Genome-wide copy number alterations in subtypes of invasive breast cancers in young white and African American women.

Genomic copy number alterations (CNA) are common in breast cancer. Identifying characteristic CNAs associated with specific breast cancer subtypes is a critical step in defining potential mechanisms of disease initiation and progression. We used genome-wide array comparative genomic hybridization to identify distinctive CNAs in breast cancer subtypes from 259 young (diagnosed with breast cancer at 40%) for TN breast tumors at 10q, 11p, 11q, 16q, 20p, and 20q. In addition, we report CNAs that differ in frequency between TN breast tumors of AA and CA women. This is of particular relevance because TN breast cancer is associated with higher mortality and young AA women have higher rates of TN breast tumors compared to CA women. These data support the possibility that higher overall frequency of genomic alteration events as well as specific focal CNAs in TN breast tumors might contribute in part to the poor breast cancer prognosis for young AA women

Supplementary Data Only: Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network.

The Myc/Max/Mad transcription factor network is critically involved in cell behavior; however, there is relatively little information on its genomic binding sites. We have employed the DamID method to carry out global genomic mapping of the Drosophila Myc, Max, and Mad/Mnt proteins. Each protein was tethered to Escherichia coli DNA adenine-methyltransferase (Dam) permitting methylation proximal to in vivo binding sites in Kc cells. Microarray analyses of methylated DNA fragments reveals binding to multiple loci on all major Drosophila chromosomes. This approach also reveals dynamic interactions among network members as we find that increased levels of dMax influence the extent of dMyc, but not dMnt, binding. Computer analysis using the REDUCE algorithm demonstrates that binding regions correlate with the presence of E-boxes, CG repeats, and other sequence motifs. The surprisingly large number of directly bound loci ( approximately 15% of coding regions) suggests that the network interacts widely with the genome. Furthermore, we employ microarray expression analysis to demonstrate that hundreds of DamID-binding loci correspond to genes whose expression is directly regulated by dMyc in larvae. These results suggest that a fundamental aspect of Max network function involves widespread binding and regulation of gene expression

cis-Expression QTL Analysis of Established Colorectal Cancer Risk Variants in Colon Tumors and Adjacent Normal Tissue

Genome-wide association studies (GWAS) have identified 19 risk variants associated with colorectal cancer. As most of these risk variants reside outside the coding regions of genes, we conducted cis-expression quantitative trait loci (cis-eQTL) analyses to investigate possible regulatory functions on the expression of neighboring genes. Forty microsatellite stable and CpG island methylator phenotype-negative colorectal tumors and paired adjacent normal colon tissues were used for genome-wide SNP and gene expression profiling. We found that three risk variants (rs10795668, rs4444235 and rs9929218, using near perfect proxies rs706771, rs11623717 and rs2059252, respectively) were significantly associated (FDR q-value ≤0.05) with expression levels of nearby genes (<2 Mb up- or down-stream). We observed an association between the low colorectal cancer risk allele (A) for rs10795668 at 10p14 and increased expression of ATP5C1 (q = 0.024) and between the colorectal cancer high risk allele (C) for rs4444235 at 14q22.2 and increased expression of DLGAP5 (q = 0.041), both in tumor samples. The colorectal cancer low risk allele (A) for rs9929218 at 16q22.1 was associated with a significant decrease in expression of both NOL3 (q = 0.017) and DDX28 (q = 0.046) in the adjacent normal colon tissue samples. Of the four genes, DLGAP5 and NOL3 have been previously reported to play a role in colon carcinogenesis and ATP5C1 and DDX28 are mitochondrial proteins involved in cellular metabolism and division, respectively. The combination of GWAS findings, prior functional studies, and the cis-eQTL analyses described here suggest putative functional activities for three of the colorectal cancer GWAS identified risk loci as regulating the expression of neighboring genes

Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A

The genetic basis of sporadic colorectal cancer (CRC) is not well explained by known risk polymorphisms. Here we perform a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, to identify genetic variants that contribute to CRC susceptibility. We replicate genome-wide statistically significant associations (P < 5×10−8) in 16,823 cases and 18,211 controls of European ancestry. This study reveals a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P=1.4×10−9), providing additional insight into the etiology of CRC and highlighting the value of association mapping in diverse populations

