<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>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-662 |
| Date | January 2001 |
| Creators | Hessman, Ola |
| Publisher | Uppsala University, Department of Surgical Sciences, Uppsala : Acta Universitatis Upsaliensis |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, text |
| Relation | Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 0282-7476 ; 1038 |
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