<p>Pancreatic endocrine tumors (PETs) occur sporadically or in the familial multiple endocrine neoplasia type 1 (MEN1) syndrome, whereas midgut carcinoids are nonfamilial, malignant endocrine tumors of the intestine. For these tumor entities morphological criteria are of limited use for prognostic prediction and selection of treatment. Genetic characterization may give additional information of clinical use and reveal pathways involved in tumor development.</p><p>Molecular genetic alterations in sporadic and MEN1-associated PETs and midgut carcinoids were studied with LOH and mutational analysis. In addition, immunohistochemistry was used to clarify gene expression. Detected genetic aberrations were correlated to the disease course of individual patients.</p><p>Somatic mutations of the<i> MEN1</i> gene at chromosome <i>11q13</i> were detected in 1/3 of sporadic PETs<i>. </i>Moreover, LOH was found in 70% of the lesions. All tumors with somatic <i>MEN1</i> mutations displayed loss of the remaining allele showing that the <i>MEN1</i> gene is involved in development of sporadic PETs.</p><p> Sporadic and MEN1 PETs were analyzed for LOH at <i>3p,</i> <i>11q13</i> and <i>18q</i>. A relation of LOH at <i>11q13</i> and <i>3p</i> to malignancy was found for the sporadic tumors. None of the benign tumors (all of them insulinomas) had allelic loss at <i>3p</i> or <i>11q13</i>, versus 92 % (p<0.01) of the malignant tumors (including malignant insulinomas). 1/4 of both sporadic and MEN1 lesions displayed LOH at <i>18q</i>, without altered <i>Smad4/DPC4</i>.</p><p>Genome-wide LOH screening of MEN1 PETs revealed multiple allelic deletions without general correlation to tumor size or malignancy. All tumors displayed LOH at the <i>MEN1 </i>locus, and 30% on chromosomes 3, 6, 8, 10, 18 and 21. Intratumoral heterogeneity was revealed, with chromosome 6 and 11 deletions in most tumor cells. Chromosome 6 deletions were mainly found in lesions from patients with malignant features. </p><p>A similar genome-wide LOH screening was performed on midgut carcinoids. Deletions at chromosome <i>18q</i> were found in 88% of the tumors indicating a potential tumor suppressor locus.</p>

Pancreatic endocrine tumors (PETs) occur sporadically or in the familial multiple endocrine neoplasia type 1 (MEN1) syndrome, whereas midgut carcinoids are nonfamilial, malignant endocrine tumors of the intestine. For these tumor entities morphological criteria are of limited use for prognostic prediction and selection of treatment. Genetic characterization may give additional information of clinical use and reveal pathways involved in tumor development. Molecular genetic alterations in sporadic and MEN1-associated PETs and midgut carcinoids were studied with LOH and mutational analysis. In addition, immunohistochemistry was used to clarify gene expression. Detected genetic aberrations were correlated to the disease course of individual patients. Somatic mutations of the MEN1 gene at chromosome 11q13 were detected in 1/3 of sporadic PETs. Moreover, LOH was found in 70% of the lesions. All tumors with somatic MEN1 mutations displayed loss of the remaining allele showing that the MEN1 gene is involved in development of sporadic PETs. Sporadic and MEN1 PETs were analyzed for LOH at 3p, 11q13 and 18q. A relation of LOH at 11q13 and 3p to malignancy was found for the sporadic tumors. None of the benign tumors (all of them insulinomas) had allelic loss at 3p or 11q13, versus 92 % (p&lt;0.01) of the malignant tumors (including malignant insulinomas). 1/4 of both sporadic and MEN1 lesions displayed LOH at 18q, without altered Smad4/DPC4. Genome-wide LOH screening of MEN1 PETs revealed multiple allelic deletions without general correlation to tumor size or malignancy. All tumors displayed LOH at the MEN1 locus, and 30% on chromosomes 3, 6, 8, 10, 18 and 21. Intratumoral heterogeneity was revealed, with chromosome 6 and 11 deletions in most tumor cells. Chromosome 6 deletions were mainly found in lesions from patients with malignant features. A similar genome-wide LOH screening was performed on midgut carcinoids. Deletions at chromosome 18q were found in 88% of the tumors indicating a potential tumor suppressor locus.

Le syndrome des Néoplasies Endocriniennes Multiples de type I (NEM1) est une maladie tumorale héréditaire rare caractérisée par l'apparition de tumeurs notamment du pancréas endocrine. Le gène de prédisposition est le suppresseur de tumeur MEN1, généralement retrouvé muté sur un des 2 allèles au niveau germinal chez les patients NEM1. Les tumeurs endocrines pancréatiques sont rares mais souvent métastatiques lors du diagnostic. Ces tumeurs forment un groupe hétérogène de par le type d'hormone qu'elles peuvent sécréter. Le développement et l'évolution de ces tumeurs sont encore très mal compris. L'origine cellulaire des différents types de tumeurs endocrines pancréatiques reste énigmatique, notamment en ce qui concerne les tumeurs exprimant des hormones non pancréatiques tels que les gastrinomes. Mon projet de thèse s'est articulé autour de la caractérisation d'un nouveau modèle murin d'invalidation du gène Men1 spécifiquement dans les cellules progénitrices endocrine pancréatiques Ngn3+ (PEPs), le modèle PancEndoMen1 KO. Ces travaux nous ont permis de démontrer que les gastrinomes pancréatiques liés à l'inactivation du gène Men1, avaient pour origines les cellules pancréatiques endocrines elles-mêmes. De plus, les souris PancEndoMen1 KO, développent des altérations de prolifération différentes suivant les lignages endocrines. De surcroît, l'invalidation du gène Men1 soit dans les cellules progénitrices pancréatiques, soit dans les cellules PEPs conduit au développement de tumeurs caractérisées par une altération de leur différentiation endocrine. Ainsi, mes travaux de thèse ont permis de mieux renseigner l'histogenèse des tumeurs endocrines pancréatiques en adressant le rôle dans la tumorigenèse de l'invalidation de Men1 dans les cellules PEPs au cours du développement / Multiple Endocrine Neoplasia Type I syndrome (MEN1) is a rare hereditary tumoral disease characterized by the apparition of tumors in multiple endocrine organs including the endocrine pancreas. MEN1 patients generally carry a germinal mutation on one allele of the predisposing gene to the disease, the tumor suppressor MEN1. Pancreatic endocrine tumors are rare, slowly evolving and often present with metastasis at diagnosis. These tumors constitute a heterogeneous group defined by their hormonal secretions. Evolution and development of these tumors is far from being understood. The cell of origin of the different pancreatic endocrine tumor types is enigmatic, notably for tumors secreting non-pancreatic hormones such as gastrinomas. My thesis project was structured toward the characterization of a new murine model allowing the specific disruption of the Men1 gene in Ngn3+ pancreatic endocrine progenitors, the PancEndoMen1 KO model. The combined study of this new model and previous model generated in the team, allowed us to demonstrate that pancreatic gastrinomas related to Men1 inactivation, originate from the endogenous pancreatic endocrine cells. In parallel, our results demonstrated that the mutant mice having Men1-deficient Ngn3+-progenitors resulted in differential cell proliferation alterations in different pancreatic endocrine cells. Importantly, Men1-disruption in either pancreatic endocrine or pan-pancreatic progenitors displayed tumors with impaired differentiation features. Thus, this thesis works allowed to better characterize pancreatic endocrine tumors histogenesis by addressing the role of pancreatic endocrine progenitors targeted Men1 disruption during development in tumorigenesis