Objective: To report experience with borderline ovarian tumors (BOTs) in a developing country like Pakistan with limited resources and weak database of health system. Methods: Patients with BOTs managed at Shaukat Khanum Cancer hospital, Lahore, Pakistan from 2004 to 2014 were included and reviewed retrospectively. Data was recorded on histopathological types, age, CA-125, stage of disease, treatment modalities and outcomes. Results: Eighty-six patients with BOT were included with a median age of 35 years. Forty-two (49%) patients had serous BOTs and 43 (50%) had mucinous BOTs, while one (1%) had mixed type. Using FIGO staging, 80 patients had stage I; two patients had IIA, IIB and stage III each. Median follow-up time was 31.5 months. All patients had primary surgery. Seventy (81%) patients underwent complete surgical resection of tumor. Forty-three (50%) patients had fertility preserving surgery. Seventy-three (85%) patients remained in remission. Recurrent disease was observed in 13 (15%) patients. Median time to recurrence was 22 months. On further analysis, age above forty years, late stage at diagnosis and incomplete surgery were significantly associated with invasive recurrence. Conclusion: Despite a low malignant potential, relapses may occur in patients above forty years of age, incomplete surgery and staging information and advanced stage at presentation. Fertility sparing surgery should be considered in young patients. Complete excision of tumor and prolonged follow-up are advised because recurrence and transformation to invasive carcinoma may occur.

Resumo: O câncer de ovário apresenta diagnóstico tardio e alta letalidade, devido à falta de biomarcadores sensíveis e específicos e à rápida progressão desse câncer, assintomático em estadios iniciais. As células imunes têm a capacidade de eliminar as células malignas e regular a progressão tumoral. Contudo, as células imunes do microambiente tumoral são disfuncionais e falham no controle da expansão tumoral podendo, inclusive, promover o crescimento da neoplasia. Apesar das inúmeras tentativas de se correlacionar o grau e o tipo de infiltrado celular com o prognóstico ou sobrevida do paciente com câncer de ovário, não há consenso sobre o real significado do infiltrado leucocitário nesses casos. Desse modo, este estudo tem como objetivo a ampliação dos conhecimentos relativos à imunidade inata em mulheres com câncer de ovário, através caracterização dos aspectos fenotípicos celulares da imunidade inata sérica. Trata-se de estudo transversal onde foram avaliadas 36 mulheres submetidas a exame clínico, ginecológico, ultrassonografia transvaginal e tratamento com laparotomia nos casos indicados de massa pélvica. De acordo com o resultado desses exames, as mulheres selecionadas foram agrupadas nos grupos: controle- ausência de neoplasia, com neoplasia ovariana benigna e neoplasia ovariana maligna. Realizou-se dosagem sérica de moléculas de expressão de superfície de células da resposta imune inata com análise através da citometria de fluxo. As diferenças entre os grupos foram avaliadas pelo teste de Mann-Whitney (dois grupos) ou Kruskal-Walis (três grupos) conforme indicados. As diferenças com valor de p<0,05 foram consideradas significativas. Foram selecionadas 36 pacientes: 10 mulheres no grupo controle, 9 no grupo de neoplasia ovariana benigna e 17 no grupo de neoplasia maligna. Mais de 70% das pacientes com câncer de ovário apresentavam-se com doença... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Ovarian cancer presents late diagnosis and high mortality due to lack of sensitive and specific biomarkers and the rapid progression of this cancer, asymptomatic in early stages. Immune cells have the ability to eliminate malignant cells and regulate tumor progression. However, the immune cells of the tumor microenvironment are dysfunctional and fail to control the tumor growth and may even promote the growth of cancer. Despite numerous attempts to correlate the degree and type of cellular infiltrate and the prognosis or survival of patients with ovarian cancer, there is no consensus about the real meaning of the leukocyte infiltrate in these cases. Thus, this study aims to increase knowledge about the innate immunity in women with ovarian cancer through