RESUMO
In line with the aims of the Chromosome-based Human Proteome Project and the Biology/Disease-based Human Proteome Project, we have been studying differentially expressed transcripts and proteins in gliomasthe most prevalent primary brain tumors. Here, we present a perspective on important insights from this analysis in terms of their co-expression, co-regulation/de-regulation, and co-localization on chromosome 12 (Chr. 12). We observe the following: (1) Over-expression of genes mapping onto amplicon regions of chromosomes may be considered as a biological validation of mass spectrometry data. (2) Their co-localization further suggests common determinants of co-expression and co-regulation of these clusters. (3) Co-localization of "missing" protein genes of Chr. 12 in close proximity to functionally related genes may help in predicting their functions. (4) Further, integrating differentially expressed gene-protein sets and their ontologies with medical terms associated with clinical phenotypes in a chromosome-centric manner reveals a network of genes, diseases, and pathwaysa diseasome network. Thus, chromosomal mapping of disease data sets can help uncover important regulatory and functional links that may offer new insights for biomarker development.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 12 , Predisposição Genética para Doença , Neoplasias Encefálicas/genética , Glioma/genética , Humanos , Proteínas de Neoplasias/genéticaRESUMO
Diffuse astrocytoma (DA; WHO grade II) is a low-grade, primary brain neoplasm with high potential of recurrence as higher grade malignant form. We have analyzed differentially expressed membrane proteins from these tumors, using high-resolution mass spectrometry. A total of 2803 proteins were identified, 340 of them differentially expressed with minimum of 2 fold change and based on ≥2 unique peptides. Bioinformatics analysis of this dataset also revealed important molecular networks and pathways relevant to tumorigenesis, mTOR signaling pathway being a major pathway identified. Comparison of 340 differentially expressed proteins with the transcript data from Grade II diffuse astrocytomas reported earlier, revealed about 190 of the proteins correlate in their trends in expression. Considering progressive and recurrent nature of these tumors, we have mapped the differentially expressed proteins for their secretory potential, integrated the resulting list with similar list of proteins from anaplastic astrocytoma (WHO Grade III) tumors and provide a panel of proteins along with their proteotypic peptides, as a resource that would be useful for investigation as circulatory plasma markers for post-treatment surveillance of DA patients.
Assuntos
Astrocitoma/genética , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Recidiva Local de Neoplasia/genética , Proteoma/genética , Adulto , Sequência de Aminoácidos , Astrocitoma/metabolismo , Astrocitoma/patologia , Astrocitoma/cirurgia , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos de Casos e Controles , Biologia Computacional , Feminino , Perfilação da Expressão Gênica , Humanos , Membranas Intracelulares/química , Membranas Intracelulares/patologia , Masculino , Microssomos/química , Microssomos/patologia , Anotação de Sequência Molecular , Gradação de Tumores , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Proteoma/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
AIM: To evaluate the association of known copy number variations (CNVs) in ulcerative colitis (UC) progressing to colorectal cancer. METHODS: Microsatellite instability analysis using the National Cancer Institute's panel of markers, and CNV association studies using Agilent 2 × 105 k arrays were done in tissue samples from four patient groups with UC: those at low risk (LR) or high risk of developing colorectal cancer, those with premalignant dysplastic lesions, and those with colitis-associated colorectal cancer (CAC). DNA from tissue samples of these groups were independently hybridized on arrays and analyzed. The data obtained were further subjected to downstream bioinformatics enrichment analysis to examine the correlation with CAC progression. RESULTS: Microarray analysis highlighted a progressive increase in the total number of CNVs [LR (n = 178) vs CAC (n = 958), 5.3-fold], gains and losses [LR (n = 37 and 141) vs CAC (n = 495 and 463), 13.4- and 3.3-fold, respectively], size [LR (964.2 kb) vs CAC (10540 kb), 10.9-fold] and the number of genes in such regions [LR (n = 119) vs CAC (n = 455), 3.8-fold]. Chromosome-wise analysis of CNVs also showed an increase in the number of CNVs across each chromosome. There were 38 genes common to all four groups in the study; 13 of these were common to cancer genes from the Genetic Disease Association dataset. The gene set enrichment analysis and ontology analysis highlighted many cancer-associated genes. All the samples in the different groups were microsatellite stable. CONCLUSION: Increasing numbers of CNVs are associated with the progression of UC to CAC, and warrant further detailed exploration.
