British Columbia Cancer Agency Cancer Research Center

Vancouver, Canada

British Columbia Cancer Agency Cancer Research Center

Vancouver, Canada
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Leung A.W.,British Columbia Cancer Agency Cancer Research Center | Leung A.W.,University of British Columbia | Kalra J.,British Columbia Cancer Agency Cancer Research Center | Kalra J.,Langara College | And 4 more authors.
Nanomedicine | Year: 2014

Epithelial ovarian cancers are a group of at least five histologically and clinically distinct diseases, yet at this time patients with these different diseases are all treated with the same platinum and taxane-based chemotherapeutic regimen. With increased knowledge of histotype-specific differences that correlate with treatment responses and resistance, novel treatment strategies will be developed for each distinct disease. Type-specific or resistance-driven molecularly targeted agents will provide some specificity over traditional chemotherapies and it is argued here that nanoscaled drug delivery systems, in particular lipid-based formulations, have the potential to improve the delivery and specificity of pathway-specific drugs and broad-spectrum cytotoxic chemotherapeutics. An overview of the current understanding of ovarian cancers and the evolving clinical management of these diseases is provided. This overview is needed as it provides the context for understanding the current role of drug delivery systems in the treatment of ovarian cancer and the need to design formulations for treatment of clinically distinct forms of ovarian cancer. © 2014 Future Medicine Ltd.


Talhouk A.,University of British Columbia | Kommoss S.,University Hospital of Tuebingen | Mackenzie R.,University of British Columbia | Cheung M.,British Columbia Center for Disease Control | And 14 more authors.
PLoS ONE | Year: 2016

A major weakness in many high-throughput genomic studies is the lack of consideration of a clinical environment where one patient at a time must be evaluated. We examined generalizable and platform-specific sources of variation from NanoString gene expression data on both ovarian cancer and Hodgkin lymphoma patients. A reference-based strategy, applicable to single-patient molecular testing is proposed for batch effect correction. The proposed protocol improved performance in an established Hodgkin lymphoma classifier, reducing batch-to-batch misclassification while retaining accuracy and precision. We suggest this strategy may facilitate development of NanoString and similar molecular assays by accelerating prospective validation and clinical uptake of relevant diagnostics. © 2016 Talhouk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


PubMed | University Hospital of Tuebingen, British Columbia Center for Disease Control, Pomeranian Medical University, University of New South Wales and 3 more.
Type: Journal Article | Journal: PloS one | Year: 2016

A major weakness in many high-throughput genomic studies is the lack of consideration of a clinical environment where one patient at a time must be evaluated. We examined generalizable and platform-specific sources of variation from NanoString gene expression data on both ovarian cancer and Hodgkin lymphoma patients. A reference-based strategy, applicable to single-patient molecular testing is proposed for batch effect correction. The proposed protocol improved performance in an established Hodgkin lymphoma classifier, reducing batch-to-batch misclassification while retaining accuracy and precision. We suggest this strategy may facilitate development of NanoString and similar molecular assays by accelerating prospective validation and clinical uptake of relevant diagnostics.


Anglesio M.S.,University of British Columbia | Wang Y.,University of British Columbia | Yang W.,Applied Genomics | Senz J.,University of British Columbia | And 8 more authors.
Journal of Pathology | Year: 2013

Our group recently described recurrent somatic mutations of the miRNA processing gene DICER1 in non-epithelial ovarian cancer. Mutations appeared to be clustered around each of four critical metal-binding residues in the RNase IIIB domain of DICER1. This domain is responsible for cleavage of the 3′ end of the 5p miRNA strand of a pre-mRNA hairpin. To investigate the effects of these cancer-associated 'hotspot' mutations, we engineered mouse DICER1-deficient ES cells to express wild-type and an allelic series of the mutant DICER1 variants. Global miRNA and mRNA profiles from cells carrying the metal-binding site mutations were compared to each other and to wild-type DICER1. The miRNA and mRNA profiles generated through the expression of the hotspot mutations were virtually identical, and the DICER1 hotspot mutation-carrying cells were distinct from both wild-type and DICER1-deficient cells. Further, miRNA profiles showed that mutant DICER1 results in a dramatic loss in processing of mature 5p miRNA strands but were still able to create 3p strand miRNAs. Messenger RNA (mRNA) profile changes were consistent with the loss of 5p strand miRNAs and showed enriched expression for predicted targets of the lost 5p-derived miRNAs. We therefore conclude that cancer-associated somatic hotspot mutations of DICER1, affecting any one of four metal-binding residues in the RNase IIIB domain, are functionally equivalent with respect to miRNA processing and are hypomorphic alleles, yielding a global loss in processing of mature 5p strand miRNA. We further propose that this resulting 3p strand bias in mature miRNA expression likely underpins the oncogenic potential of these hotspot mutations. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Wang Y.,University of British Columbia | Wang Y.,British Columbia Cancer Agency Cancer Research Center | Chen J.,University of British Columbia | Yang W.,British Columbia Cancer Agency Cancer Research Center | And 11 more authors.
Neoplasia (United States) | Year: 2015