characterization of phenotypic cellular aspects of innate immunity levels. Methods: This is a Cross-sectional study evaluated 36 women who underwent clinical examination, gynecological examination, transvaginal ultrasound and treatment with laparotomy as indicated pelvic mass. According to the results of these tests, the women selected were grouped into two groups: control, absence of malignancy, with benign ovarian neoplasm and malignant ovarian neoplasm. The serum levels of serum molecules surface expression of cells of the innate immune response with analysis by flow cytometry. Differences between groups were evaluated by the Mann-Whitney (two groups) or Kruskal-Wallis (three groups) as indicated. Differences with p <0.05 were considered significant. Results: We selected 36 patients: 10 women in the control group, 9 in the group of benign ovarian neoplasm and 17 in the group of malignancy. More than 70% of patients with ovarian cancer presented with advanced disease and values of CA125 much changed. For the analysis found, there was a change between the groups for molecules expression in neutrophils... (Complete abstract click electronic access below) / Orientador: Agnaldo Lopes da Silva Filho / Coorientador: Andréa Teixeira de Carvalho / Banca: Paulo Traiman / Banca: Luciana Maria da Silva / Mestre

Made available in DSpace on 2014-06-11T19:29:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-02-26Bitstream added on 2014-06-13T18:59:45Z : No. of bitstreams: 1 paula_soc_me_botfm.pdf: 316334 bytes, checksum: 6b85b467e2fa0ecca5eec101c94687cd (MD5) / O câncer de ovário apresenta diagnóstico tardio e alta letalidade, devido à falta de biomarcadores sensíveis e específicos e à rápida progressão desse câncer, assintomático em estadios iniciais. As células imunes têm a capacidade de eliminar as células malignas e regular a progressão tumoral. Contudo, as células imunes do microambiente tumoral são disfuncionais e falham no controle da expansão tumoral podendo, inclusive, promover o crescimento da neoplasia. Apesar das inúmeras tentativas de se correlacionar o grau e o tipo de infiltrado celular com o prognóstico ou sobrevida do paciente com câncer de ovário, não há consenso sobre o real significado do infiltrado leucocitário nesses casos. Desse modo, este estudo tem como objetivo a ampliação dos conhecimentos relativos à imunidade inata em mulheres com câncer de ovário, através caracterização dos aspectos fenotípicos celulares da imunidade inata sérica. Trata-se de estudo transversal onde foram avaliadas 36 mulheres submetidas a exame clínico, ginecológico, ultrassonografia transvaginal e tratamento com laparotomia nos casos indicados de massa pélvica. De acordo com o resultado desses exames, as mulheres selecionadas foram agrupadas nos grupos: controle- ausência de neoplasia, com neoplasia ovariana benigna e neoplasia ovariana maligna. Realizou-se dosagem sérica de moléculas de expressão de superfície de células da resposta imune inata com análise através da citometria de fluxo. As diferenças entre os grupos foram avaliadas pelo teste de Mann-Whitney (dois grupos) ou Kruskal-Walis (três grupos) conforme indicados. As diferenças com valor de p<0,05 foram consideradas significativas. Foram selecionadas 36 pacientes: 10 mulheres no grupo controle, 9 no grupo de neoplasia ovariana benigna e 17 no grupo de neoplasia maligna. Mais de 70% das pacientes com câncer de ovário apresentavam-se com doença... / Introduction: Ovarian cancer presents late diagnosis and high mortality due to lack of sensitive and specific biomarkers and the rapid progression of this cancer, asymptomatic in early stages. Immune cells have the ability to eliminate malignant cells and regulate tumor progression. However, the immune cells of the tumor microenvironment are dysfunctional and fail to control the tumor growth and may even promote the growth of cancer. Despite numerous attempts to correlate the degree and type of cellular infiltrate and the prognosis or survival of patients with ovarian cancer, there is no consensus about the real meaning of the leukocyte infiltrate in these cases. Thus, this study aims to increase knowledge about the innate immunity in women with ovarian cancer through characterization of phenotypic cellular aspects of innate immunity