Applying Data Mining Techniques to Medical Databases

The data mining techniques such as Neural Network, Naïve Bayes, and Association rules are at present not well explored on medical databases. In this paper, we present and analyze our experimental results on thrombosis medical database by employing data mining tool of XLMiner and using different data mining techniques such as Naive Bayes and Neural Network for classification, Association rules, and Neural Network and K-Nearest Neighbors for prediction. As seen from experiments, some results are common across various mining techniques while others are unique

Increased MACC1 levels in tissues and blood identify colon adenoma patients at high risk

Background Colorectal cancer is a preventable disease if caught at early stages. This disease is highly aggressive and has a higher incidence in African Americans. Several biomarkers and mutations of aggressive tumor behavior have been defined such as metastasis-associated in colon cancer 1 (MACC1) that was associated with metastasis in colorectal cancer patients. Here, we aim to assess colon tissue MACC1 protein and circulating MACC1 transcripts in colon preneoplastic and neoplastic African American patients. Methods Patients’ tissue samples (n = 143) have been arranged on three tissue microarrays for normal (n = 26), adenoma (n = 68) and cancer (n = 49) samples. Immunohistochemistry was used to detect MACC1 expression. Blood samples (n = 93) from normal (n = 45), hyperplastic (n = 15) and tubular adenoma (n = 33) patients were used to assess MACC1 transcripts using qRT-PCR. Distribution of continuous variables was tested between different diagnoses with Kruskal–Wallis test. Categorical variables were tested by Chi square test. We assessed the prognostic ability of IHC staining by calculating area under receiver operating characteristics curve (ROC) for adenoma and cancer separately. Differences between groups in terms of MACC1 transcript levels in plasma were calculated by using non-parametric (exact) Wilcoxon-Mann–Whitney tests. We performed all calculations with SPSS, version 21. Results In patient tissues, there was a statistically significant difference in MACC1 expression in normal vs. adenoma samples (p = 0.004) and normal vs. cancer samples (p < 0.001). There was however no major difference in MACC1 expression between adenoma vs. cancer cases or tubular adenomas vs tubulovillous adenomas. The area under the curve for both normal vs. adenoma and normal vs. cancer cases were 70 and 67 %, respectively. MACC1 expression was not correlated to age, gender or anatomical sample location. In patient plasma, MACC1 transcripts in adenoma patients were significantly higher than in plasma from normal patients (p = 0.014). However, the difference between normal and hyperplastic plasma MACC1 transcripts was not statistically significant. Conclusion Metastasis- associated in colon cancer 1 is expressed at early stages of colorectal oncogenesis within the affected colonic tissue in this patient cohort. The plasma transcripts can be used to stratify African American patients at risk for potential malignant colonic lesions

Distinct Genetic Alterations in Colorectal Cancer

Colon cancer (CRC) development often includes chromosomal instability (CIN) leading to amplifications and deletions of large DNA segments. Epidemiological, clinical, and cytogenetic studies showed that there are considerable differences between CRC tumors from African Americans (AAs) and Caucasian patients. In this study, we determined genomic copy number aberrations in sporadic CRC tumors from AAs, in order to investigate possible explanations for the observed disparities.We applied genome-wide array comparative genome hybridization (aCGH) using a 105k chip to identify copy number aberrations in samples from 15 AAs. In addition, we did a population comparative analysis with aCGH data in Caucasians as well as with a widely publicized list of colon cancer genes (CAN genes). There was an average of 20 aberrations per patient with more amplifications than deletions. Analysis of DNA copy number of frequently altered chromosomes revealed that deletions occurred primarily in chromosomes 4, 8 and 18. Chromosomal duplications occurred in more than 50% of cases on chromosomes 7, 8, 13, 20 and X. The CIN profile showed some differences when compared to Caucasian alterations. as the most frequently amplified genes. The observed CIN may play a distinctive role in CRC in AAs

Reduced Representation Bisulfite Sequencing Determination of Distinctive DNA Hypermethylated Genes in the Progression to Colon Cancer in African Americans

Background and Aims. Many studies have focused on the determination of methylated targets in colorectal cancer. However, few analyzed the progressive methylation in the sequence from normal to adenoma and ultimately to malignant tumors. This is of utmost importance especially in populations such as African Americans who generally display aggressive tumors at diagnosis and for whom markers of early neoplasia are needed. We aimed to determine methylated targets in the path to colon cancer in African American patients using Reduced Representation Bisulfite Sequencing (RRBS). Methods. Genomic DNA was isolated from fresh frozen tissues of patients with different colon lesions: normal, a tubular adenoma, a tubulovillous adenoma, and five cancers. RRBS was performed on these DNA samples to identify hypermethylation. Alignment, mapping, and confirmed CpG methylation analyses were performed. Preferential hypermethylated pathways were determined using Ingenuity Pathway Analysis (IPA). Results. We identified hypermethylated CpG sites in the following genes: L3MBTL1, NKX6-2, PREX1, TRAF7, PRDM14, and NEFM with the number of CpG sites being 14, 17, 10, 16, 6, and 6, respectively, after pairwise analysis of normal versus adenoma, adenoma versus cancer, and normal versus cancer. IPA mapped the above-mentioned hypermethylated genes to the Wnt/β-catenin, PI3k/AKT, VEGF, and JAK/STAT3 signaling pathways. Conclusion. This work provides insight into novel differential CpGs hypermethylation sites in colorectal carcinogenesis. Functional analysis of the novel gene targets is needed to confirm their roles in their associated carcinogenic pathways