DICER1, an endoribonuclease required for microRNA (miRNA) biogenesis, is essential for embryogenesis and the development of many organs including ovaries. We have recently identified somatic hotspot mutations in RNase IIIb domain of DICER1 in half of ovarian Sertoli-Leydig cell tumors, a rare class of sex-cord stromal cell tumors in young women. These hotspot mutations lost IIIb cleavage activity of DICER1 in vitro and failed to produce 5p-derived miRNAs in mouse Dicer1-null ES cells. However, the oncogenic potential of these hotspot DICER1 mutations has not been studied. Here, we further revealed that the global expression of 5p-derived miRNAs was dramatically reduced in ovarian Sertoli-Leydig cell tumors carrying DICER1 hotspot mutations compared with those without DICER1 hotspot mutation. The miRNA production defect was associated with the deregulation of genes controlling cell proliferation and the cell fate. Using an immortalized human granulosa cell line, SVOG3e, we determined that the D1709N-DICER1 hotspot mutation failed to produce 5p-derived miRNAs, deregulated the expression of several genes that control gonadal differentiation and cell proliferation, and promoted cell growth. Re-expression of let-7 significantly inhibited the growth of D1709N-DICER1 SVOG3e cells, accompanied by the suppression of key regulators of cell cycle control and ovarian gonad differentiation. Taken together, our data revealed that DICER1 hotspot mutations cause systemic loss of 5p-miRNAs that can both drive pseudodifferentiation of testicular elements and cause oncogenic transformation in the ovary. © 2015 The Authors.


Anglesio M.S.,University of British Columbia | Wang Y.K.,British Columbia Cancer Agency Cancer Research Center | Maassen M.,University Hospital of Tuebingen | Horlings H.M.,University of British Columbia | And 17 more authors.
Journal of the National Cancer Institute | Year: 2016

Many women with ovarian endometrioid carcinoma present with concurrent endometrial carcinoma. Organ-confined and low-grade synchronous endometrial and ovarian tumors (SEOs) clinically behave as independent primary tumors rather than a single advanced-stage carcinoma. We used 18 SEOs to investigate the ancestral relationship between the endometrial and ovarian components. Based on both targeted and exome sequencing, 17 of 18 patient cases of simultaneous cancer of the endometrium and ovary from our series showed evidence of a clonal relationship, ie, primary tumor and metastasis. Eleven patient cases fulfilled clinicopathological criteria that would lead to classification as independent endometrial and ovarian primary carcinomas, including being of FIGO stage T1a/1A, with organ-restricted growth and without surface involvement; 10 of 11 of these cases showed evidence of clonality. Our observations suggest that the disseminating cells amongst SEOs are restricted to physically accessible and microenvironment-compatible sites yet remain indolent, without the capacity for further dissemination. © 2016 The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.


Wong J.C.T.,University of British Columbia | Chan S.K.,British Columbia Cancer Agency Cancer Research Center | Schaeffer D.F.,University of British Columbia | Sagaert X.,University Hospitals | And 7 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Treatments for colorectal cancer (CRC) are primarily disease stage based. However, heterogeneity in outcome within even a single stage highlights its limitations in predicting disease behavior. Recently, the role of gene expression as predictive and prognostic markers has been explored. Our objectives were to identify consistently differentially expressed genes through meta-analysis of high-throughput gene-expression studies, and evaluate their predictive and prognostic significance in colon (CC) and rectal (RC) cancers. Experimental Design: Publications applying high-throughput gene- expression technologies to specific CRC stages were identified. A vote counting strategy was used to identify the most significant differentially expressed genes. Their predictive and prognostic values were independently assessed in a tissuemicroarray of 191cases of stage II-IVCC/RCfromtwotertiary care centers.Their biological effectswere also examinedin vitro. Results: MMP1 and MMP2 were identified as consistently underexpressed in liver metastasis compared with primary CRC. Shorter time to distant metastasis and overall survival occurred in stage III CC lacking MMP1 expression, and in stage III RC lacking MMP2. MMP1 levels in stage II and III CC were associated with increased likelihood of distant metastasis, whereas the risk of local recurrence in stage III RC could be stratified by MMP2. Promotion of cell invasion of CRC cell lines exposed to MMP1/2 inhibitors were confirmed in vitro. Conclusions: MMP1 and MMP2 may be useful biomarkers that can help stratify patients at higher risk of developing recurrence in colorectal cancer, and guide individualized treatment decisions to achieve better outcomes. ©2011 AACR.


PubMed | University of British Columbia, Vancouver Prostate Cancer Center and British Columbia Cancer Agency Cancer Research Center
Type: Journal Article | Journal: Neoplasia (New York, N.Y.) | Year: 2015

DICER1, an endoribonuclease required for microRNA (miRNA) biogenesis, is essential for embryogenesis and the development of many organs including ovaries. We have recently identified somatic hotspot mutations in RNase IIIb domain of DICER1 in half of ovarian Sertoli-Leydig cell tumors, a rare class of sex-cord stromal cell tumors in young women. These hotspot mutations lost IIIb cleavage activity of DICER1 in vitro and failed to produce 5p-derived miRNAs in mouse Dicer1-null ES cells. However, the oncogenic potential of these hotspot DICER1 mutations has not been studied. Here, we further revealed that the global expression of 5p-derived miRNAs was dramatically reduced in ovarian Sertoli-Leydig cell tumors carrying DICER1 hotspot mutations compared with those without DICER1 hotspot mutation. The miRNA production defect was associated with the deregulation of genes controlling cell proliferation and the cell fate. Using an immortalized human granulosa cell line, SVOG3e, we determined that the D1709N-DICER1 hotspot mutation failed to produce 5p-derived miRNAs, deregulated the expression of several genes that control gonadal differentiation and cell proliferation, and promoted cell growth. Re-expression of let-7 significantly inhibited the growth of D1709N-DICER1 SVOG3e cells, accompanied by the suppression of key regulators of cell cycle control and ovarian gonad differentiation. Taken together, our data revealed that DICER1 hotspot mutations cause systemic loss of 5p-miRNAs that can both drive pseudodifferentiation of testicular elements and cause oncogenic transformation in the ovary.

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