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Patenaude A.,Genome science Center | Fuller M.,Genome science Center | Chang L.,Genome science Center | Wong F.,Genome science Center | And 11 more authors.
Cancer Research | Year: 2014

Notch signaling is important for tumor angiogenesis induced by vascular endothelial growth factor A. Blockade of theNotch ligandDll4 inhibits tumor growth in a paradoxicalway. Dll4 inhibition increases endothelial cell sprouting, but vessels showreduced perfusion. The reason for this lack of perfusion is not currently understood. Here we report that inhibition of Notch signaling in endothelial cell using an inducible binary transgenic system limits VEGFAdriven tumor growth and causes endothelial dysfunction. Neither excessive endothelial cell sprouting nor defects of pericyte abundance accompanied the inhibition of tumor growth and functional vasculature. However, biochemical and functional analysis revealed that endothelial nitric oxide production is decreased by Notch inhibition. Treatment with the soluble guanylate cyclase activator BAY41-2272, a vasorelaxing agent that acts downstream of endothelial nitric oxide synthase (eNOS) by directly activating its soluble guanylyl cyclase receptor, rescued blood vessel function and tumor growth.Weshowthat reduction in nitric oxide signaling is an early alteration induced by Notch inhibition and suggest that lack of functional vessels observed with Notch inhibition is secondary to inhibition of nitric oxide signaling. Coculture and tumor growth assays reveal that Notch-mediated nitric oxide production in endothelial cell requires VEGFA signaling. Together, our data support that eNOS inhibition is responsible for the tumor growth and vascular function defects induced by endothelial Notch inhibition. This study uncovers a novel mechanism of nitric oxide production in endothelial cells in tumors, with implications for understanding the peculiar character of tumor blood vessels. © 2014 AACR.


PubMed | University of Alberta, Genome science Center, University of Groningen and McMaster University
Type: | Journal: Scientific reports | Year: 2016

Microbial communities reside in healthy tissues but are often disrupted during disease. Bacterial genomes and proteins are detected in brains from humans, nonhuman primates, rodents and other species in the absence of neurological disease. We investigated the composition and abundance of microbiota in frozen and fixed autopsied brain samples from patients with multiple sclerosis (MS) and age- and sex-matched nonMS patients as controls, using neuropathological, molecular and bioinformatics tools. 16s rRNA sequencing revealed Proteobacteria to be the dominant phylum with restricted diversity in cerebral white matter (WM) from MS compared to nonMS patients. Both clinical groups displayed 1,200-1,400 bacterial genomes/cm


Zayed H.,University of California at San Francisco | Chao R.,University of California at San Francisco | Moshrefi A.,University of California at San Francisco | LopezJimenez N.,University of California at San Francisco | And 4 more authors.
American Journal of Medical Genetics, Part A | Year: 2010

Using an Affymetrix GeneChip® Human Mapping 100K Set to study a patient with a late-presenting, right-sided diaphragmatic hernia and microphthalmia, we found a maternally inherited deletion that was 2.7Mb in size at chromosome 18q22.1. Mapping of this deletion using fluorescence in situ hybridization revealed three deleted genes - CDH19, DSEL, and TXNDC10, and one gene that contained the deletion breakpoint, CCDC102B. We selected DSEL for further study in 125 patients with diaphragmatic hernias, as it is involved in the synthesis of decorin, a protein that is required for normal collagen formation and that is upregulated during myogenesis.We found p.Met14Ile in an unrelated patient with a late-presenting, anterior diaphragmatic hernia. In the murine diaphragm, Dsel was only weakly expressed at the time of diaphragm closure and its expression in C2C12 myoblast cells did not change significantly during myoblast differentiation, thus reducing the likelihood that the gene is involved in myogenesis of the diaphragm. Although it is possible that the 18q22.1 deletion and haploinsufficiency for DSEL contributed to the diaphragmatic defect in the patient, a definite role for DSEL and decorin in the formation of the collagencontaining, central tendon of the diaphragm has not yet been established. © 2010 Wiley-Liss, Inc.


Najafzadeh M.,University of British Columbia | Lynd L.D.,University of British Columbia | Lynd L.D.,St Pauls Hospital | Davis J.C.,University of British Columbia | And 6 more authors.
Genetics in Medicine | Year: 2012

