Deletion mapping on the distal third region of chromosome 1p in multiple endocrine neoplasia type IIA.

Multiple endocrine neoplasia type IIA (MEN IIA) syndrome is an autosomal-dominant endocrine disorder that consists of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia. The susceptibility gene to this disorder has been mapped to chromosome 10. However, molecular studies of tumor cells from patients with familial and sporadic MTC and/or pheochromocytoma have shown a high frequency (50%) of abnormalities on chromosome 1p. In the present study, we examined MTC or pheochromocytoma tumor specimens from eight patients (familial and nonfamilial cases) to investigate gene losses on chromosomes 1 and 10 as potential mechanisms for the tumors' development. The patients studies had homozygous genotypes in their leukocyte DNAs for the chromosome 10 marker used in this study, and the patients were, therefore, uninformative. However, the patients were informative for the chromosome 1 markers and five of the patients' tumor-cell DNAs (63%) had allelic deletions at one or multiple loci on chromosome 1p, and one tumor DNA had evidence of possible gene rearrangement; in all six cases, the abnormalities involved the distal third of chromosome 1p. Furthermore, we determined that the common break point for the 1p deletions was at 1p32. These results suggest that a tumor suppressor gene in this defined region is involved in the development/progression of MTC and pheochromocytoma by being either lost or inactivated.

C-myc, N-myc, N-ras, and c-erb-B: lack of amplification or rearrangement in human medullary thyroid carcinoma and a derivative cell line.

We investigated the copy number and possible rearrangement of the four protooncogenes, c-myc, N-myc, N-ras, and c-erb-B, in DNA from seven untreated primary cancers or metastases of medullary thyroid carcinoma and an established human medullary thyroid carcinoma cell line, TT, using the Southern blotting technique. The purpose of this study was two-fold: 1) to examine whether protooncogene perturbations in medullary thyroid carcinoma could be considered as a prognostic marker; and 2) to determine whether the protooncogenes could have a possible role in medullary thyroid tumorigenesis. Neither amplification nor rearrangement of the protooncogenes was detectable in the DNA from any tumor samples or in the cell line. Our results suggest that DNA-evident amplification and rearrangement of the c-myc, N-myc, N-ras, and c-erb-B oncogenes may not be mechanisms through which these oncogenes become activated in this malignancy.

Role of insulin-like growth factor-I in the autocrine regulation of cell growth in TT human medullary thyroid carcinoma cells.

Since the TT human medullary thyroid carcinoma cell line required fewer exogenous growth factors (serum), we investigated whether this line has an autocrine mechanism by examining the effects of antibodies directed toward insulin-like growth factor I (IGF-I) and its receptor on TT cell growth in serum-free conditions. Treating cells with anti-IGF-I antibody for four days reduced the cell number by more than 50% compared with a nonimmune IgG control. Furthermore, a monoclonal antibody to the IGF-I receptor suppressed DNA synthesis when determined by a [3H]thymidine incorporation assay. Exogenous IGF-I (20 ng/mL) stimulated [3H]thymidine incorporation in serum-free medium; approximately 70% of the IGF-I-induced stimulation was blocked by the presence of the receptor antibody. Treating TT cells with IGF-I for 48 hours increased the cell population in the S phase by 62% when analyzed by flow cytometry. These data suggest that TT cells might respond to endogenously produced IGF-I and therefore provide an in vitro model for autocrine regulation of human tumor cell growth by IGF-I.