levels. Methods: This is a Cross-sectional study evaluated 36 women who underwent clinical examination, gynecological examination, transvaginal ultrasound and treatment with laparotomy as indicated pelvic mass. According to the results of these tests, the women selected were grouped into two groups: control, absence of malignancy, with benign ovarian neoplasm and malignant ovarian neoplasm. The serum levels of serum molecules surface expression of cells of the innate immune response with analysis by flow cytometry. Differences between groups were evaluated by the Mann-Whitney (two groups) or Kruskal-Wallis (three groups) as indicated. Differences with p <0.05 were considered significant. Results: We selected 36 patients: 10 women in the control group, 9 in the group of benign ovarian neoplasm and 17 in the group of malignancy. More than 70% of patients with ovarian cancer presented with advanced disease and values of CA125 much changed. For the analysis found, there was a change between the groups for molecules expression in neutrophils... (Complete abstract click electronic access below)

Immune cytokines tumor necrosis factor alpha and type I interferons provide front-line defense against viral infection and are regulated in part by ubiquitin (Ub) and Ub-like molecules. Ubiquitin and Ub-like molecule ISG15 share a conserved C-terminal motif where a terminal glycine residue becomes attached to cellular target proteins. Nairoviruses and arteriviruses contain an ovarian tumor domain-containing protease (OTU protease) that was found to corrupt pathways by removing Ub or ISG15 from target proteins. This broad substrate specificity is unlike mammalian deubiquitinating enzymes, which cannot recognize both substrates. To understand how viral OTU domain-containing proteases remove Ub and ISG15, the crystal structure of the Crimean-Congo Heamorhaggic Fever nairovirus (CCHFV) was determined with Ub to 2.5 Å resolution. A computational model was built of the CCHFV Otu protease bound to ISG15 as well. The CCHFV Otu protease has several structural differences from known OTU proteases, manifesting in its broad substrate recognition capability.

Immune cytokines tumor necrosis factor alpha and type I interferons provide front-line defense against viral infection and are regulated in part by ubiquitin (Ub) and Ub-like molecules. Ubiquitin and Ub-like molecule ISG15 share a conserved C-terminal motif where a terminal glycine residue becomes attached to cellular target proteins. Nairoviruses and arteriviruses contain an ovarian tumor domain-containing protease (OTU protease) that was found to corrupt pathways by removing Ub or ISG15 from target proteins. This broad substrate specificity is unlike mammalian deubiquitinating enzymes, which cannot recognize both substrates. To understand how viral OTU domain-containing proteases remove Ub and ISG15, the crystal structure of the Crimean-Congo Heamorhaggic Fever nairovirus (CCHFV) was determined with Ub to 2.5 Å resolution. A computational model was built of the CCHFV Otu protease bound to ISG15 as well. The CCHFV Otu protease has several structural differences from known OTU proteases, manifesting in its broad substrate recognition capability.

Orientador: Sophie Françoise Mauricette Derchain / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-11T15:16:33Z (GMT). No. of bitstreams: 1 Borba_PatriciaPatury_M.pdf: 2453144 bytes, checksum: b4164eabded853c9e2f9d0610b08c22a (MD5) Previous issue date: 2008 / Resumo: Introdução: os tumores borderline serosos e mucinosos de ovário formam um grupo especial de neoplasias, que difere dos tumores benignos e malignos das mesmas linhagens histológicas. Os marcadores moleculares estão atualmente provendo informações sobre as características biológicas e o comportamento clínico de vários tumores, entre eles, os tumores borderline. A ciclo-oxigenase-2 (COX-2), uma enzima ligada ao processo inflamatório, é sabidamente correlacionada com a carcinogênese. Por outro lado, o Ki67, marcador de proliferação celular, é capaz de identificar alterações do controle do ciclo celular e da apoptose. Objetivo: comparar a expressão da COX-2 em tumores borderline de ovário, serosos e mucinosos e verificar se essa expressão está relacionada à atividade proliferativa