Indiana University-Purdue University Indianapolis (IUPUI) / Triple-negative breast cancers (TNBCs) are negative for the expression of estrogen (ER), progesterone (PR), and HER-2 receptors. TNBC accounts for 15% of all breast cancers and results in disproportionally higher mortality compared to ER & HER2-positive tumours. Moreover, there is a paucity of therapies for this subtype of breast cancer resulting primarily from an inadequate understanding of the transcriptional differences that differentiate TNBC from normal breast. To this end, we embarked on a comprehensive examination of the transcriptomes of TNBCs and normal breast tissues using next-generation whole transcriptome sequencing (RNA-Seq). By comparing RNA-seq data from these tissues, we report the presence of differentially expressed coding and non-coding genes, novel transcribed regions, and mutations not previously reported in breast cancer. From these data we have identified two major themes. First, BRCA1 mutations are well known to be associated with development of TNBC. From these data we have identified many genes that work in concert with BRCA1 that are dysregulated suggesting a role of BRCA1 associated genes with sporadic TNBC. In addition, we observe a mutational profile in genes also associated with BRCA1 and DNA repair that lend more evidence to its role. Second, we demonstrate that using microdissected normal epithelium maybe an optimal comparator when searching for novel therapeutic targets for TNBC. Previous studies have used other controls such as reduction mammoplasties, adjacent normal tissue, or other breast cancer subtypes, which may be sub-optimal and have lead to identifying ineffective therapeutic targets. Our data suggests that the comparison of microdissected ductal epithelium to TNBC can identify potential therapeutic targets that may lead to be better clinical efficacy. In summation, with these data, we provide a detailed transcriptional landscape of TNBC and normal breast that we believe will lead to a better understanding of this complex disease.

No description available.

Le diagnostic de prédisposition génétique du cancer du sein et de l’ovaire est détenu par la firme de biotechnologie Myriad Genetics depuis 1996, sous la forme d’un brevet, qui lui octroie une licence d’exploitation internationale, infirmant le droit d’analyse moléculaire aux autres laboratoires. Ce monopole, lui permet de statuer sur un prix excessivement plus élevé qu’en milieu public et d’astreindre en justice, les laboratoires contrevenants. Depuis 2001, le Québec est la seule province qui se soumet (en partie) au brevet, en faisant appel à la compagnie pour le séquençage complet. À travers cette recherche, j’analyse les politiques de brevetage génétique, dans sa construction juridique de la propriété intellectuelle et dans les significations culturelles des biotechnologies. Je m’appuie sur un cadre analytique des théories de propriété et sur la recherche en biomédical. Je procède également à l’analyse du discours des médecins et conseillers généticiens au Québec, à travers des entrevues conduites dans des centres hospitaliers de la région de Montréal et de Sherbrooke. Cette étude qualitative identifie comment les conseillers et médecins généticiens conçoivent le rôle des brevets dans les dépistages et diagnostics du cancer et comment les brevets génétiques expriment une culture médicale. Je cherche à déterminer comment sont perçus par des professionnels de santé les brevets génétiques en analysant et en comparant les variations entre limites idéologiques et limites pratiques. / The biotechnology company Myriad Genetics owns the diagnosis of genetic predisposition of breast and ovarian cancer since 1996. The patent, which grants an international license, reverses the right of molecular analysis by other laboratories. This monopoly allows the company to apply an excessively higher price than public laboratories and pursue the offenders in justice. However, since 2001, Quebec is the only province to respect (in part) the patent, using the company for the complete sequencing. This research analyzes the gene patent politics in its legal structure of intellectual property and the cultural meanings of biotechnology. I rely on an analytical framework of theories of property and biomedical research. I also proceeded to the discourse analysis of physicians and genetic counsellors in Quebec through interviews conducted in hospitals in the region of Montreal and Sherbrooke. This qualitative study identifies how doctors and genetic counsellors analysis the role of patents in the screening and diagnosis of cancer and how genetic patents express a medical culture. The study aims to explore how gene patents are perceived in analyzing and comparing the variations between ideological limits and practical limits.

