Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids

International audienceThe worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary car-cinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low-and high-grade lung neuroendocrine neoplasms

Study of mesothelioma associated factors in women

Le mésothéliome est une tumeur maligne rare des séreuses, au pronostic sombre, dont le facteur de risque principal connu est l’exposition à l’amiante. Il se déclare avec un temps de latence d’environ 30 ans après le début de l’exposition, atteint principalement la plèvre et touche majoritairement les hommes. L’analyse de cette pathologie, reconnue comme une maladie professionnelle et pour laquelle une Déclaration Obligatoire de maladie a été instituée en janvier 2012, s’est focalisée jusqu’alors essentiellement sur l’homme, tant sur le plan épidémiologique que sur le plan biologique. Il apparaît pourtant dans la littérature internationale des différences notables par sexe.Ces constations posent la question d’investiguer d’autres facteurs de risque, en particulier l’hypothèse d’une prédisposition génétique, les mécanismes biologiques intervenant dans les voies de la carcinogenèse du mésothéliome étant partiellement connus. Ceci incite à étudier les facteurs épidémiologiques, cliniques, biologiques et immunohistochimiques, prédisposant chez la femme au développement du mésothéliome pleural et péritonéal, et d’évaluer leurs impacts pronostiques, à partir des cas diagnostiqués entre 1998 et 2013, issus de la plus importante base de données française. Elle incite également à établir un état des lieux épidémiologique actualisé par sexe en France pour le mésothéliome pleural et péritonéal ; ces données étant inexistantes pour la France pour le péritoine.Mesothelioma is a rare malignant serous tumor with a poor prognosis of which asbestos exposure is the major known risk factor. It occurs with a latent period about 30 years after exposure, reaches mainly the pleura and affects mainly the men. The study of this pathology, recognized as an occupationnal disease and for which a Mandatory Declaration of Disease was introduced in January 2012, focused until then mainly on men, both epidemiologically and biologically. However, there are significant gender differences in the international literature.These results raise the question of investigating other risk factors, in particular the hypothesis of genetic predisposition, the biological mechanisms involved in mesothelioma carcinogenesis pathways being partially known. This encourages the study of epidemiological, clinical, biological and immunohistochemical factors predisposing women to the development of pleural and peritoneal mesothelioma, and to evaluate their prognostic impacts, based on cases diagnosed between 1980 and 2015, from the largest French database. It also encourages the establishment of an updated epidemiological inventory by gender in France for pleural and peritoneal mesothelioma; these data are non-existent for peritoneum

Etude des facteurs associés au mésothéliome chez la femme

Mesothelioma is a rare malignant serous tumor with a poor prognosis of which asbestos exposure is the major known risk factor. It occurs with a latent period about 30 years after exposure, reaches mainly the pleura and affects mainly the men. The study of this pathology, recognized as an occupationnal disease and for which a Mandatory Declaration of Disease was introduced in January 2012, focused until then mainly on men, both epidemiologically and biologically. However, there are significant gender differences in the international literature.These results raise the question of investigating other risk factors, in particular the hypothesis of genetic predisposition, the biological mechanisms involved in mesothelioma carcinogenesis pathways being partially known. This encourages the study of epidemiological, clinical, biological and immunohistochemical factors predisposing women to the development of pleural and peritoneal mesothelioma, and to evaluate their prognostic impacts, based on cases diagnosed between 1980 and 2015, from the largest French database. It also encourages the establishment of an updated epidemiological inventory by gender in France for pleural and peritoneal mesothelioma; these data are non-existent for peritoneum.Le mésothéliome est une tumeur maligne rare des séreuses, au pronostic sombre, dont le facteur de risque principal connu est l’exposition à l’amiante. Il se déclare avec un temps de latence d’environ 30 ans après le début de l’exposition, atteint principalement la plèvre et touche majoritairement les hommes. L’analyse de cette pathologie, reconnue comme une maladie professionnelle et pour laquelle une Déclaration Obligatoire de maladie a été instituée en janvier 2012, s’est focalisée jusqu’alors essentiellement sur l’homme, tant sur le plan épidémiologique que sur le plan biologique. Il apparaît pourtant dans la littérature internationale des différences notables par sexe.Ces constations posent la question d’investiguer d’autres facteurs de risque, en particulier l’hypothèse d’une prédisposition génétique, les mécanismes biologiques intervenant dans les voies de la carcinogenèse du mésothéliome étant partiellement connus. Ceci incite à étudier les facteurs épidémiologiques, cliniques, biologiques et immunohistochimiques, prédisposant chez la femme au développement du mésothéliome pleural et péritonéal, et d’évaluer leurs impacts pronostiques, à partir des cas diagnostiqués entre 1998 et 2013, issus de la plus importante base de données française. Elle incite également à établir un état des lieux épidémiologique actualisé par sexe en France pour le mésothéliome pleural et péritonéal ; ces données étant inexistantes pour la France pour le péritoine

Incidence and survival of peritoneal malignant mesothelioma between 1989 and 2015: A population-based study