Purpose: As advances in genomics make genome sequencing more affordable, the availability of new genome-based diagnostic and therapeutic strategies (i.e., personalized medicine) will increase. This wave will hit front-line physicians who may be faced with a plethora of patients' expectations of integrating genomic data into clinical care. The objective of this study was to elicit the preferences of physicians about regarding applying personalized medicine in their clinical practice as these strategies become available. Methods: Using a best-worst scaling (BWS) choice experiment, we estimated the relative importance of attributes that influence physicians' decision for using personalized medicine. Six attributes were included in the BWS: type of genetic tests, training for genetic testing, clinical guidelines, professional fee, privacy protection laws, and cost of genetic tests. A total of 197 physicians in British Columbia completed the experiment. Using latent class analysis (LCA), we explored the physicians' heterogeneities in preferences. Results: "Type of genetic tests" had the largest importance, suggesting that the physicians' decision was highly influenced by the availability of genetic tests for patients' predisposition to diseases and/or drug response. "Training" and "guidelines" were the attributes with the next highest importance. LCA identified two classes of physicians. Relative to class 2, class 1 had a larger weight for the "type of genetic tests," but smaller weights for "professional fee" and "cost of tests. "Conclusion: We measured relative importance of factors that affect the decision of physicians to incorporate personalized medicine in their practice. These results can be used to design the policies for supporting physicians and facilitating the use of personalized medicine in the future. ©American College of Medical Genetics and Genomics.


Hanna C.W.,University of British Columbia | Hanna C.W.,Child and Family Research Institute | Bretherick K.L.,Genome science Center | Liu C.-C.,Child and Family Research Institute | And 4 more authors.
Human Reproduction | Year: 2010

BACKGROUND: Recurrent miscarriage affects 1-2 of couples trying to conceive, and is idiopathic in nearly half. Female fertility is controlled by the hypothalamus-pituitary-ovarian (HPO) axis and we hypothesize that genetic polymorphisms affecting the function of genes involved in regulating the HPO axis will be associated with recurrent miscarriage. METHODS: Whole peripheral blood DNA from 227 women with recurrent miscarriage and 130 control women was obtained for this study. Using the Sequenom iPlex assay for fragment analysis, 31 single-nucleotide polymorphisms (SNPs) and 4 short tandem repeat (STR) polymorphisms in 20 candidate genes were evaluated for genetic association with recurrent miscarriage. RESULTS: Several candidate associations were identified with an uncorrected P-value of 0.05. Genotype distribution at an SNP (rs37389) in the prolactin receptor gene (P = 0.03), and allele distributions at an SNP (rs41423247) in the glucocorticoid receptor gene (P = 0.04) and an STR polymorphism in the estrogen receptor β gene (P = 0.03) were associated with recurrent miscarriage. The T allele of an SNP (rs2033962) within the activin receptor type 1 gene (ACVR1) was associated with increased number of miscarriages in an additive manner (P = 0.02). These candidate associations were not statistically significant after correcting for multiple analyses. CONCLUSIONS: Candidate associations were identified between recurrent miscarriage and genetic variation within ESR2, PRLR, GCCR and ACVR1 genes. Independent confirmation of these results is needed, as limitations of this study include the heterogeneous etiology of recurrent miscarriage, limited sample size, partial availability of reproductive history of the control group and investigation of only a subset of the genetic variation within each gene. © 2010 The Author. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Starczynowski D.T.,Genome science Center | Starczynowski D.T.,Cancer Research Center | Starczynowski D.T.,University of British Columbia | Karsan A.,Genome science Center | And 3 more authors.
Hematology/Oncology Clinics of North America | Year: 2010

Myelodysplastic syndromes (MDS) are heterogeneous clonal hematologic malignancies characterized by cytopenias caused by ineffective hematopoiesis and propensity to progress to acute myeloid leukemia. Innate immunity provides immediate protection against pathogens by coordinating activation of signaling pathways in immune cells. Given the prominent role of the innate immune pathway in regulating hematopoiesis, it is not surprising that aberrant signaling of this pathway is associated with hematologic malignancies. Increased activation of the innate immune pathway may contribute to dysregulated hematopoiesis, dysplasia, and clonal expansion in myelodysplastic syndromes. © 2010 Elsevier Inc.


Cheung K.-J.J.,British Columbia Cancer Agency | Johnson N.A.,British Columbia Cancer Agency | Affleck J.G.,University of British Columbia | Severson T.,Genome science Center | And 17 more authors.
Cancer Research | Year: 2010

Clinical correlative studies have linked 1p36 deletions with worse prognosis in follicular lymphoma (FL). In this study, we sought to identify the critical gene(s) in this region that is responsible for conferring inferior prognosis. BAC array technology applied to 141 FL specimens detected a minimum region of deletion (MRD) of ∼97 kb within 1p36.32 in 20% of these cases. Frequent single-nucleotide polymorphism-detected copyneutral loss of heterozygosity was also found in this region. Analysis of promoter CpGs in the MRD did not reveal differential patterns of DNA methylation in samples that differed in 1p36 status. Exon sequencing of MRD genes identified somatic alterations in the TNFRSF14 gene in 3 of 11 selected cases with matching normal DNA. An expanded cohort consisting of 251 specimens identified 46 cases (18.3%) with nonsynonymous mutations affecting TNFRSF14. Overall survival (OS) and disease-specific survival (DSS) were associated with the presence of TNFRSF14 mutation in patients whose overall treatment included rituximab. We further showed that inferior OS and DSS were most pronounced in patients whose lymphomas contained both TNFRSF14 mutations and 1p36 deletions after adjustment for the International Prognostic Index [hazard ratios of 3.65 (95% confidence interval, 1.35-9.878, P = 0.011) and 3.19 (95% confidence interval, 1.06-9.57, P = 0.039), respectively]. Our findings identify TNFRSF14 as a candidate gene associated with a subset of FL, based on frequent occurrence of acquired mutations and their correlation with inferior clinical outcomes. ©2010 AACR.


