第65回日本内分泌学会学術総会会長講演

内分泌腫瘍の病態生理と遺伝子異常

抄録

Various functioning and non-functioning tumors arise from endocrine glands in both the sporadic and familial forms and pathophysiology of the tumors is variable due to differences in the sort of tumor-bearing endocrine organs and in the amount of hormones released. In this paper, gene abnormalities in growth hormone (GH)-secreting pituitary adenoma, ectopic GHRH-producing tumor, multiple endocrine neoplasia (MEN) and ectopic parathyroid hormone (PTH)-producing tumor are documented in relation to etiology and pathophysiology.
GH-secreting pituitary adenoma is heterogeneous in clinical features, pathological findings and GH responses to various secretagogues. A point mutation of codon 201 of Gs a gene was observed in 2 out of 45 GH-secreting pituitary adenomas (4.4%), but no point mutation of Gi2 α gene was found. Pituitary tumors may occur at any stage of differentiation from the totipotent cells to mature anterior pituitary cells, and the mutations of Gs α and H-ras genes as well as loss of heterozygosity (LOH) found on chromosome 11 in some adenomas must be involved in their tumorigeneses.
Since 1959, 34 patients with ectopic GHRH-producing tumor associated with acromegaly have been reported. In our case of MEN type 1, the paradoxical rise of plasma GH after TRH or glucose administration disappeared after resection of the tumor. The tumor cells showed neither rearrangement nor amplification of GHRH gene and 20 oncogenes including ras, myc, and erb. Only LOHs of HRAS1 and D11S151 were detected in this tumor, but no point mutation was found in HRAS1 gene. Therefore, a kind of tumor suppressor gene may be involved in the tumorigenesis of the tumor in addition to inactivation of MEN-1 locus.
In MEN-1 patients, we reported LOH on chromosomes 1, 9, 11 and 16, while we reported point mutation as being present only in Gs α gene on chromosome 20. This point mutation was found specifically in GH-secreting pituitary adenoma but not in hyperplastic parathyroid and pancreas adenoma. These data suggest that in MEN-1 patients tumorigenesis occurs and advances from hyperplasia and adenoma to cancer during multistep changes of genes such as inactivation of MEN-1 gene and other tumor suppressor genes and activation of oncogenes.
Ectopic PTH-producing tumor was first reported by us in 1989, and this was followed by 2 papers. These patients showed a disturbance of consciousness and high levels of serum calcium and plasma PTH. Our patient did not reveal the rearrangement and amplification of PTH gene, although one of another two cases showed those upstream of the transcription site of PTH gene. Ectopic PTH-producing tumors are rare but should be considered as one of the causes of humoral hypercalcemia of malignancy.