Endocrine Abstracts

Carcinoid tumours are neuroendocrine tumours that may arise as isolated non-familial cancers or in association with multiple endocrine neoplasia type 1 (MEN1), which is an autosomal dominant disorder characterised by the combined occurrence of tumours of the parathyroids, the anterior pituitary and the pancreatic islets. The molecular mechanisms underlying carcinoid tumourogenesis have not been fully defined and in order to further characterise these, we undertook 2 approaches. Firstly, we performed comparative genomic hybridisation (CGH) studies to search for abnormalities of DNA copy number, and secondly, we investigated the MEN1 gene for mutations in carcinoid tumours. We investigated 7 carcinoid tumours (6 non-familial and 1 from a familial MEN1 patient). Tumour DNA was extracted and used for:1) CGH that utilized lymphocyte metaphase spreads from a healthy male donor; and 2) for mutational analysis of the MEN1 gene, which is located on chromosome 11q13, and consists of 10 exons that encode a 610 amino acid protein. The CGH studies revealed losses of chromosomes 1p21-qter, 2q34-qter, 3, 9p21-pter, 11q12-qter, 20q, and 22q13-qter, and gains of chromosomes 5, 14, 17 and 20q in the carcinoid tumours. Mutational analysis of the MEN1 gene revealed 2 somatic mutations, which consisted of one missense (Val162Phe) and one nonsense mutation (Glu191Stop). The chromosome 9p21-pter deletion and the MEN1 nonsense mutation (Glu191Stop) were observed in the tumour of the familial MEN1 patient, while the other chromosomal deletions and duplications as well as the MEN1 missense mutation (Val162Phe) were observed in tumours from the non-familial carcinoid patients. Thus, our studies have demonstrated 2 distinct molecular mechanisms that are implicated in carcinoid tumourogenesis, firstly, point mutations of the MEN1 gene and secondly, allelic deletions and amplifications at a number of different chromosomal loci.