International audienceBACKGROUND:Peritoneal malignant mesothelioma is a rare disease for which few population-based studies are available. The aim of this study was to describe the evolution of the incidence and survival of peritoneal malignant mesothelioma in France between 1989 and 2015, using data derived from the French network of cancer registries.METHODS:Age world-standardized incidence rates and overall survival were calculated using data from 16 French cancer registries. Log-linear Poisson regression analysis was used to estimate the average annual percentage change in incidence rates. Overall survival was performed using age-adjusted Cox proportional hazards model.RESULTS:In French men, the incidence has increased quietly over the reporting period from 0.07 to 0.10 with a maximum of 0.16 per 100,000 persons-years in 2001-2003. For women, the increase in incidence has been lower than for men over the period 1989-2015, ranging from 0.04 to 0.11. A better prognosis was associated with a diagnosis made after 2000 (HR = 1.76; p = 0.013), the epithelioid histological type (p = 0.003), and the fact of being a woman, which has a 5-year risk of death half that of men (HR = 0.55; p = 0.001), regardless of age, diagnosis period or histology.CONCLUSION:Our results are similar to those currently available for other countries. In France, peritoneal mesothelioma remains a rare and fatal cancer with a small increase in the incidence rate since 1989 and a median survival of 1 year; it seemed to develop equally in women and men over this period of time

Release of c-FLIP brake selectively sensitizes human cancer cells to TLR3-mediated apoptosis

Abstract Toll-like receptor 3 (TLR3) mediates innate immune responses by sensing viral dsRNA, but also induces apoptosis selectively in cancer cells. Our analysis by immunohistochemistry revealed that TLR3 is frequently overexpressed in 130 non-small cell lung cancer (NSCLC) patients’ samples compared with normal bronchial epithelium (P < 0.0001, Mann–Whitney test), supporting the therapeutic potential of TLR3 ligand for this type of cancer. However, a proportion of TLR3-expressing cancer cell lines, including NSCLC, remain resistant to TLR3-mediated apoptosis, and the underlying mechanism of resistance remains unclear. We here investigated the molecular basis conferring resistance to non-transformed vs. transformed cells against TLR3-mediated cell death. In non-transformed epithelial cells cellular FLICE-like inhibitory protein (c-FLIP) and cellular Inhibitor of APoptosis (cIAPs) ubiquitin ligases exerted an efficient double brake on apoptosis signaling. In contrast, releasing only one of these two brakes was sufficient to overcome the resistance of 8/8 cancer cell lines tested. Remarkably, the release of the c-FLIP, but not cIAPs, brake only results in the sensitization of all human cancer cells to TLR3-mediated apoptosis. Taking advantage of the difference between transformed and non-transformed cells, we developed a rational strategy by combining the chemotherapeutic agent paclitaxel, which decreases c-FLIP expression, with TLR3 ligand. This combination was highly synergistic for triggering apoptosis in cancer cells but not in non-transformed cells. In vivo, the combination of paclitaxel with dsRNA delayed tumor growth and prolonged survival in a mouse xenograft lung tumor model. In conclusion, combining the release of the c-FLIP brake with TLR3 ligand synergizes to selectively kill cancer cells, and could represent an efficient and safe therapy against TLR3-expressing cancers such as NSCLC

Plasma Cell Membrane Localization of c-MET Predicts Longer Survival in Patients with Malignant Mesothelioma: A Series of 157 Cases from the MESOPATH Group

International audienc

Interobserver variation in the assessment of the sarcomatoid and transitional components in biphasic mesotheliomas

The percentage of sarcomatoid component has an impact on prognosis in patients with biphasic malignant pleural mesothelioma. Recent study showed that the transitional pattern similar to sarcomatoid component of malignant mesothelioma has negative prognostic significance. Practice guidelines recommend quantification of sarcomatoid component despite poor diagnostic reproducibility of biphasic mesothelioma among thoracic pathologists. The aim of this study was to determine the interobserver agreement in the quantification of sarcomatoid component, and in the diagnosis of a transitional component in the biphasic malignant mesothelioma. Thirteen experts in thoracic pathology reviewed the representative H&E and cytokeratin whole-slide images of the 54 biphasic mesotheliomas, without knowledge of BAP1 or p16 deletion status, and completed the survey of 25 questions. The overall interobserver agreement in the assessment of the percentage of the sarcomatoid component in 25% increments was good (wK = 0.62). Excellent agreement was present in 14 of 54 cases (26%), and 3 cases were unanimously scored. Excellent agreement was reached for the cases with 0-24% and > 75% of the sarcomatoid component.The most commonly used criteria for the diagnosis of sarcomatoid component were malignant spindle cells, frank sarcomatoid features and high N/C ratio. The overall interobserver agreement for transitional pattern was fair (wK = 0.40). Unanimous opinion about the absence of transitional pattern was observed in only one case. At least 70% agreement regarding the presence of transitional pattern was observed in 12 cases, with the rest of the cases showing a wide range of disagreement. Morphologic characteristics that favor transitional pattern over non-transitional include sheet-like growth of cohesive, plump, elongated epithelioid cells with well-defined cell borders and a tendency to transition into spindle cells. Our study defined precise morphologic criteria that may be used in the differential diagnosis between transitional pattern and other mesothelioma subtypes including sarcomatoid and epithelioid.status: publishe