pp60src-mediated phosphorylation of connexin43, a gap junction protein

Thesis (Ph. D.)--University of Hawaii at Manoa, 1995.Includes bibliographical references (leaves 76-93).Microfiche.vii, 93 leaves, bound ill. (some col.) 29 cmSeveral laboratories have demonstrated a decrease in gap junctional communication in cells transformed by the src oncogene of the Rous sarcoma virus. The decrease In gap junctional communication was associated with tyrosine phosphorylation of the gap junction protein, connexin43 (Cx43). This study was initiated to determine if the phosphorylation of Cx43 is the result of a direct kinase-substrate interaction between the highly active tyrosine kinase, pp60v-src, and Cx43. Confocal microscopy data indicates that the two proteins are within physical proximity allowing for a potential kinase-substrate interaction. Previous biochemical studies have been limited by the low levels of Cx43 protein in fibroblast cell lines. To obtain larger quantities of Cx43 we constructed a recombinant baculovirus expressing Cx43 in Spodoptera frugiperda (Sf-9) cells and subsequently purified the expressed Cx43 by immunoaffinity chromatography. We observed that this partially-purified Cx43 was phosphorylated on tyrosine in vitro in the presence of kinase-active pp60src. Phosphotryptic peptide mapping indicated that the in vitro phosphorylated Cx43 contained phosphopeptides which comigrated with a subset of tryptic peptides prepared from Cx43 phosphorylated in vivo. This phosphorylation event occurred in the COOH-tail region of the Cx43 molecule because pp60src phosphorylated a GST-fusion protein containing the COOH-tail region of Cx43 and the phosphotryptic peptides generated using this construct comigrated with the subset mentioned above. Furthermore, coinfection of Sf-9 cells with recombinant baculoviruses encoding pp60v-src and Cx43 resulted in the accumulation of phosphotyrosine in Cx43. Taken together, the evidence presented in this dissertation demonstrates that kinase active pp60src is capable of phosphorylating Cx43 In a direct manner. Since the presence of phosphotyrosine on Cx43 is correlated with the down regulation of gap-junctional communication, these results suggest that pp60v-src regulates gap junctional gating activity via tyrosine phosphorylation of Cx43

In silico pathway analysis and tissue specific cis-eQTL for colorectal cancer GWAS risk variants

Abstract Background Genome-wide association studies have identified 55 genetic variants associated with colorectal cancer risk to date. However, potential causal genes and pathways regulated by these risk variants remain to be characterized. Therefore, we performed gene ontology enrichment and pathway analyses to determine if there was an enrichment of genes in proximity to the colorectal cancer risk variants that could further elucidate the probable causal genes and pathways involved in colorectal cancer biology. Results For the 65 unique genes that either contained, or were immediately neighboring up- and downstream, of these variants there was a significant enrichment for the KEGG pathway, Pathways in Cancer (p-value = 2.67 × 10−5) and an enrichment for multiple biological processes (FDR < 0.05), such as cell junction organization, tissue morphogenesis, regulation of SMAD protein phosphorylation, and odontogenesis identified through Gene Ontology analysis. To identify potential causal genes, we conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using gene expression and genotype data from the Genotype-Tissue Expression (GTEx) Project portal in normal sigmoid (n = 124) and transverse (n = 169) colon tissue. In addition, we also did a cis-eQTL analysis on colorectal tumor tissue (n = 147) from The Cancer Genome Atlas (TCGA). We identified two risk alleles that were significant cis-eQTLs for FADS2 (rs1535) and COLCA1 and 2 (rs3802842) genes in the normal transverse colon tissue and two risk alleles that were significant cis-eQTLs for the CABLES2 (rs2427308) and LIPG (rs7229639) genes in the normal sigmoid colon tissue, but not tumor tissue. Conclusions Our data reaffirm the potential to identify an enrichment for biological processes and candidate causal genes based on expression profiles correlated with genetic risk alleles of colorectal cancer, however, the identification of these significant cis-eQTLs is context and tissue specific

Návrh materiálu a jeho tepelné zpracování pro výrobu ozubených kol

Import 20/04/2006Prezenční výpůjčkaFakulta strojní a elektrotechnická VŠB (Ostrava). Katedra mechanické technologie (345

Additional file 2: Table S2. of In silico pathway analysis and tissue specific cis-eQTL for colorectal cancer GWAS risk variants

Transcription regulatory features of intronic colorectal cancer risk alleles and linked variants with significant eQTL of neighboring genes. (XLSX 16 kb

Characterizing breast cancer incidence and trends among Asian American, Native Hawaiian, and non-Hispanic White women in Hawaii, 1990-2014.

PURPOSE: To characterize breast cancer (BC) incidence by age at diagnosis and BC subtype among disaggregated Asian American, Native Hawaiian, and Pacific Islander (AANHPI) women and non-Hispanic White (NHW) women in Hawaii. METHODS: Using 1990-2014 data from the Hawaii tumor registry, we estimated age-adjusted incidence rates (AAIR) of BC and the annual percent change in BC incidence by age (&lt;50 and ≥50 years) and BC subtype (hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-, HR+/HER2+, HR-/HER2+, triple negative BC) for Filipino American (FA), Japanese American (JA), Native Hawaiian (NH), and NHW women. RESULTS: Among young (&lt;50 years) women, annual BC incidence increased 2.9% (1994-2014) among JA and 1.0% (1990-2014) among NHW women. Incidence was highest among young JA women (2010-2014 AAIR 52.0 per 100,000; 95% confidence interval [CI] 45.6, 58.9). HR+/HER2- BC, the major BC subtype, was similarly highest among young JA women (AAIR 39.5; 95% CI 33.9, 45.4). Among older (≥50 years) women, annual BC incidence increased 1.6% (1990-2014) among FA and 4.2% (2006-2014) for JA women. BC incidence was highest among older NH women (AAIR 137.6, 95% CI 128.2, 147.4), who also displayed highest incidence of two subtypes: HR+/HER2- (AAIR 106.9; 95% CI 98.6, 115.5) and HR+/HER2+ (AAIR 12.1; 95% CI 9.4, 15.1). CONCLUSION: We observed high and increasing BC incidence among JA women ages &lt;50 years and high incidence among NH women ages ≥50 years. These results highlight racial and ethnic differences in BC incidence among disaggregated AANHPI populations in Hawaii by age and BC subtype