Résumé Introduction L’efficacité de la mastectomie prophylactique est bien démontrée. La mastectomie NSM (nipple-sparing mastectomy) peut potentiellement améliorer les résultats esthétiques, mais elle n’est pas pratiquée d’emblée en raison de doutes face à sa sécurité oncologique. Objectif Évaluer la faisabilité et la sécurité oncologique de la NSM dans un contexte prophylactique ainsi que les résultats esthétiques et la satisfaction des patientes. Méthodologie Une étude rétrospective fut conduite chez toutes les femmes ayant subi une mastectomie prophylactique suivie d’une reconstruction mammaire immédiate au centre hospitalier de l’Université de Montréal (CHUM) entre1997 et 2008. Les données concernant les facteurs de risque de cancer, les complications post-opératoires et les incidences de cancer furent notées. La satisfaction des patientes était évaluée par questionnaire. Deux chirurgiens ont évalué les résultats esthétiques sur des photos. Résultats Soixante et onze patientes ont subi 86 mastectomies prophylactiques, dont 21 NSM et 65 SSM (skin-sparing mastectomy). Suivant une SSM, 34 CAM (complexe aréolo- mamelonaire) furent reconstruits. Une nécrose totale s’est produite dans 2 CAM préservés et dans 2 CAM reconstruits. Le taux général de complications était significativement plus élevé parmi les CAM reconstruits. La satisfaction des patientes quant à l’apparence du CAM était significativement plus élevée dans le groupe NSM et les résultats esthétiques, meilleurs. Avec un temps de suivi moyen de 50 mois, aucune incidence au niveau du CAM n’est survenue. i Conclusion Les NSM offrent de meilleures résultats, n’augmentent pas les complications post- opératoire et semblent sécuritaires au plan oncologique. / Introduction The efficiency of prophylactic mastectomy is well acknowledged. Nipple sparing mastectomy (NSM) can potentially improve cosmetic results, but it is not the current practice because of doubts regarding its oncological safety. Objectives To evaluate NSM’s feasibility and oncological safety in a prophylactic setting, as well as aesthetic results and patient satisfaction. Methods A retrospective study was conducted on every women that underwent prophylacitc mastectomy followed by immediate breast reconstruction in the centre hospitalier de l’Université de Montréal (CHUM) between 1997 and 2008. Data regarding cancer risk factors, post operative complication and cancer incidence were compiled. Patient satisfaction was evaluated using a questionnaire and two plastic surgeons rated the aesthetic results on photos. Results Seventy-one patients underwent 21 NSM et 65 skin-sparing mastectomies (SSM) for a total of 86 prophylactic procedures. Following SSM, 34 nipple areolar-complexes (NAC) were reconstructed. Necrosis was noted in 2 preserved NAC and in 2 reconstructed NAC. The overall complication rate was superior among the reconstructed NAC. Patient satisfaction regarding NAC appearance was significantly higher within the preserved NAC group and the aesthetic results were evaluated as better. With a mean follow-up time of 50 months, no incidence was noted in the NAC area. iii Conclusion NSM offer superior aesthetic results, do not increase post-operative complications and appear the be oncologicaly safe.