celular, avaliada através da expressão do Ki67, à presença de implantes peritoneais e ao estádio da doença. Sujeitos e métodos: para este estudo descritivo de corte transversal, foram selecionados os blocos de parafina das mulheres com tumores borderline de ovário, tratadas entre Janeiro de 1998 a Dezembro de 2004 na Universidade Estadual de Campinas (Unicamp), São Paulo, e no Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brasil. Após revisão dos prontuários foram excluídas as mulheres grávidas no momento do diagnóstico, portadoras de outras neoplasias ou em uso registrado de antiinflamatórios não esteroidais. Todas as lâminas foram revisadas por dois patologistas e foram incluídos 86 casos de tumores borderline de ovário cujos blocos eram disponíveis para avaliação imunoistoquímica. Os tumores incluídos foram classificados como: serosos (36), mucinosos (46) e seromucinosos (4). Foram avaliadas a expressão citoplasmática da COX-2 e a expressão nuclear do Ki67, determinadas por imunoistoquímica realizada nestes cortes de tumores borderline de ovário conservados em parafina. Resultados: A idade média das mulheres estudadas foi de 42,4 anos (desvio padrão 16,5) não havendo diferença significativa entre aquelas com tumores serosos, mucinosos ou seromucinosos (p=0,62). Setenta e uma mulheres apresentaram a doença em estádio I e apenas três apresentaram doença em estádio II. Entre as treze mulheres com implantes peritoneais, sete eram portadoras de tumores borderline serosos, três apresentavam tumores mucinosos e três, tumores seromucinosos, sendo a proporção de mulheres com implantes peritoneais e estádio III significativamente maior, em mulheres com tumores seromucinosos (p=0,001). A expressão nuclear do Ki67 foi maior nos tumores mucinosos (65,8%), em comparação com os serosos (25%) e seromucinosos (25%) (p=0,001). Após análises multivariadas observou-se que a expressão citoplasmática da COX-2 foi significativamente maior nos tumores serosos em comparação com os tumores mucinosos (68.5% vs 52.5%; p<0.01). Não houve diferenças na expressão da COX-2 entre os tumores seromucinosos versus mucinosos, e tumores seromucinosos versus serosos. A maior expressão citoplasmática da COX-2 esteve significativamente associada com uma maior expressão do Ki67 em todos os tipos histológicos (p=0.03). Por outro lado, a expressão da COX-2 não se relacionou com o estádio da doença nem com a presença de implantes peritoneais. Conclusões: Esses resultados indicam que a expressão da COX-2 é maior nos tumores borderline serosos de ovário do que nos mucinosos. Também indicam que a COX-2 é uma boa preditora da proliferação celular pois, sua expressão aumenta com a expressão do Ki67. Entretanto, este estudo impede inferir se a COX-2 é uma moduladora do comportamento do tumor ou apenas um marcador de outros eventos biológicos já que não se associou com o estádio ou presença de implantes peritoneais / Abstract: Background: borderline serous and mucinous ovarian tumors form a special group of neoplasia, which differs from benign and malignant tumors of the same histological category. Molecular markers are currently providing information on the biological characteristics and clinical behavior of the ovarian tumors; among them, borderline tumors. Cyclooxygenase-2 (COX-2), an enzyme linked to the inflammation process, is known to correlate with carcinogenesis. On the other hand, the Ki67, a marker of cell proliferation, is capable of identifying abnormalities of the cell-cycle control system and apoptosis. Objective: to compare the expression of COX-2 in serous and mucinous borderline ovarian tumors and to evaluate whether this expression is related to cell proliferative activity, by its turn assessed with the expression of Ki67, to the presence of peritoneal implants and to the disease stage. Subjects and methods: for this cross-sectional descriptive study we selected paraffin blocks from women with borderline ovarian tumors, treated at the State University of Campinas, São Paulo, and at The National Institute of Cancer, Rio de Janeiro, Brazil, between January 1998 and December 2004. After revision of the medical records, women that were pregnant at the moment of diagnosis, that harbored other malignancies or that were using nonsteroidal antinflammatory