrolled and divided into the discovery and validation cohorts. The serum samples were collected and the gene expression profiles were detected by microarray analysis based on the discovery cohort. Then, eight genes (BIRC3, CBL, CCR5, LYN, PAK1, PTEN, RAF1 and TLR4) were identified as the candidate serum biomarkers of SONFH due to the significant differential expression patterns and the topological importance in the interaction network of SONFH-related differentially expressed genes. Functionally, these candidate serum biomarkers were significantly involved into several pathological processes during SONFH progression, such as the immune regulation and inflammation, bone metabolism and angiogenesis. After that, a prediction model for the early diagnosis of SONFH was constructed using Partial least squares regression based on the serum levels of the candidate biomarkers. Notably, both the 10-fold cross-validation and the independent dataset test demonstrated the good performance of this model. In conclusion, our study identified eight promising serum biomarkers and developed the circulating gene-based prediction model as a new, efficient and non-invasive diagnostic tool for the early detection of SONFH, as well as benefit the administration of SONFH in a daily clinical setting. Funding Statement: This study is funded by National Natural Science Foundation of China (No 81373656 & 81473695). Declaration of Interests: The authors declare that there is no conflict of interests regarding the publication of this paper. Ethics Approval Statement: The study was approved by the Research Ethics Committee of Institute of Chinese Materia Medica, Wangjing Hospital, China (SFDA approval number: 81473695). The informed consent was obtained from all patients.

Amplified visual detection of microRNA-378 through a T4 DNA ligase-mediated circular template specific to target and target-triggering rolling circle amplification

MicroRNA-378 (miRNA-378) is widely regarded as a novel noninvasive serum biomarker for early detection of gastric cancer.

MicroRNAs as Potential Serum Biomarkers for Early Detection of Ectopic Pregnancy.

Diagnosis of ectopic pregnancy relies on both ultrasound findings and human chorionic gonadotropin (hCG) measurements but due to the need for serial tests, tubal rupture and death represent major maternal and fetal risks. Early detection of ectopic pregnancy is essential and thus a noninvasive diagnostic tool seems crucial for the prevention of adverse effects since studies suggest there is a specific relationship between ectopic pregnancy and increasing microRNA factors. Human fluids in women with ectopic pregnancy reveal a particular change in comparison to healthy women. In addition to certain placental microRNAs circulating through plasma that present a specific concentration and serum profile, microRNAs seem to be possible biomarkers for the detection of pregnancy complications linked to placental pathologies. The aim of this study is to review current literature considering the expression levels of several circulating microRNAs that have shown to be novel potential biomarkers for the diagnosis of tubal ectopic pregnancy.

Apelin: A potential novel serum biomarker for early detection of diabetic nephropathy in patients with type 2 diabetes.

OBJECTIVE:Diabetic nephropathy (DN) is the major cause of chronic renal failure, and proteinuria is an independent risk factor for the end stage renal disease. The random urine protein: creatinine ratio (P:C ratio) can accurately predict the amount of 24-hour urinary protein excretion. Apelin is thought to be associated with endothelial dysfunction, angiogenesis, and inflammation. This study investigated the apelin concentration and its association with the urine P:C ratio, and metabolic parameters in subjects with and without type 2 diabetes mellitus (T2D).METHODS:This study involved 86 subjects: 56 with newly diagnosed and untreated T2D and 30 non-diabetic controls. All subjects underwent a complete clinical examination that included anthropometric and laboratory measurements.RESULTS:Twenty-four males and sixty-two females participated in this study, and their mean age was 52.27±11.34 years. There were no differences in age, thyrotropin-stimulating hormone (TSH), creatinine clearance, and apelin levels between groups. As expected, fasting plasma glucose, weight, body mass index, and HbA1C were higher in T2D subjects (p=0.001, p=0.02, p=0.03, and p=0.001, respectively). Although apelin levels were higher in the control group, the differences were not statistically significant (p=0.93). The P:C ratio levels were lower in the control group, and the differences were statistically significant (p=0.006). A Spearman correlation analysis revealed that serum apelin levels were not correlated with the urine P:C ratio.CONCLUSION:Our study demonstrates that T2D is associated with decreased serum apelin levels and increased urine P:C ratios compared to those in non-diabetic subjects. This association may depend on impaired glucose homeostasis. Our results show that the serum apelin levels were not correlated with the urine protein: creatinine ratio and provide further evidence regarding the relationship between apelin and DN.