Hasan M.R.,University of British Columbia | Hasan M.R.,Genome science Center | Ho S.H.Y.,University of British Columbia | Ho S.H.Y.,Genome science Center | And 3 more authors.
International Journal of Cancer | Year: 2011

Vascular endothelial growth factor (VEGF) inhibitors, such as bevacizumab, have improved outcomes in metastatic colorectal cancer (CRC). Recent studies have suggested that VEGF can delay the onset of cellular senescence in human endothelial cells. As VEGF receptors are known to be upregulated in CRC, we hypothesized that VEGF inhibition may directly influence cellular senescence in this disease. In our study, we observed that treatment with bevacizumab caused a significant increase (p < 0.05) in cellular senescence in vitro in several CRC cells, such as MIP101, RKO, SW620 and SW480 cells, compared to untreated or human IgG-treated control cells. Similar results were also obtained from cells treated with a VEGFR2 kinase inhibitor Ki8751. In vivo, cellular senescence was detected in MIP101 tumor xenografts from 75% of mice treated with bevacizumab, while cellular senescence was undetectable in xenografts from mice treated with saline or human IgG (p < 0.05). Interestingly, we also observed that the proportion of senescent cells in colon cancer tissues obtained from patients treated with bevacizumab was 4.4-fold higher (p < 0.01) than those of untreated patients. To understand how VEGF inhibitors may regulate cellular senescence, we noted that among the two important regulators of senescent growth arrest of tumor cells, bevacizumab-associated increase in cellular senescence coincided with an upregulation of p16 but appeared to be independent of p53. siRNA silencing of p16 gene in MIP101 cells suppressed bevacizumab-induced cellular senescence, while silencing of p53 had no effect. These findings demonstrate a novel antitumor activity of VEGF inhibitors in CRC, involving p16. © 2011 UICC.


PubMed | University of British Columbia, Genome Science Center and University of Illinois at Chicago
Type: Journal Article | Journal: Molecular human reproduction | Year: 2015

Studies of copy number variants (CNVs) in miscarriages are rare in comparison to post-natal cases with developmental abnormalities. The overall characteristics of miscarriage CNVs (size, gene content and function) are therefore largely unexplored. Our goal was to assess and compare the characteristics of CNVs identified in 101 euploid miscarriages from four high-resolution array studies that documented both common miscarriage CNVs (i.e. CNVs found in controls from the Database of Genomic Variants, DGV) and rare miscarriage CNVs (not reported in DGV). Our miscarriage analysis included 24 rare CNVs with 93 genes, and 372 common CNVs (merged into 119 common CNV regions; CNVRs) with 354 genes. The rare and common CNVs were comparable in size (median size of 0.16 and 0.14 Mb, respectively); however, rare CNVs showed a significantly higher gene density, with 56 genes/Mb in rare and 24 genes/Mb in common CNVs (P = 0.03). Rare CNVs also had two times more genes with mouse knock-out models which were reported for 42% of rare and 19% of common CNV genes. No specific pathway enrichment was noted for 24 rare CNV genes, but common CNV genes showed significant enrichment in genes from immune-response related pathways and pregnancy/reproduction-related biological processes. Our analysis of CNVs from euploid miscarriages suggests that both rare and common CNVs could have a role in miscarriage by impacting pregnancy-related genes or pathways. Cataloguing of all CNVs and detailed description of their characteristics (e.g. gene content, genomic breakpoints) is desirable in the future for better understanding of their relevance to pregnancy loss.


Mwenifumbo J.C.,Genome science Center | Marra M.A.,Genome science Center
Nature Reviews Genetics | Year: 2013

Discoveries from cancer genome sequencing have the potential to translate into advances in cancer prevention, diagnostics, prognostics, treatment and basic biology. Given the diversity of downstream applications, cancer genome-sequencing studies need to be designed to best fulfil specific aims. Knowledge of second-generation cancer genome-sequencing study design also facilitates assessment of the validity and importance of the rapidly growing number of published studies. In this Review, we focus on the practical application of second-generation sequencing technology (also known as next-generation sequencing) to cancer genomics and discuss how aspects of study design and methodological considerations-such as the size and composition of the discovery cohort-can be tailored to serve specific research aims. © 2013 Macmillan Publishers Limited. All rights reserved.

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