Endocrine tumour development : With special focus on chromosome arms 1p and 11q
Abstract: The overall goal of this thesis has been to characterise the involvement of chromosome arms 1p and 11 q in the development of endocrine tumours. The MEN1 gene was analysed as a candidate tumour suppressor gene by screening for mutations in follicular thyroid tumours, malignant melanomas, pheochromocytomas, and abdominal paragangliomas. One mutation was detected in one sporadic malignant melanoma, while the other tumour types did not show any mutations. In addition, LOH was used to screen the 11q13 region for loss of tumour material in follicular thyroid tumours and malignant melanomas. Both tumours types showed frequent LOH at the MEN1 although distal target regions were also implicated from the deletion pattems. To screen for sequence copy number changes, we used comparative genomic hybridisation (CGH), in midgut carcinoids, pheochromocytomas and abdominal paragangliomas. A few recurrently involved regions were identified of which the most common were loss of 18q22-qter in midgut carcinoids (67%), and 1 cen-p31 in both pheochromocytomas and abdominal paraganglioms (82%). Aberrations of chromosome 18 in midgut carcinoids seem to be an early event together with loss of 11 q22-23, whereas loss of 16q21-qter and gain of 4p14-qter represents late event. Overall, the pheochromocytomas and abdominal paragangliomas showed very similar pattems of gains and losses with a genetic progression of early loss of 1p, 3p, 3q, 1 11p and 11q, followed by loss of 4q and gain of 11q, 19p, 19q, 16p, 17q, and 17p. This genetic progression did not correlate with the conversion from benign to malignant tumours. However, loss of 1 1q22-23 was significantly more frequent in the malignant than in the benign tumours. To further investigate the importance of the 11 q22-23 region, mutation screening of the SDHD gene was performed in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas and abdominal paragangliomas, which all show frequent deletions in this region. Altogether, three sequence alterations were found in two midgut carcinoids and two Merkel cell carcinomas. In one midgut carcinoid and one Merkel cell carcinoma a G 12S alteration was found together with the known S68S polymorphism. The G 12S alteration has however been reported earlier in one normal sample, while it remains to be elucidated whether it is a true mutation or a polymorphism. The other two tumours harboured the H50R alteration, which were not detected in 200 controls. Since loss of 1p was commonly detected in pheochromocytomas and abdominal paragangliomas, we intended to refine the region(s) of loss on this chromosome arm. Deletion of I p was seen in more than 80% of the pheochromocytomas and abdominal paragangliomas, and at least three distinct regions were identified. The most commonly deleted region was the 18cM interval between the markers D1S2134 and D1S1669 (1p32). Furthermore, tumours secreting dopamine had a higher frequency of LOH in the region telomeric of D1S1612 (1p36.2-ter) as compared to non-dopamine secreting tumours. A third region was assigned centromeric of D1S429 (1cen-p13). RIZ in 1p36.2 provides a good candidate tumour suppressor gene, since it is frequently inactivated in other types of tumours. This gene showed loss of mRNA expression in 57% of the pheochromocytomas and abdominal paragangliomas studied. However, this alteration was not interpreted as an initiating event since RIZ1 expression was lost in a primary tumour but not its metastasis.
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