O6-Methyguanine-DNA Methyl Transferase (MGMT) Promoter Methylation in Serum DNA of Iranian Patients with Colorectal Cancer

Introduction:Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide but current molecular targeted therapy is not providing major success in CRC treatment, so early detection by non-invasive methods continues to be vital. Aberrant methylation of CpG islands in promoter regions is associated with inactivation of various tumor suppressor genes. O6-methyguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that removes mutagenic and cytotoxic adducts from O6-guanine in DNA. Aberrant hypermethylation of the MGMT promoter has been associated with lack of mRNA expression, with concomitant loss of protein content and enzyme activity.AIM:Our aim was to determine whether MGMT promoter methylation might be detectable in circulating free DNA in the serum of CRC patients and normal individuals using a methylation specific (MSP) polymerase chain reaction (PCR) method.Methods:A total of 70 subjects were enrolled in the study. Of these, 30 patients who were diagnosed previously as untreated colon adenocarcinoma by a gastroenterologist and the other 40 were nearly age-matched individuals who had a normal colonoscopic evaluation (except for hemorrhoids or fissures) and normal pathologic reports. After bisulphite modification of DNA, serum samples were examined for MGMT promoter methylation using MSP.Results:Ninety percent of CRC patients had MGMT promoter hypermethylation as compared to no methylation in normal subjects’ serum. Most of the cancers were stage П and moderately differentiated adenocarcinomas; nearly 60% were found in the left colon. No statistically significant correlation was found between the promoter methylation status and gender and age.Discussion and Conclusions:MGMT hypermethylation can be detected in free circulating DNA in serum of CRC patients and can be used “as a clinical biomarker” for early diagnosis and prognostic assessment of the disease. Our data confirm previous studies indicating utility for free circulating DNA as a serum biomarker for early detection, diagnosis and monitoring of CRC patients.

Potential serum biomarkers for early detection of diabetic nephropathy

AimDiabetic nephropathy (DN) is considered as one of the diabetic complications affecting up to 40% of patients with type 1 or type 2 diabetes. In clinical practice, the frequently used markers of renal disease and progression are serum creatinine, estimated glomerular filtration rate (eGFR) and albuminuria. The aim of this study is to determine new biomarkers in human serum which are promising for early detection of DN. MethodsThis study included 50 patients with type 2 diabetes mellitus (T2DM) and 25 clinically healthy individuals. The patients were divided into two groups; group I included 25 T2DM patients with normoalbuminuria, and group II consisted of 25 T2DM patients with microalbuminuria. In all groups, neutrophil gelatinase-associated lipocalin (NGAL), β-trace protein (βTP) and microRNA- 130b (miR-130b) were estimated. ResultsThe serum levels of NGAL and βTP were significantly elevated in T2DM patients with microalbuminuria (group II) compared with T2DM patients with normoalbuminuria (group I) and control subjects but there was no significant difference between group I and control subjects. Serum miR-130b level was significantly decreased in patients with T2DM (groups I and II) compared with healthy control subjects, with a higher decrease in their levels in group II compared with group I. ConclusionOur results suggest that serum NGAL and βTP as tubular and glomerular markers respectively, together with serum miR-130b may be independent and reliable biomarkers for early detection of DN in patients with T2DM.

ERBB3: A potential serum biomarker for early detection and therapeutic target for devil facial tumour 1 (DFT1).