Résumé Introduction L’efficacité de la mastectomie prophylactique est bien démontrée. La mastectomie NSM (nipple-sparing mastectomy) peut potentiellement améliorer les résultats esthétiques, mais elle n’est pas pratiquée d’emblée en raison de doutes face à sa sécurité oncologique. Objectif Évaluer la faisabilité et la sécurité oncologique de la NSM dans un contexte prophylactique ainsi que les résultats esthétiques et la satisfaction des patientes. Méthodologie Une étude rétrospective fut conduite chez toutes les femmes ayant subi une mastectomie prophylactique suivie d’une reconstruction mammaire immédiate au centre hospitalier de l’Université de Montréal (CHUM) entre1997 et 2008. Les données concernant les facteurs de risque de cancer, les complications post-opératoires et les incidences de cancer furent notées. La satisfaction des patientes était évaluée par questionnaire. Deux chirurgiens ont évalué les résultats esthétiques sur des photos. Résultats Soixante et onze patientes ont subi 86 mastectomies prophylactiques, dont 21 NSM et 65 SSM (skin-sparing mastectomy). Suivant une SSM, 34 CAM (complexe aréolo- mamelonaire) furent reconstruits. Une nécrose totale s’est produite dans 2 CAM préservés et dans 2 CAM reconstruits. Le taux général de complications était significativement plus élevé parmi les CAM reconstruits. La satisfaction des patientes quant à l’apparence du CAM était significativement plus élevée dans le groupe NSM et les résultats esthétiques, meilleurs. Avec un temps de suivi moyen de 50 mois, aucune incidence au niveau du CAM n’est survenue. i Conclusion Les NSM offrent de meilleures résultats, n’augmentent pas les complications post- opératoire et semblent sécuritaires au plan oncologique. / Introduction The efficiency of prophylactic mastectomy is well acknowledged. Nipple sparing mastectomy (NSM) can potentially improve cosmetic results, but it is not the current practice because of doubts regarding its oncological safety. Objectives To evaluate NSM’s feasibility and oncological safety in a prophylactic setting, as well as aesthetic results and patient satisfaction. Methods A retrospective study was conducted on every women that underwent prophylacitc mastectomy followed by immediate breast reconstruction in the centre hospitalier de l’Université de Montréal (CHUM) between 1997 and 2008. Data regarding cancer risk factors, post operative complication and cancer incidence were compiled. Patient satisfaction was evaluated using a questionnaire and two plastic surgeons rated the aesthetic results on photos. Results Seventy-one patients underwent 21 NSM et 65 skin-sparing mastectomies (SSM) for a total of 86 prophylactic procedures. Following SSM, 34 nipple areolar-complexes (NAC) were reconstructed. Necrosis was noted in 2 preserved NAC and in 2 reconstructed NAC. The overall complication rate was superior among the reconstructed NAC. Patient satisfaction regarding NAC appearance was significantly higher within the preserved NAC group and the aesthetic results were evaluated as better. With a mean follow-up time of 50 months, no incidence was noted in the NAC area. iii Conclusion NSM offer superior aesthetic results, do not increase post-operative complications and appear the be oncologicaly safe.

Introdução: Mulheres portadoras de mutações germinativas BRCA1 ou BRCA2 apresentam um risco aumentado de câncer de mama e de ovário em comparação com a população geral, enquanto a salpingo-ooforectomia redutora de risco (SORR) reduz significativamente a incidência desses cânceres. O objetivo deste estudo foi analisar as características clínicas e patológicas de uma população franco-canadense que realizou a SORR. A morbidade cirúrgica também foi avaliada. Materiais e Métodos: Entre dezembro de 1999 e dezembro de 2009, todas as pacientes submetidas à SORR foram identificadas. Os prontuários médicos foram revisados. Estatística descritiva, teste exato de Fischer, e teste t de Student foram utilizados para análise. Resultados: Durante o período de estudo, a SORR foi realizada em 119 mulheres. A média de idade no momento da cirurgia foi de 49 anos (35-72 anos); e 63 