British Columbia Cancer Agency Bcca, Catalan Institute of Nanoscience, Nanotechnology, Rikshospitalet Radiumhospitalet Medical Center, St. Bartholomew's Hospital, Arizona Cancer Center, University of Barcelona, University of Nebraska Medical Center, University of Rochester and Powell | Date: 2011-03-23
Gene expression data provides a basis for more accurate identification and diagnosis of lymphoproliferative disorders. In addition, gene expression data can be used to develop more accurate predictors of survival. The present invention discloses methods for identifying, diagnosing, and predicting survival in a lymphoma or lymphoproliferative disorder on the basis of gene expression patterns. The invention discloses a novel microarray, the Lymph Dx microarray, for obtaining gene expression data from a lymphoma sample. The invention also discloses a variety of methods for utilizing lymphoma gene expression data to determine the identity of a particular lymphoma and to predict survival in a subject diagnosed with a particular lymphoma. This information will be useful in developing the therapeutic approach to be used with a particular subject.
Pinheiro H.,University of Porto |
Carvalho J.,University of Porto |
Oliveira P.,University of Porto |
Ferreira D.,University of Porto |
And 11 more authors.
Human Molecular Genetics | Year: 2012
Disruption of E-cadherin (CDH1 gene) expression, subcellular localization or function arises during initiation and progression of almost 90% of all epithelial carcinomas. Nevertheless, the mechanisms through which this occurs are largely unknown. Previous studies showed the importance of CDH1 intron 2 sequences for proper gene and protein expression, supporting these as E-cadherin cis-modulators. Through RACE and RT-PCR, we searched for transcription events arising from CDH1 intron 2 and discovered several new transcripts. One, named CDH1a, with high expression in spleen and absent from normal stomach, was demonstrated to be translated into a novel isoform, differing from canonical E-cadherin in its N-terminal, as determined by mass spectrometry. Quantitative and functional assays showed that when overexpressed in an E-cadherin negative context, CDH1a replaced canonical protein interactions and functions. However, when co-expressed with canonical E-cadherin, CDH1a increased cell invasion and angiogenesis. Further, interferon-induced gene IFITM1 and IFI27 levels were increased upon CDH1a overexpression. Effects on invasion and IFITM1 and IFI27 expression were reverted upon CDH1a-specific knockdown. Importantly, CDH1a was de novo expressed in gastric cancer cell lines. This study presents a new mechanism by which E-cadherin functions are impaired by cis-regulatory mechanisms possibly with the involvement of inflammatory machinery. If confirmed in other cancer models, our data enclose potential for designing targeted therapies to rescue E-cadherin function. © The Author 2012. Published by Oxford University Press. All rights reserved.
PubMed | Medical Oncology, Canadian Center for Applied Research in Cancer Control, University of British Columbia, British Columbia Cancer Agency BCCA and 2 more.
Type: Journal Article | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2014
The primary purpose of this study was to measure the impact of the 21-gene Recurrence Score result on systemic treatment recommendations and to perform a prospective health economic analysis in stage I-II, node-negative, oestrogen receptor positive (ER+) breast cancer.Consenting patients with ER+ node negative invasive breast cancer and their treating medial oncologists were asked to complete questionnaires about treatment preferences, level of confidence in those preferences and a decisional conflict scale (patients only) after a discussion of their diagnosis and risk without knowledge of the Recurrence Score. At a subsequent visit, the assay result and final treatment recommendations were discussed prior to both parties completing a second set of questionnaires. A Markov health state transition model was constructed, simulating the costs and outcomes experienced by a hypothetical assay nave population and an assay informed population.One hundred and fifty-six patients across two cancer centres were enrolled. Of the 150 for whom successful assay results were obtained, physicians changed their chemotherapy recommendations in 45 cases (30%; 95% confidence interval (CI) 22.8-38.0%); either to add (10%; 95% CI 5.7-16.0%) or omit (20%; 95% CI 13.9-27.3%) adjuvant chemotherapy. There was an overall significant improvement in physician confidence post-assay (p<0.001). Patient decisional conflict also significantly decreased following the assay (p<0.001). The simulation model found an incremental cost-effectiveness ratio of Canadian Dollars (CAD) $6630/quality-adjusted life years (QALY).Within the context of a publicly funded health care system, the Recurrence Score assay significantly affects adjuvant treatment recommendations and is cost effective in ER+ node negative breast cancer.
Lengoc S.,British Columbia Cancer Agency BCCA |
Soo J.,British Columbia Cancer Agency BCCA |
McGahan C.E.,Vancouver Center |
French J.,British Columbia Cancer Agency BCCA |
And 3 more authors.