Assuntos
Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Colite Ulcerativa/genética , Neoplasias Colorretais/genética , Variações do Número de Cópias de DNA , Lesões Pré-Cancerosas/genética , Adulto , Colite Ulcerativa/diagnóstico , Neoplasias Colorretais/diagnóstico , Biologia Computacional , Bases de Dados Genéticas , Progressão da Doença , Feminino , Perfilação da Expressão Gênica/métodos , Predisposição Genética para Doença , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Lesões Pré-Cancerosas/diagnóstico , Prognóstico , Fatores de RiscoRESUMO
BACKGROUND AND AIM: Longstanding ulcerative colitis (UC) predisposes to colorectal cancer (CRC). To understand the molecular pathogenesis of colitis-associated colorectal neoplasia (UC-CRN), we studied the frequency of microsatellite instability (MSI) and mutations in p53, BRAF and KRAS genes in the tissues of patients with long standing UC with or without neoplasia and compared them with colitis patients without risk of neoplasia, and those with sporadic colorectal neoplasia (S-CRN) in an area with lower prevalence for either disease. METHODS: Biopsies were obtained during magnifying chromo colonoscopy or routine colonoscopy in consecutive UC patients with high risk (UC-HR) and low risk (UC-LR) of neoplasia, and those with S-CRN. MSI (NCI-Bethesda panel) and mutations in p53, KRAS and BRAF genes were analysed. RESULTS: Twenty-eight patients with UC-HR, 30 with UC-LR and 30 with S-CRN were included. Six (21.4%) of UC-HR had neoplasia (Progressors). MSI was not detected in the UC-CRN group as compared to 5 (16.7%) in the S-CRN group. p53 mutations occurred in 1 (3.3%) of UC-LR, increasing to 6 (27.3%, P<0.05) and 3 (50%, P<0.05) in the UC-HR subgroups without and with neoplasia respectively, as against 10 (33.3%) in sporadic neoplasia group. KRAS mutations were found only in the presence of neoplasia. None showed the BRAF mutation. CONCLUSIONS: In a population with a lower prevalence for UC and CRC, the molecular pathogenesis of colitis-associated colorectal neoplasia is comparable to that reported from areas with a higher prevalence of these diseases, MSI being an exception.
Assuntos
Adenocarcinoma/genética , Adenoma/genética , Biomarcadores Tumorais/genética , Colite Ulcerativa/genética , Colonoscopia , Neoplasias Colorretais/genética , Adenocarcinoma/epidemiologia , Adenocarcinoma/etiologia , Adenocarcinoma/patologia , Adenoma/epidemiologia , Adenoma/etiologia , Adenoma/patologia , Adulto , Colite Ulcerativa/complicações , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/patologia , Colonoscopia/métodos , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Progressão da Doença , Feminino , Genes p53 , Marcadores Genéticos , Humanos , Índia/epidemiologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prevalência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Risco , Proteínas ras/genéticaRESUMO
AIM: Undernutrition is considered to be a cause of tropical pancreatitis (TP) since this disease is commonly seen in the underprivileged populations of the world. This study was done to compare the nutritional status in patients with TP and alcoholic chronic pancreatitis (ACP) using anthropometric measurements. METHODS: Anthropometric measurements were done in patients with TP and ACP aged >18 years and matched healthy controls. Presence of pain, recent dietary restriction, diabetes mellitus (DM), calcification, serum prealbumin (PAB), and quantitative fecal elastase (FE) was assessed. Premorbid body mass index (BMI) was determined from weight before the onset of illness as reported by the patients. RESULTS: Of 54 patients (47 male), 39 (72.2%) had TP and the rest had ACP. Patients with TP were younger than those with ACP; the frequency of pain, DM, calcification, and exocrine insufficiency was similar in the two groups. Compared to control subjects, patients had lower BMI, triceps skin fold thickness (TSFT) and mid-arm circumference (MAC) (p < 0.01), but waist-to-hip ratio (W/H) was similar. Undernutrition was equally common in TP and ACP (15 [38.5%] vs. 6 [40%]). The BMI, TSFT, MAC, and W/H were similar in TP and ACP. The premorbid BMI was higher than that at presentation (20.2 [3.8] kg/m² vs. 19.1 [3.3] kg/m², p < 0.01). There was no association between BMI and features contributing to undernutrition (DM, pain, recent dietary restriction, FE level, and calcification) on univariate analysis. CONCLUSIONS: Energy undernutrition occurs equally commonly in TP and ACP and this appears to develop after the onset of illness.