pacientes (53%) estavam na pré-menopausa. Sessenta e duas mulheres (52%) tinham uma história de câncer de mama in situ ou invasor. Mutações nos genes BRCA1 e BRCA2 estavam presentes em 34 pacientes (29%) e 42 pacientes (35%), respectivamente. Desse modo, 43 pacientes (36%) foram consideradas como tendo um risco aumentado de câncer de mama e de ovário, apesar de um teste negativo para ambos os genes (n = 23) ou desconhecido, porque o paciente recusou teste genético (n = 20). A maioria das pacientes com útero foi submetida a uma histerectomia complementar (65%). Seis complicações ocorreram (3 hematomas, 2 arritmias cardíacas e uma cistostomia). Em uma paciente (0,8%), um carcinoma ovariano de alto grau estadio II foi descoberto no momento da cirurgia. Atipias de tubas de falópio foram identificadas na patologia final em 8 casos (6,7%). Após um acompanhamento médio de 22 meses, 4 mulheres (3,4%) desenvolveram câncer de mama e uma paciente (0,8%) desenvolveu câncer peritoneal. Conclusões: a SORR é altamente eficaz na prevenção de câncer de ovário, tuba de falópio, e de carcinomas de mama em uma população franco-canadense de alto risco, sendo que a morbidade cirúrgica é baixa. / Background: Women with germ line BRCA1 or BRCA2 mutations have a marked increased risk of breast and ovarian cancer compared with the general population, whereas risk-reducing salpingo-oophorectomy (RRSO) significantly lowers the incidence of these cancers. The objective of this study was to review the clinical and pathological characteristics of a French Canadian population undergoing RRSO. Surgical morbidity was also evaluated. Materials and Methods: From December 1999 to December 2009, all women who underwent RRSO at our institution were identified. Medical records were retrospectively reviewed. Descriptive statistics, the Fischer exact test, and the Student t test were used for analysis. Results: During the study period, RRSO was performed on 119 women. Mean age at surgery was 49 years (35-72 years), and 63 patients (53%) were premenopausal. Sixty two women (52%) had a history of in situ or invasive breast cancer. BRCA1 and BRCA2 mutations were present in 34 patients (29%) and 42 patients (35%), respectively, whereas 43 patients (36%) were considered to have an increased risk of breast and ovarian cancer, despite a personal genetic test, which was either negative (n = 23) or unknown because the patient declined genetic testing (n = 20). Most patients with an uterus in place had a complementary hysterectomy (65%). Six complications occurred (3 hematomas, 2 cardiac arrhythmias, and 1 cystotomy). In one patient (0.8%), a high-grade stage II ovarian cancer was discovered at the time of surgery. Fallopian tube atypias were identified on final pathology in 8 cases (6.7%). After a median follow-up of 22 months, 4 women (3.4%) developed breast cancer and one woman (0.8%) developed peritoneal cancer. Conclusions: Risk-reducing salpingo-oophorectomy is highly effective in preventing ovarian, fallopian tube, and breast cancers in a high-risk French Canadian population; and the surgical morbidity is low.

Introdução: Mulheres portadoras de mutações germinativas BRCA1 ou BRCA2 apresentam um risco aumentado de câncer de mama e de ovário em comparação com a população geral, enquanto a salpingo-ooforectomia redutora de risco (SORR) reduz significativamente a incidência desses cânceres. O objetivo deste estudo foi analisar as características clínicas e patológicas de uma população franco-canadense que realizou a SORR. A morbidade cirúrgica também foi avaliada. Materiais e Métodos: Entre dezembro de 1999 e dezembro de 2009, todas as pacientes submetidas à SORR foram identificadas. Os prontuários médicos foram revisados. Estatística descritiva, teste exato de Fischer, e teste t de Student foram utilizados para análise. Resultados: Durante o período de estudo, a SORR foi realizada em 119 mulheres. A média de idade no momento da cirurgia foi de 49 anos (35-72 anos); e 63 pacientes (53%) estavam na pré-menopausa. Sessenta e duas mulheres (52%) tinham uma história de câncer de mama in situ ou invasor. Mutações nos genes BRCA1 e