Journal of Medical Imaging and Radiation Sciences | Year: 2012
Background: Previous studies have shown that palliative radiation therapy (PRT) is often underused, especially in rural and remote settings despite evidence supporting its effectiveness in managing symptoms from advanced or metastatic cancer. Purpose: To identify factors which influence family physicians (FPs) in British Columbia (BC) to refer patients for PRT at the BC Cancer Agency (BCCA) and to compare referral patterns between FPs in rural and urban areas. Methods and Materials: A total of 1,001 questionnaires were sent to all FPs practicing in rural areas and randomly to FPs in urban areas (351 and 650, respectively). Rural and urban areas were chosen based on our previous study of utilization rates of PRT in BC. The questionnaire was adapted from a previously validated survey, and was used to obtain information on referral practices of FPs in BC. FPs who did not practice family medicine or where 80% of their practice was spent with either obstetrical or pediatric patients were excluded. Results: The overall response rate was 33% (44% rural vs. 28% urban). Rural FPs were more involved in both palliative care and metastatic cancer management of their patients (88% vs. 74%; P = .01 and 58% vs. 39%; P = .01). No difference was observed in the FPs' awareness of the BCCA's Radiation Oncology Program. The most significant factors influencing an FP to refer a patient for PRT were: poor functional status, inconvenience to travel and life expectancy. A higher proportion of rural FPs had 10 years or less of experience in family practice than the urban FPs (P = .03). There was no significant difference in the formal training or additional training between the rural and urban FPs. Conclusions: This study found that FPs practicing in rural areas were more involved in palliative management of their patients and participated more in the care of patients with advanced or metastatic cancer than those in urban areas. They also more commonly referred patients for palliative radiotherapy than their urban counterparts. The reported factors that influenced rural and urban FPs to refer were patients' functional status and life expectancy, combined with uncertain benefit and potential side effects of radiotherapy. More than twice as many FPs from rural compared to urban areas were influenced by perceived inconvenience to travel for palliative radiotherapy. After controlling for potential confounding factors, FP awareness of the radiotherapy program, high participation in advanced, metastatic, or palliative care of cancer patients, formal training in radiation oncology, and additional training in palliative care were all associated with an increased probability of ever referring for palliative radiotherapy. © 2012 Elsevier Inc.
Mager D.E.,State University of New York at Buffalo |
Mody V.,State University of New York at Buffalo |
Xu C.,State University of New York at Buffalo |
Forrest A.,State University of New York at Buffalo |
And 7 more authors.
Pharmaceutical Research | Year: 2012
Purpose To characterize temporal exposure and elimination of 5 gold/dendrimer composite nanodevices (CNDs) (5 nm positive, negative, and neutral, 11 nm negative, 22 nm positive) in mice using a physiologically based mathematical model. Methods 400 ug of CNDs is injected intravenously to mice bearing melanoma cell lines. Gold content is determined from plasma and tissue samples using neutron activation analysis. A physiologically based pharmacokinetic (PBPK) model is developed for 5 nm positive, negative, and neutral and 11 nm negative nanoparticles and extrapolated to 22 nm positive particles. A global sensitivity analysis is performed for estimated model parameters. Results Negative and neutral particles exhibited similar distribution profiles. Unique model parameter estimates and distribution profiles explain similarities and differences relative to positive particles. The model also explains mechanisms of elimination by kidney and reticuloendothelial uptake in liver and spleen, which varies with particle size and charge. Conclusion Since the PBPK model can capture the diverse temporal profiles of non-targeted nanoparticles, we propose that when specific binding ligands are lacking, size and charge of nanodevices govern most of their in vivo interactions. © Springer Science+Business Media, LLC 2012.
Ali R.H.,Kuwait University |
Kalloger S.E.,Vancouver General Hospital |
Santos J.L.,British Columbia Cancer Agency BCCA |
Swenerton K.D.,British Columbia Cancer Agency BCCA |
Blake Gilks C.,Vancouver General Hospital
International Journal of Gynecological Pathology | Year: 2013
Low-grade serous carcinoma (LGSC) of the ovary has only recently been recognized as a disease entity distinct from the more common high-grade serous carcinoma (HGSC). When confined to the ovary, LGSC is associated with a very favorable prognosis, and chemotherapy is typically not recommended. There is little available information on the prognosis of patients with LGSC with extraovarian spread, from population-based tumor registries where there has been full pathology review. Thirty-two cases of Stage II to IV ovarian LGSC were identified in the Cheryl Brown Ovarian Cancer Outcomes Unit (1984-2000). In 19 cases, blocks were available and immunostaining for p53, p16, Ki-67, WT1, and E-cadherin was performed. Expression of these markers was then compared with a series of >400 cases of HGSC from the outcomes unit. LGSCs presented at Stage II in 10/32 cases, Stage III in 21/32 cases, and Stage IV in 1/32 cases. On follow-up, most patients died of disease, with <30% survival at 10 years. Compared with HGSCs, the LGSCs were significantly less likely to express p16 at high levels, or to show abnormal p53 expression (P=0.049 and <0.0001, respectively). Ki-67 staining indices were lower in the LGSCs (P<0.0001). There were no significant differences between LGSCs and HGSCs with respect to expression of WT1 and E-cadherin (P=0.27 and 0.62, respectively). This population-based series of LGSC with extraovarian spread at presentation had an unfavorable prognosis, similar to that of HGSC. As previously reported, LGSC shows lower tumor proliferation and fewer p53 abnormalities than in HGSC. © 2013 Lippincott Williams & Wilkins.
