Browsing by Author "Köbel, Martin"
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- ItemOpen AccessCharacteristics and outcome of the COEUR Canadian validation cohort for ovarian cancer biomarkers(2018-03-27) Le Page, Cécile; Rahimi, Kurosh; Köbel, Martin; Tonin, Patricia N; Meunier, Liliane; Portelance, Lise; Bernard, Monique; Nelson, Brad H; Bernardini, Marcus Q; Bartlett, John M S; Bachvarov, Dimcho; Gotlieb, Walter H; Gilks, Blake; McAlpine, Jessica N; Nachtigal, Mark W; Piché, Alain; Watson, Peter H; Vanderhyden, Barbara; Huntsman, David G; Provencher, Diane M; Mes-Masson, Anne-MarieAbstract Background Ovarian carcinoma is the most lethal gynecological malignancy due to early dissemination and acquired resistance to platinum-based chemotherapy. Reliable markers that are independent and complementary to clinical parameters are needed to improve the management of patients with this disease. The Canadian Ovarian Experimental Unified Resource (COEUR) provides researchers with biological material and associated clinical data to conduct biomarker validation studies. Using standards defined by the Canadian Tissue Repository Network (CTRNet), we have previously demonstrated the quality of the biological material from this resource. Here we describe the clinical characteristics of the COEUR cohort. Methods With support from 12 Canadian ovarian cancer biobanks in Canada, we created a central retrospective cohort comprised of more than 2000 patient tissue samples with associated clinical data, including 1246 high-grade serous, 102 low-grade serous, 295 endometrioid, 259 clear cell and 89 mucinous carcinoma histotypes. A two-step reclassification process was applied to assure contemporary histological classification (histotyping). For each histotypes individually, we evaluated the association between the known clinico-pathological parameters (stage, cytoreduction, chemotherapy treatment, BRCA1 and BRCA2 mutation) and patient outcome by using Kaplan-Meier and Cox proportional hazard regression analyses. Results The median follow-up time of the cohort was 45 months and the 5-year survival rate for patients with high-grade serous carcinomas was 34%, in contrast to endometrioid carcinomas with 80% at 5 years. Survival profiles differed by histotype when stratified by stage or cytoreduction. Women with mucinous or clear cell carcinomas at advanced stage or with non-optimally debulked disease had the worst outcomes. In high-grade serous carcinoma, we observed significant association with longer survival in women harboring BRCA1 or BRCA2 mutation as compared to patients without detectable mutation. Conclusions Our results show the expected survival rates, as compared with current literature, in each histotype suggesting that the cohort is an unbiased representation of the five major histotypes. COEUR, a one stop comprehensive biorepository, has collected mature outcome data and relevant clinical data in a comprehensive manner allowing stratified analysis.
- ItemOpen AccessDifferentially Methylated Loci Distinguish Ovarian Carcinoma Histological Types: Evaluation of a DNA Methylation Assay in FFPE Tissue(2013-09-24) Kelemen, Linda E.; Köbel, Martin; Chan, Angela; Taghaddos, Soreh; Dinu, IrinaEpigenomic markers can identify tumor subtypes, but few platforms can accommodate formalin-fixed paraffin-embedded (FFPE) tumor tissue. We tested different amounts of bisulfite-converted (bs) DNA from six FFPE ovarian carcinomas (OC) of serous, endometrioid, and clear cell histologies and two HapMap constitutional genomes to evaluate the performance of the GoldenGate methylation assay. Methylation status at each 1,505 CpG site was expressed as β-values. Comparing 400 ng versus 250 ng bsDNA, reproducibility of the assay ranged from Spearman to 0.90, indicating that β-values obtained with a lower DNA amount did not always correlate well with the higher amount. Average methylation for the six samples was higher using 250 ng (β-value = 0.45, ) than with 400 ng (β-value = 0.36, ). Reproducibility between duplicate HapMap samples ( to 0.92) was also variable. Using 400 ng input bsDNA, THBS2 and ERG were differentially methylated across all histologic types and between endometrioid and clear cell types at ud_less_than0.1% false discovery rate. Methylation did not always correlate with gene expression ( to 0.15). We found that lower bsDNA overestimates methylation, and, using higher bsDNA amounts, we confirmed a previous report of higher methylation of THBS2 in clear cell OC, which could provide new insight into biological pathways that distinguish OC histological types.