BRCA2 estavam presentes em 34 pacientes (29%) e 42 pacientes (35%), respectivamente. Desse modo, 43 pacientes (36%) foram consideradas como tendo um risco aumentado de câncer de mama e de ovário, apesar de um teste negativo para ambos os genes (n = 23) ou desconhecido, porque o paciente recusou teste genético (n = 20). A maioria das pacientes com útero foi submetida a uma histerectomia complementar (65%). Seis complicações ocorreram (3 hematomas, 2 arritmias cardíacas e uma cistostomia). Em uma paciente (0,8%), um carcinoma ovariano de alto grau estadio II foi descoberto no momento da cirurgia. Atipias de tubas de falópio foram identificadas na patologia final em 8 casos (6,7%). Após um acompanhamento médio de 22 meses, 4 mulheres (3,4%) desenvolveram câncer de mama e uma paciente (0,8%) desenvolveu câncer peritoneal. Conclusões: a SORR é altamente eficaz na prevenção de câncer de ovário, tuba de falópio, e de carcinomas de mama em uma população franco-canadense de alto risco, sendo que a morbidade cirúrgica é baixa. / Background: Women with germ line BRCA1 or BRCA2 mutations have a marked increased risk of breast and ovarian cancer compared with the general population, whereas risk-reducing salpingo-oophorectomy (RRSO) significantly lowers the incidence of these cancers. The objective of this study was to review the clinical and pathological characteristics of a French Canadian population undergoing RRSO. Surgical morbidity was also evaluated. Materials and Methods: From December 1999 to December 2009, all women who underwent RRSO at our institution were identified. Medical records were retrospectively reviewed. Descriptive statistics, the Fischer exact test, and the Student t test were used for analysis. Results: During the study period, RRSO was performed on 119 women. Mean age at surgery was 49 years (35-72 years), and 63 patients (53%) were premenopausal. Sixty two women (52%) had a history of in situ or invasive breast cancer. BRCA1 and BRCA2 mutations were present in 34 patients (29%) and 42 patients (35%), respectively, whereas 43 patients (36%) were considered to have an increased risk of breast and ovarian cancer, despite a personal genetic test, which was either negative (n = 23) or unknown because the patient declined genetic testing (n = 20). Most patients with an uterus in place had a complementary hysterectomy (65%). Six complications occurred (3 hematomas, 2 cardiac arrhythmias, and 1 cystotomy). In one patient (0.8%), a high-grade stage II ovarian cancer was discovered at the time of surgery. Fallopian tube atypias were identified on final pathology in 8 cases (6.7%). After a median follow-up of 22 months, 4 women (3.4%) developed breast cancer and one woman (0.8%) developed peritoneal cancer. Conclusions: Risk-reducing salpingo-oophorectomy is highly effective in preventing ovarian, fallopian tube, and breast cancers in a high-risk French Canadian population; and the surgical morbidity is low.

Introdução: Mulheres portadoras de mutações germinativas BRCA1 ou BRCA2 apresentam um risco aumentado de câncer de mama e de ovário em comparação com a população geral, enquanto a salpingo-ooforectomia redutora de risco (SORR) reduz significativamente a incidência desses cânceres. O objetivo deste estudo foi analisar as características clínicas e patológicas de uma população franco-canadense que realizou a SORR. A morbidade cirúrgica também foi avaliada. Materiais e Métodos: Entre dezembro de 1999 e dezembro de 2009, todas as pacientes submetidas à SORR foram identificadas. Os prontuários médicos foram revisados. Estatística descritiva, teste exato de Fischer, e teste t de Student foram utilizados para análise. Resultados: Durante o período de estudo, a SORR foi realizada em 119 mulheres. A média de idade no momento da cirurgia foi de 49 anos (35-72 anos); e 63 pacientes (53%) estavam na pré-menopausa. Sessenta e duas mulheres (52%) tinham uma história de câncer de mama in situ ou invasor. Mutações nos genes BRCA1 e BRCA2 estavam presentes em 34 pacientes (29%) e 42 pacientes (35%), respectivamente. Desse modo, 43 pacientes (36%) foram consideradas como tendo um risco