Wong J.C.T.,University of British Columbia |
Hasan M.R.,University of British Columbia |
Hasan M.R.,British Columbia Cancer Agency BCCA |
Rahman M.,University of British Columbia |
And 10 more authors.
International Journal of Cancer | Year: 2013
Dysregulation of nucleophosmin 1 (NPM1) has been found in numerous solid and hematological malignancies. Our previous meta-analysis of colorectal cancer (CRC) high throughput gene expression profiling studies identified it as a consistently reported up-regulated gene in the malignant state. Our aims were to compare NPM1 expression in normal colon, adenoma and CRC, to correlate their expressions with clinico-pathological parameters, and to assess the biological role of aberrant NPM1 expression in CRC cells. NPM1 transcript levels were studied in human CRC cell lines, whereas a tissue microarray of 57 normal human colon, 40 adenoma and 185 CRC samples were used to analyze NPM1 protein expression by immunohistochemistry. CRC cell lines were subjected to transient siRNA-mediated knockdown to study NPM1's roles on cell viability and senescence. NPM1 transcript levels were 7-11-folds higher in three different human CRC cell lines compared to normal colon cells. NPM1 protein expression was found to be progressively and significantly upregulated in CRC compared to adenomas and in adenomas compared to normal mucosa. Reducing NPM1 expression by siRNA had caused a significant decrease in cell viability, a concomitant increase in cellular senescence and cell cycle arrest. Cellular senescence induced under conditions of forced NPM1 suppression could be prevented by knocking down p53. The differential expression of NPM1 along the normal colon-adenoma-carcinoma progression and its involvement in resisting p53 related senescent growth arrest in CRC cell lines implicate its role in supporting CRC tumorigenesis. What's new? Previous studies have found consistent overexpression of the multifunctional protein nucleophosmin 1 (NPM1) in various malignancies, though its status and role in colorectal cancer (CRC) have remained unclear. This report describes upregulation of NPM1 transcripts in CRC cell lines and increasing NPM1 protein expression with progression from normal colon to adenoma to CRC in a tissue microarray. Modulation of NPM1 expression in CRC cells affected cellular viability, p53-dependent senescence, and cell-cycle progression. The results suggest that NPM1 may play a fundamental role in colorectal carcinogenesis. © 2013 UICC.
PubMed | British Columbia Cancer Agency BCCA, Translational Genomics Research Institute and Illumina
Type: | Journal: Scientific reports | Year: 2016
Large-scale multiplexed identification of somatic alterations in cancer has become feasible with next generation sequencing (NGS). However, calibration of NGS somatic analysis tools has been hampered by a lack of tumor/normal reference standards. We thus performed paired PCR-free whole genome sequencing of a matched metastatic melanoma cell line (COLO829) and normal across three lineages and across separate institutions, with independent library preparations, sequencing, and analysis. We generated mean mapped coverages of 99X for COLO829 and 103X for the paired normal across three institutions. Results were combined with previously generated data allowing for comparison to a fourth lineage on earlier NGS technology. Aggregate variant detection led to the identification of consensus variants, including key events that represent hallmark mutation types including amplified BRAF V600E, a CDK2NA small deletion, a 12 kb PTEN deletion, and a dinucleotide TERT promoter substitution. Overall, common events include >35,000 point mutations, 446 small insertion/deletions, and >6,000 genes affected by copy number changes. We present this reference to the community as an initial standard for enabling quantitative evaluation of somatic mutation pipelines across institutions.
Ali R.H.,Vancouver General Hospital |
Lee C.-H.,Vancouver General Hospital |
Hayes M.M.,British Columbia Cancer Agency BCCA
Diagnostic Cytopathology | Year: 2014
We report the fine-needle aspiration cytology of a case of metastatic small cell osteosarcoma to the liver with rosette formation, originating from distal femur, in a 36-year-old female. The aspirate of the liver metastases revealed a relatively monomorphic population of mitotically active small blue round cells arranged in clusters with prominent rosette formation simulating a neuroendocrine carcinoma or other rosette-forming small round cell tumors such as Ewing sarcoma. No extracellular mineralized matrix material was present. Comparison of the liver aspirate with the biopsy from the distal femoral lesion was crucial in reaching the correct diagnosis of metastatic small cell osteosarcoma with rosette formation. This is a potential diagnostic pitfall, particularly if interpreted without the knowledge of a suspected primary bone tumor. Copyright © 2012 Wiley Periodicals, Inc.