- ItemOpen AccessOvarian cancer: diagnostic accuracy and tumor types distribution in East Africa compared to North America(2020-07-16) Rambau, Peter F; Köbel, Martin; Tilley, Derek; Mremi, Alex; Lukande, Robert; Muller, WilliamAbstract Background Ovarian cancer is a spectrum of several histologically distinct tumor types that differ in etiology, response to therapy, and prognosis. In resource-limited settings, the diagnosis of ovarian cancer can be challenging. This study describes the distribution of ovarian cancer tumor types in East Africa as well as assessing the diagnostic accuracy by using contemporary methods. Methods Data from 210 women identified from the records with a diagnosis of ovarian cancer in a period of 15 years were included. Two tissue microarrays were constructed and stained with 20 antibodies relevant to ovarian cancer subtyping. An integrated diagnosis was reached by the review of full Haematoxylin and Eosin stained sections, with consideration of immunohistochemical results. The integrated diagnoses were compared with the original diagnoses, and the degree of agreement was evaluated by percentage and Kappa statistics. Results Though limited by selection bias, the results suggest lower rates of ovarian cancer in East Africa compared to a North American population from Alberta, Canada. There was a higher proportion of sex cord stromal tumors and germ cell tumors in the East African population. Diagnostic accuracy for main ovarian tumor type categories was substantial (Kappa 0.70), but only fair for specific ovarian carcinoma histotypes (Kappa 0.34). Poor Haematoxylin and Eosin stain was the main factor hindering the correct diagnosis, which was not related to tissue processing. Conclusions In a resource-limited setting, where immunohistochemistry is not routinely carried out, diagnostic accuracy for the main categories of ovarian carcinoma is substantial and could be further improved by standardization of the basic Haematoxylin and Eosin stain.
- ItemOpen AccessRecent alcohol consumption and risk of incident ovarian carcinoma: a pooled analysis of 5,342 cases and 10,358 controls from the Ovarian Cancer Association Consortium(BioMed Central, 2013-01-22) Kelemen, Linda E; Bandera, Elisa V; Terry, Kathryn L; Rossing, Mary Anne; Brinton, Louise A; Doherty, Jennifer A; Ness, Roberta B; Kjær, Susanne Krüger; Chang-Claude, Jenny; Köbel, Martin; Lurie, Galina; Thompson, Pamela J; Carney, Michael E; Moysich, Kirsten; Edwards, Robert; Bunker, Clare; Jensen, Allan; Høgdall, Estrid; Cramer, Daniel W; Vitonis, Allison F; Olson, Sara H; King, Melony; Chandran, Urmila; Lissowska, Jolanta; Garcia-Closas, Montserrat; Yang, Hannah; Webb, Penelope M; Schildkraut, Joellen M; Goodman, Marc T; Risch, Harvey A
- ItemOpen AccessTailoring Ovarian Cancer Strategies to a Sub-Saharan Region: Testing the Developed Country Experience(2018-08-16) Rambau, Peter Fabian; Köbel, Martin; Manyama, Mange J.; Benediktsson, Hallgrímur; Hallgrímsson, Benedikt; Lukowiak, Ken D.; Quan, May LynnOvarian carcinoma is a spectrum of different histotypes which differ in risk factors, precursor lesions, molecular alterations and prognosis. Most of the research focused on high grade serous carcinoma which constitutes the majority of ovarian carcinoma. Endometrioid carcinoma (EC) constitutes 11% of ovarian carcinoma. Studies on EC have been limited by lack of sufficient number of cases for a meaningful conclusion. Seromucinous carcinoma, a newly introduced histotype shows resemblance to EC with no studies on its diagnostic reproducibility and molecular alterations. In developing countries, few studies have addressed the tumor types and histotype distribution of ovarian cancer, which could be useful in resource allocation, in addition the diagnostic accuracy of histotyping is not known. This study utilized immunohistochemical markers in a cohort of EC to study the diagnostic and prognostic biomarkers, as well as histotyping of ovarian cancers from Tanzania to establish diagnostic accuracy. Morphological studies and targeted deep sequencing was applied to seromucinous carcinoma to detect recurrent mutations known to occur in ovarian carcinoma, to justify whether it deserves a separate classification. This study found that, a defect in mismatch repair proteins was restricted to EC, and therefore screening for Lynch syndrome should be restricted to endometrioid histotype. This study also validated the association of hormone receptor (estrogen and progesterone) expression with ovarian cancer specific survival, with limited clinical utility. For seromucinous carcinoma, this study shows that the morphological diagnosis of seromucinous carcinomas is not very reliable. It did not show a distinct immunophenotype or genotype, and molecular features overlaps with endometrioid and low-grade serous carcinomas. Therefore, seromucinous carcinoma can be assigned to one of the major histotypes by ancillary molecular tests. Ovarian cancer in Tanzania shows relatively few cases compared to the Alberta population, with poor diagnostic agreement by using the current WHO criteria and immunohistochemistry. Improvement of H&E staining and adoption of current WHO classification can achieve a reasonable correct histotyping of ovarian carcinoma which can be meaningful in this area where the resource are scarce.