drugs were excluded. All slides were reviewed by two pathologists and 86 blocks were selected to undergo immunohistochemical evaluation. The tumors that were included were categorized as: serous (36), mucinous (46) and seromucinous (4). The cytoplasmatic expression of COX-2 and the nuclear expression of Ki67 were determined with immunohistochemistry in slides obtained from these borderline tumor paraffin blocks. Results: the mean age of the women was 42.4 years (standard deviation 16.5), and there was no significant difference between the mean ages of women with serous, mucinous or seromucinous tumors (p=0.62). Seventy-one women had stage I disease and only three had stage II disease. Of the thirteen women with peritoneal implants, seven had serous borderline tumors, three had mucinous and three seromucinous tumors. The proportion of women with peritoneal implants and stage III disease was significantly higher among women with seromucinous tumors (p=0.0001). The nuclear expression of Ki67 was higher in mucinous tumors (65.8%) in comparison to serous (25%) and seromucinous (25%) (p=0.001). After multivariate analysis it was observed that the cytoplasmatic expression of COX- 2 was significantly higher in serous tumors compared to mucinous (68.5% vs 52.5%; p<0.01). There were no differences regarding the expression of COX-2 comparing seromucinous versus mucinous and mucinous versus seromucinous. The higher cytoplasmatic expression of COX-2 was significantly associated with an increased expression of Ki67 in all histological types (p=0.03). On the other hand, the expression of COX-2 was not related to disease stage and peritoneal implants. Conclusions: these results indicate that the expression of COX-2 is higher in serous borderline ovarian tumors compared to mucinous ones. They also indicate that COX-2 is a good predictor of cell proliferation because its expression increases in parallel to that of Ki67. However, this study does not allow concluding whether COX-2 is a modulator of the tumor's behavior or just a marker of other biological events, considering that it bore no relation to disease stage or peritoneal implants / Mestrado / Ciencias Biomedicas / Mestre em Tocoginecologia

Les lymphocytes T régulateurs (Treg) jouent un rôle prépondérant dans la tolérance du système immunitaire. En physiopathologie, un défaut quantitatif ou fonctionnel en Treg favorise le développement de maladies auto-immunes tandis que leur présence participe au développement tumoral. En particulier, la présence de Treg dans le stroma immunitaire de la tumeur (TiTreg) est de mauvais pronostic pour la survie des patientes atteintes de cancers du sein et de l'ovaire. Les Treg sont recrutés dans la tumeur via l'axe CCL22/CCR4 et sont activés et amplifiés via leur interaction avec les pDC et l'axe de co-stimulation ICOS-ICOSL qui favorise leurs capacités suppressives. Ce projet contribue aux efforts réalisés ces dernières années visant à la compréhension des mécanismes d'immunosuppression des Treg opérant dans les tumeurs humaines. En effet, ce projet met en évidence que les Ti-Treg humains expriment fortement l'ectonucléotidase membranaire CD39. Cette enzyme extracellulaire catabolise l'Adénosine tri-phosphate (ATP) en Adénosine Monophosphate (AMP) pouvant être ensuite dégradé, via l'ectonucléotidase CD73, en Adénosine (Ado). Alors que l'ATP représente une Alarmine (signal de danger extracellulaire) qui en particulier contribue à l'activation de l'inflammasome, l'Ado possède un fort pouvoir immunosuppresseur qui est illustré chez les patients atteints d'une déficience de l'enzyme Adénosine Déaminase (ADA), ne pouvant dégrader l'Ado en Inosine (Ino), développent un Syndrome d'Immunodéficience Sévère. Contrairement au Treg murins, les Treg humains n'expriment pas CD73. Cependant nous avons pu identifier une population de lymphocytes T CD4+ mémoires non régulateurs (Tconv) exprimant CD73 et coopérant ainsi avec les Treg CD39+ pour la génération d'Ado. Cette population présente une capacité accrue de sécrétion de cytokines inflammatoires (IFNgamma, IL-17A, IL-22, GM-CSF) et l'expression de molécules (CXCR3, CCR6, MDR1) caractéristiques du profil Th1/17. De plus ces cellules semblent être moins sensibles à une régulation médiée par les points de contrôles