Distinct High-Profile Methylated Genes in Colorectal Cancer

Background: Mutations and promoters ’ methylation of a set of candidate cancer genes (CAN genes) are associated with progression of colorectal cancer (CRC). We hypothesized that these genes ’ promoters are inactivated through epigenetic silencing and may show a different profile in high-risk populations. We investigated the status of CAN gene methylation and CHD5 protein expression in African American CRC tissue microarrays (TMA) using immunohistochemical staining. Methodology/Principal Findings: The promoter methylation status of the CAN genes was studied by methylation-specific PCR (MSP) in 51 Iranians (a white population) and 51 African Americans (AA). Microsatellite instability (MSI) was analyzed as well. The differential frequency of methylation for each gene was tested by chi-square analysis between the two groups based on matched age and sex. CHD5 protein expression was evaluated in moderate to well differentiated and poorly differentiated carcinomas compared to matched normal tissue using TMA. In addition, the correlation between these epigenetic biomarkers and various clinicopathological factors, including, age, location, and stage of the disease were analyzed. Seventy-seven and 34 % of tumors were distal in Iranian and African American patients, respectively. In both populations, the percentage of methylation was.65 % for SYNE1, MMP2, APC2, GPNMB, EVL, PTPRD, and STARD8, whereas methylation was,50 % for LGR6, RET, CD109, and RNF. The difference in methylation between the two populations was statistically significant for CHD5, ICAM5 and GPNMB. Thirty-one percent AA tumors showed MSI-H, compared to 28 % i

Saffron Crudes and Compounds Restrict MACC1-Dependent Cell Proliferation and Migration of Colorectal Cancer Cells

The high mortality rate of colorectal cancer (CRC) patients is directly associated with metastatic dissemination. However, therapeutic options specifically for metastasis are still limited. We previously identified Metastasis-Associated in Colon Cancer 1 (MACC1) as a major causal metastasis-inducing gene. Numerous studies confirmed its value as a biomarker for metastasis risk. We investigated the inhibitory impact of saffron on MACC1-induced cancer cell growth and motility. Saffron crudes restricted the proliferation and migration of MACC1-expressing CRC cells in a concentration- and MACC1-dependent manner. Saffron delays cell cycle progression at G2/M-phase and does not induce apoptosis. Rescue experiments showed that these effects are reversible. Analysis of active saffron compounds elucidated that crocin was the main compound that reproduced total saffron crudes effects. We showed the interaction of MACC1 with the cancer stem cell (CSC) marker DCLK1, which contributes to metastasis formation in different tumor entities. Saffron extracts reduced DCLK1 with crocin being responsible for this reduction. Saffron's anti-proliferative and anti-migratory effects in MACC1-expressing cells are mediated by crocin through DCLK1 down-regulation. This research is the first identification of saffron-based compounds restricting cancer cell proliferation and motility progression via the novel target MACC1

Helicobacter pylori-induced gastric cancer is orchestrated by MRCK beta-mediated Siah2 phosphorylation

Background Helicobacter pylori-mediated gastric carcinogenesis is initiated by a plethora of signaling events in the infected gastric epithelial cells (GECs). The E3 ubiquitin ligase seven in absentia homolog 2 (Siah2) is induced in GECs in response to H. pylori infection. Posttranslational modifications of Siah2 orchestrate its function as well as stability. The aim of this study was to evaluate Siah2 phosphorylation status under the influence of H. pylori infection and its impact in gastric cancer progression. Methods H. pylori-infected various GECs, gastric tissues from H. pylori-infected GC patients and H. felis-infected C57BL/6 mice were evaluated for Siah2 phosphorylation by western blotting or immunofluorescence microscopy. Coimmunoprecipitation assay followed by mass spectrometry were performed to identify the kinases interacting with Siah2. Phosphorylation sites of Siah2 were identified by using various plasmid constructs generated by site-directed mutagenesis. Proteasome inhibitor MG132 was used to investigate proteasome degradation events. The importance of Siah2 phosphorylation on tumorigenicity of infected cells were detected by using phosphorylation-null mutant and wild type Siah2 stably-transfected cells followed by clonogenicity assay, cell proliferation assay, anchorage-independent growth and transwell invasion assay. Results Siah2 was phosphorylated in H. pylori-infected GECs as well as in metastatic GC tissues at residues serine(6) (Ser(6)) and threonine(279) (Thr(279)). Phosphorylation of Siah2 was mediated by MRCK beta, a Ser/Thr protein kinase. MRCK beta was consistently expressed in uninfected GECs and noncancer gastric tissues but its level decreased in infected GECs as well as in metastatic tissues which had enhanced Siah2 expression. Infected murine gastric tissues showed similar results. MRCK beta could phosphorylate Siah2 but itself got ubiquitinated from this interaction leading to the proteasomal degradation of MRCK beta and use of proteasomal inhibitor MG132 could rescue MRCK beta from Siah2-mediated degradation. Ser(6) and Thr(279) phosphorylated-Siah2 was more stable and tumorigenic than its non-phosphorylated counterpart as revealed by the proliferation, invasion, migration abilities and anchorage-independent growth of stable-transfected cells. Conclusions Increased level of Ser(6) and Thr(279)-phosphorylated-Siah2 and downregulated MRCK beta were prominent histological characteristics of Helicobacter-infected gastric epithelium and metastatic human GC. MRCK beta-dependent Siah2 phosphorylation stabilized Siah2 which promoted anchorage-independent survival and proliferative potential of GECs. Phospho-null mutants of Siah2 (S6A and T279A) showed abated tumorigenicity.Peer reviewe