Devil Facial Tumour 1 (DFT1) is one of two transmissible neoplasms of Tasmanian devils (Sarcophilus harrisii) predominantly affecting their facial regions. DFT1’s cellular origin is that of Schwann cell lineage where lesions are evident macroscopically late in the disease. Conversely, the pre-clinical timeframe from cellular transmission to appearance of DFT1 remains uncertain demonstrating the importance of an effective pre-clinical biomarker. We show that ERBB3, a marker expressed normally by the developing neural crest and Schwann cells, is immunohistohemically expressed by DFT1, therefore the potential of ERBB3 as a biomarker was explored. Under the hypothesis that serum ERBB3 levels may increase as DFT1 invades local and distant tissues our pilot study determined serum ERBB3 levels in normal Tasmanian devils and Tasmanian devils with DFT1. Compared to the baseline serum ERBB3 levels in unaffected Tasmanian devils, Tasmanian devils with DFT1 showed significant elevation of serum ERBB3 levels. Interestingly Tasmanian devils with cutaneous lymphoma (CL) also showed elevation of serum ERBB3 levels when compared to the baseline serum levels of Tasmanian devils without DFT1. Thus, elevated serum ERBB3 levels in otherwise healthy looking devils could predict possible DFT1 or CL in captive or wild devil populations and would have implications on the management, welfare and survival of Tasmanian devils. ERBB3 is also a therapeutic target and therefore the potential exists to consider modes of administration that may eradicate DFT1 from the wild.

Testing breast cancer serum biomarkers for early detection and prognosis in pre-diagnosis samples

Background:Breast cancer is a leading cause of morbidity and mortality worldwide. Although mammography screening is available, there is an ongoing interest in improved early detection and prognosis. Herein, we have analysed a combination of serological biomarkers in a case–control cohort of sera taken before diagnosis.Methods:This nested case–control study within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) used serum samples from 239 women who subsequently developed breast cancer and 239 matched cancer-free controls. Sera were screened by ELISA for 9 candidate markers. Univariate and multivariate analyses were performed to examine associations with clinico-pathological features and between case controls in different time groups before diagnosis.Results:Significant associations with clinico-pathological features related to prognosis were found for several candidates (CA15-3, HSP90A and PAI-1). However, there were no consistent differences between cases and controls for any candidate in the lead up to diagnosis. Whilst combination models outperformed single markers, there was no increase in performance towards diagnosis.Conclusions:This study using unique pre-diagnosis samples shows that CA15-3, HSP90A and PAI-1 have potential as early prognostic markers and warrant further investigation. However, none of the candidates or combinations would be useful for screening.

Exosomal miRs in Lung Cancer: A Mathematical Model

Lung cancer, primarily non-small-cell lung cancer (NSCLC), is the leading cause of cancer deaths in the United States and worldwide. While early detection significantly improves five-year survival, there are no reliable diagnostic tools for early detection. Several exosomal microRNAs (miRs) are overexpressed in NSCLC, and have been suggested as potential biomarkers for early detection. The present paper develops a mathematical model for early stage of NSCLC with emphasis on the role of the three highest overexpressed miRs, namely miR-21, miR-205 and miR-155. Simulations of the model provide quantitative relationships between the tumor volume and the total mass of each of the above miRs in the tumor. Because of the positive correlation between these miRs in the tumor tissue and in the blood, the results of the paper may be viewed as a first step toward establishing a combination of miRs 21, 205, 155 and possibly other miRs as serum biomarkers for early detection of NSCLC.