dits immune-checkpoints (ICPs) tel que PD-1, CTLA-4, TIM-3, TIGIT. Par contre, les Tconv CD73+ sont sensibles à l'Ado généré lors de la coopération avec les Treg CD39+ qui engendre l'inhibition de leur prolifération et de leur sécrétion d'IFNgamma et de GM-CSF mais pas de l'IL-17A. L'Ado qui agit localement, peut également entrainer la suppression des Tconv CD73neg dans l'environnement proche. L'ensemble de ces résultats montre que l'expression de CD73 caractérise une population de T CD4 effecteurs polyfonctionnelle Th1/17 qui est une cible privilégiée et coopérative de l'immunosuppression des Treg dans l'environnement tumoral. En outre l'action d'Ado transforme ce puissant effecteur anti-tumoral en cellule potentiellement pro-tumorale via l'unique sécrétion privilégiée d'IL17 / Regulatory T cells (Tregs) play a key role in the immune system tolerance. In pathophysiology, a quantitative or functional defect in Treg promotes development of autoimmune diseases while their presence involved in tumor development. In particular, the presence of Treg in the immune stromal tumor environment (Ti-Treg) is associated with a poor prognosis for survival of patients suffering from breast cancer and ovarian cancer. Treg are recruited in the tumor through the CCL22 / CCR4 axis and are activated and amplified through their interaction with pDC expressing costimulatory axis ICOS-ICOSL and promoting their suppressive capacity. This project contributes to the efforts made in recent years to understand suppressive mechanisms of Treg operating in human tumors. Indeed, this project demonstrates that humans Ti-Treg strongly express the membrane ectonucleotidase CD39. This extracellular enzyme catabolizes Adenosine-triphosphate (ATP) to adenosine-monophosphate (AMP) which can then be degraded through the ectonucleotidase CD73 into Adenosine (Ado). While ATP is an Alarmine (extracellular danger signal) that particularly contributes to the inflammasome activation, Ado has strong immunosuppressive effect which is illustrated in patients with deficiency of the enzyme Adenosine Deaminase (ADA), which cannot degrade Ado into Inosine (Ino) and develop an Immunodeficiency Syndrome Severe. Unlike murine Treg, human Treg do not express CD73. However we could identify a non-regulatory population of CD4+ T cells (Tconv) expressing CD73, and thus cooperating with CD39+ Treg for Ado generation. This population has an increased capacity of secretion of inflammatory cytokines (IFNgamma, IL-17A, IL-22, GM-CSF) and the expression of molecules (CXCR3, CCR6, MDR1) characteristics of Th1/17 profile. Moreover, these cells appear to be less sensitive to regulation mediated by the immunocheckpoints (ICPs), such as PD-1, CTLA-4, TIM-3, TIGIT. Nonetheless CD73+ Tconv are sensitive to Ado generated in cooperation with CD39+ Treg which induce the inhibition of their proliferation and their secretion of IFNgamma and GM-CSF but not IL-17A . Ado acting locally, can also inhibit the Tconv CD73neg in the surrounding environment. All these results show that the expression of CD73 characterizes a population of multifunctional effector T CD4 Th1/17, which is a specific and cooperative target of Treg immunosuppression in the tumor environment. In addition the action of Ado transforms this potent anti-tumor effector to potentially pro-tumor cells which only secret IL17

Nous avons étudié le transcriptome de neuf échantillons d'ARN extraits de cultures primaires de cellules non tumorales de l’épithélium de surface de l’ovaire (NOSE) provenant de quatre donneuses non porteuses de mutation, deux mutées sur BRCA1 et trois sur BRCA2, ainsi que de quatre échantillons d’ARN extraits de cultures primaires de cellules tumorales de l’ovaire (TOV) provenant de trois donneuses porteuses de mutation sur BRCA1 et une sur BRCA2. Nous avons identifié, pour la première fois, les signatures moléculaires associées à la présence d’une mutation de BRCA1 et BRCA2 dans les cellules NOSEs ainsi que la signature associée à la transformation tumorale des cellules NOSEs en TOVs chez les porteuses de mutation de BRCA1. Nous avons également localisé les domaines chromosomiques comportant des gènes corégulés en association avec la présence d’une mutation de BRCA1 dans les cellules NOSEs. Les allèles sauvage