Role of life events in the presence of colon polyps among African Americans

African Americans have disproportionately higher incidence and death rates of colorectal cancer among all ethnic groups in the United States. Several lifestyle factors (e.g. diet, physical activity and alcohol intake) have been suggested as risk factors for colorectal cancer. Stressful life events have also been identified as risk factors for colorectal cancer. The association between stressful life events and colon polyps, which are precursors of colorectal cancer, has yet to be determined. We aimed to evaluate the relationship between stressful life events and the presence of colon polyps and adenomas in African American men and women. In this cross-sectional study, 110 participants were recruited from a colon cancer screening program at Howard University Hospital. Participants completed an 82-item Life Events Questionnaire (Norbeck 1984), assessing major events that have occurred in the participants’ life within the past 12 months. Participants also reported whether the event had a positive or negative impact. Three scores were derived (total, positive, and negative). Total life events scores were higher (Median [M] = 29 and Interquartile range [IQR] = 18-43) in patients with one or more polyps compared to patients without polyps (M, IQR = 21,13-38; P = 0.029). Total, positive or negative Life Events scores did not differ significantly between normal and adenoma patients. Total, negative and positive Life Events scores did not differ between patients who underwent diagnostic colonoscopy (symptomatic) and patients who underwent colonoscopy for colon cancer screening (asymptomatic) and patients for surveillance colonoscopies due to a personal history of colon polyps. Linear regression analysis indicated that male gender is associated with 9.0 unit lower total Life Events score (P = 0.025). This study suggests that patients who experienced total life events may be at higher risk of having colon polyps and adenomas which indicates an association between stress and the development of colorectal polyps.https://doi.org/10.1186/1471-230X-13-10

Impact of BRAF, MLH1 on the incidence of microsatellite instability high colorectal cancer in populations based study

We have identified an alternative pathway of tumorigenesis in sporadic colon cancer, involving microsatellite instability due to mismatched repair methylation, which may be driven by mutations in the BRAF gene (V600E). Colorectal cancer (CRC) is the most common cancer in the world, and African Americans show a higher incidence than other populations in the United States. We analyzed sporadic CRCs in Omani (of African origin, N = 61), Iranian (of Caucasian origin, N = 53) and African American (N = 95) patients for microsatellite instability, expression status of mismatched repair genes (hMLH1, hMSH2) and presence of the BRAF (V600E) mutation. In the Omani group, all tumors with BRAF mutations were located in the left side of the colon, and for African Americans, 88% [7] of tumors with BRAF mutations were found in the right side of the colon. In African Americans, 31% of tumors displayed microsatellite instability at two or more markers (MSI-H), while this rate was 26% and 13% for tumors in the Iranian and Omani groups, respectively. A majority of these MSI-H tumors were located in the proximal colon (right side) in African American and Iranian subjects, whereas most were located in the distal colon (left side) in Omani subjects. Defects in hMLH1 gene expression were found in 77% of MSI-H tumors in both African Americans and Iranians and in 38% of tumors in Omanis. BRAF mutations were observed in all subjects: 10% of tumors in African Americans (8/82), 2% of tumors in Iranians (1/53), and 19% of tumors in Omanis (11/59). Our findings suggest that CRC occurs at a younger age in Omani and Iranian patients, and these groups showed a lower occurrence of MSI-H than did African American patients. Our multivariate model suggests an important and significant role of hMLH1 expression and BRAF mutation in MSI-H CRC in these populations. The high occurrence of MSI-H tumors in African Americans may have significant implications for treatment, since patients with MSI-H lesions display a different response to chemotherapeutic agents such as 5-fluorouracil