Exosomal microRNA concentrations in colorectal cancer: A mathematical model

Colorectal cancer (CRC) is the second leading cause of cancer related deaths in the United States. Early detection increases survival very significantly. Indeed, five year survival for people diagnosed at stage I-II is 90%, while for those diagnosed at stage IV it is only 13%. The gold standard for early detection is colonoscopy, but this procedure is limited due to its invasive nature and its high cost. Hence there is a need to identify non-invasive biomarkers for CRC. Exosomal miRs secreted by cancer cells and overexpressed in the blood have been suggested as biomarkers for cancer. In particular, exosomal miRs 21, 23a, 92a and 1246 are overexpressed in CRC, and thus have the potential to be used as serum biomarkers for early detection of the disease. The present paper develops for the first time a mathematical model for early stage of CRC which includes the effect of these miRs on the growth of the cancer. The model is represented by a system of partial differential equations. Simulations of the model show a relationship between the growth of the tumor diameter and the total mass of these miRs under some of the common mutations which occur in CRC, namely, KRAS, PI3K, APC, p53 and SMAD mutations. The model may serve as a step toward establishing miRs 21, 23a, 92a and 1246 as reliable blood biomarkers for CRC as more experimental results and clinical data become available.

Abstract 2838: TP53 autoantibody can detect CA125 screen negative ovarian cancer cases and can be elevated prior to CA125 in preclinical ovarian cancer

Abstract Detection of ovarian cancer in early stage could improve mortality from the disease by 10-30%. Most attempts to utilize serum biomarkers for early detection of ovarian cancer have focused on CA125. As CA125 is expressed by only 80% of ovarian cancers, multiple biomarkers will be required to detect ovarian cancers that fail to express the antigen. In studies with preclinical samples to date, no biomarker has been consistently elevated prior to CA125. Detecting an autologous immune response to tumor associated antigens might provide improved lead time. TP53 is mutated and overexpressed in virtually all high grade serous ovarian cancers. Autoantibodies reactive with wtTP53 have been reported in approximately 15% of ovarian cancers at the time of conventional diagnosis, but most reports have studied a limited number of cases and preclinical sera have not previously been tested. We have developed a novel immunoassay for quantitating TP53-specific autoantibody (AAb) in small volumes (2 uL) of serum. Samples from the MD Anderson Cancer Center Tissue Bank (MDACC), the MDACC Ovarian SPORE NROS screening study, the Australian Ovarian Cancer Study (AOCS) and the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) were used for discovery and validation. Assay cut-offs were determined by including less than 2% false positive samples in each control group (98% specificity of the assay). Elevated titers of TP53 AAb were detected in 13 of 50 sera (26%) from MDACC patients with stage III-IV ovarian cancer and in 4 of 216 sera (1.9%) from healthy controls from the NROS study. Using the same cut-off we detected TP53 AAb in 28 of 108 cases (25.9%), 7 of 109 benign controls (6.4%) and 10 of 464 normal controls (2.1%) from the AOCS study. TP53 AAb was found in 3 of 12 cases (25.0%) in early stage (I/II) and 22 of 90 cases (24.4%) in late stage (III/IV). To further validate the result in the AOCS, we analyzed 2,471 serial serum samples from the UKCTOCS trial. Elevated TP53 AAb was found in 18 of 87 cases (20.7%) and 8 of 435 normal controls (1.8%). Increased titers were detected in 6 of 32 cases (18.8%) in early stage and 12 of 55 cases (21.8%) in late stage. Positivity was found in 11 of 49 cases (22.5%) detected with rising CA125 and 7 of 38 (18.4%) cases not detected with rising CA125. TP53 AAb titers rose prior to CA125 in 7 of 11 cases (63.6%). In 11 TP53 AAb (+) and CA125 (-) cases, TP53 AAb titers rose a mean of 13.5 months and a median of 5 months prior to CA125. In 7 TP53 AAb (+) and CA125 (-) cases, titers rose a mean of 33 months and a median of 29 months prior to cancer diagnosis. Consequently, quantitative assessment of TP53 AAb titers holds promise for earlier detection of ovarian cancer in combination with CA125. Citation Format: Wei-Lei Yang, Archana Simmons, Zhen Lu, Keith Baggerly, Karen Lu, Alex Gentry-Maharaj, Usha Menon, Ian Jacobs, Robert C. Bast. TP53 autoantibody can detect CA125 screen negative ovarian cancer cases and can be elevated prior to CA125 in preclinical ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2838. doi:10.1158/1538-7445.AM2015-2838