et muté de BRCA2 étaient exprimés dans les cellules TOVs provenant des porteuses de la mutation 8765delAG sur BRCA2. Nous avons observé que le niveau d’expression des transcrits de BRCA2 était plus élevé dans les cellules provenant des tumeurs ovariennes les plus agressives chez les femmes porteuses de la mutation 8765delAG sur BRCA2, les transcrits correspondants à l’allèle muté contribuant avec un pourcentage élevé du niveau d’expression total du gène. Le phénotype tumoral observé chez les Canadiennes Françaises porteuses de cette mutation pourrait résulter d’un effet de dosage de l’allèle muté. / We analyzed the transcriptome of nine primary cultures of non-tumor ovarian surface epithelium cells (NOSE) from four non-carriers, two BRCA1 and three BRCA2 carriers, and four primary cultures of tumor ovarian cells (TOV) from three BRCA1 and one BRCA2 carriers. We identified the first molecular signatures associated with the presence of BRCA1 and BRCA2 mutations in NOSEs and the first molecular signature associated with the transformation from NOSEs to TOVs in French Canadian women carriers of BRCA1 mutation. Moreover, we localized some co-regulated chromosomal domains associated with the presence of a BRCA1 mutation in NOSE cells. Wild-type and mutated BRCA2 allelic transcripts were expressed in tumor cells from 8765delAG BRCA2 mutation carriers, with the highest level of BRCA2 transcript expression and the highest contribution of the mutated allele in cells originating from the most aggressive ovarian tumors. The observed phenotype in BRCA2-mutated cells as well as the aggressiveness of the tumor could result from a dosage effect of the BRCA2 mutated allele.

Nous avons étudié le transcriptome de neuf échantillons d'ARN extraits de cultures primaires de cellules non tumorales de l’épithélium de surface de l’ovaire (NOSE) provenant de quatre donneuses non porteuses de mutation, deux mutées sur BRCA1 et trois sur BRCA2, ainsi que de quatre échantillons d’ARN extraits de cultures primaires de cellules tumorales de l’ovaire (TOV) provenant de trois donneuses porteuses de mutation sur BRCA1 et une sur BRCA2. Nous avons identifié, pour la première fois, les signatures moléculaires associées à la présence d’une mutation de BRCA1 et BRCA2 dans les cellules NOSEs ainsi que la signature associée à la transformation tumorale des cellules NOSEs en TOVs chez les porteuses de mutation de BRCA1. Nous avons également localisé les domaines chromosomiques comportant des gènes corégulés en association avec la présence d’une mutation de BRCA1 dans les cellules NOSEs. Les allèles sauvage et muté de BRCA2 étaient exprimés dans les cellules TOVs provenant des porteuses de la mutation 8765delAG sur BRCA2. Nous avons observé que le niveau d’expression des transcrits de BRCA2 était plus élevé dans les cellules provenant des tumeurs ovariennes les plus agressives chez les femmes porteuses de la mutation 8765delAG sur BRCA2, les transcrits correspondants à l’allèle muté contribuant avec un pourcentage élevé du niveau d’expression total du gène. Le phénotype tumoral observé chez les Canadiennes Françaises porteuses de cette mutation pourrait résulter d’un effet de dosage de l’allèle muté. / We analyzed the transcriptome of nine primary cultures of non-tumor ovarian surface epithelium cells (NOSE) from four non-carriers, two BRCA1 and three BRCA2 carriers, and four primary cultures of tumor ovarian cells (TOV) from three BRCA1 and one BRCA2 carriers. We identified the first molecular signatures associated with the presence of BRCA1 and BRCA2 mutations in NOSEs and the first molecular signature associated with the transformation from NOSEs to TOVs in French Canadian women carriers of BRCA1 mutation. Moreover, we localized some co-regulated chromosomal domains associated with the presence of a BRCA1 mutation in NOSE cells. Wild-type and mutated BRCA2 allelic transcripts were expressed in tumor cells from 8765delAG BRCA2 mutation carriers, with the highest level of BRCA2 transcript expression and the highest contribution of the mutated allele in cells originating from the most aggressive ovarian tumors. The observed phenotype in BRCA2-mutated cells as well as the aggressiveness of the tumor could result from a dosage effect of the BRCA2 mutated allele.