aumentado de câncer de mama e de ovário, apesar de um teste negativo para ambos os genes (n = 23) ou desconhecido, porque o paciente recusou teste genético (n = 20). A maioria das pacientes com útero foi submetida a uma histerectomia complementar (65%). Seis complicações ocorreram (3 hematomas, 2 arritmias cardíacas e uma cistostomia). Em uma paciente (0,8%), um carcinoma ovariano de alto grau estadio II foi descoberto no momento da cirurgia. Atipias de tubas de falópio foram identificadas na patologia final em 8 casos (6,7%). Após um acompanhamento médio de 22 meses, 4 mulheres (3,4%) desenvolveram câncer de mama e uma paciente (0,8%) desenvolveu câncer peritoneal. Conclusões: a SORR é altamente eficaz na prevenção de câncer de ovário, tuba de falópio, e de carcinomas de mama em uma população franco-canadense de alto risco, sendo que a morbidade cirúrgica é baixa. / Background: Women with germ line BRCA1 or BRCA2 mutations have a marked increased risk of breast and ovarian cancer compared with the general population, whereas risk-reducing salpingo-oophorectomy (RRSO) significantly lowers the incidence of these cancers. The objective of this study was to review the clinical and pathological characteristics of a French Canadian population undergoing RRSO. Surgical morbidity was also evaluated. Materials and Methods: From December 1999 to December 2009, all women who underwent RRSO at our institution were identified. Medical records were retrospectively reviewed. Descriptive statistics, the Fischer exact test, and the Student t test were used for analysis. Results: During the study period, RRSO was performed on 119 women. Mean age at surgery was 49 years (35-72 years), and 63 patients (53%) were premenopausal. Sixty two women (52%) had a history of in situ or invasive breast cancer. BRCA1 and BRCA2 mutations were present in 34 patients (29%) and 42 patients (35%), respectively, whereas 43 patients (36%) were considered to have an increased risk of breast and ovarian cancer, despite a personal genetic test, which was either negative (n = 23) or unknown because the patient declined genetic testing (n = 20). Most patients with an uterus in place had a complementary hysterectomy (65%). Six complications occurred (3 hematomas, 2 cardiac arrhythmias, and 1 cystotomy). In one patient (0.8%), a high-grade stage II ovarian cancer was discovered at the time of surgery. Fallopian tube atypias were identified on final pathology in 8 cases (6.7%). After a median follow-up of 22 months, 4 women (3.4%) developed breast cancer and one woman (0.8%) developed peritoneal cancer. Conclusions: Risk-reducing salpingo-oophorectomy is highly effective in preventing ovarian, fallopian tube, and breast cancers in a high-risk French Canadian population; and the surgical morbidity is low.

Recent knowledge suggests that the onset of cancer is modulated by the interplay of internal and external environmental factors along with numerous gene variants. Structural chromsomal aberrations in peripheral blood lymphocytes are considered as biomarkers of effect of genotoxic carcinogens and reflect elevated risk of cancer. Incomplete or deficient repair of double-strand breaks in DNA underlie chromosomal aberrations and the measurement of cytogenetic alterations may reflect interindividual differences in the response towards the mutagen. In this study the expected deficiences in the DNA repair capacity have been determined in incident oncological patients with breast, colorectal and urogenital cancers. The determination of chromosomal aberrations have been supplemented by the measurement of variants in genes involved in double-strand breaks repair (XRCC3, rs861539; RAD54L, rs1048771). Methodologically, we employed conventional cytogenetic analysis, cytogenetic analysis following the induction of chromocomal damage by bleomycin ("Challenge assay"), TaqMan discrimination analysis for the detection of allelic variants and statistical analyses. By using these methods we did not observe statistically signifiant differences either in chromosomal breaks (p=0,354) or in a percentage of cells with...

No description available.