Analysis of the Ret Proto-Oncogene in Sporadic Parathyroid Adenomas

Abstract

Missense germline mutations of the RET proto‐oncogene have recently been identified in the hereditary cancer syndromes MEN2A, MEN2B, and FMTC, all characterized by medullary carcinoma, but also including phaeochromocytoma in MEN2A and MEN2B and parathyroid disease in MEN2A. In addition, somatic RET proto‐oncogene mutations have been identified in a subset of sporadic medullary carcinomas and phaeochromocytomas. This study investigated the possibility that RET plays a role in sporadic parathyroid neoplasia. Firstly, normal and neoplastic parathyroid tissues were screened for expression of the RET proto‐oncogene, using an RT‐PCR approach on autopsy material. Secondly, 20 archival parathyroid adenomas were screened for somatic mutations in the transmembrane region of RET, the region associated with germline mutations in MEN2A and hence parathyroid disease, using a PCR–solid phase direct sequencing approach. RET expression was identified in all the parathyroid tissues analysed. However, no mutations were identified in any of the 20 adenomas, suggesting either that other mechanisms of RET activation occur, such as translocation, or that RET plays a more minor role in the growth control of the parathyroid cells than in C cells or phaeochromocytes.

RET is expressed but not mutated in extra-adrenal paragangliomas

“…Our results indicate that RET mutations in exons 10, 11, and 13–16 do not account for the formation of PGLs, as opposed to MTCs and PCCs, and that there is no common genetic defect in PGLs and PCCs, despite their common embryological origin and histological similarities. Similarly, in sporadic parathyroid adenomas, no exon 10 or 11 RET mutations were detected, although RET expression was shown by RT‐PCR20. However, because not all parts of the RET proto‐oncogene have been examined and we did not test for RET translocations, we cannot entirely exclude a possible role for RET in the formation of PGLs.…”

The RET proto-oncogene in medullary and papillary thyroid carcinoma

“…Furthermore, the activation of RET by other mechanisms or rearrangements that are currently not yet identified might also be involved in the carcinogenesis of PTCs. These might explain the slightly higher proportion of PTCs with RET activation identified by Williams et al using an RT-PCR approach to identify RET mRNA expression compared with results obtained from studies identifying specific types of RET rearrangements with Southern blotting or RT-PCR [104].…”

“…These include Southern blotting, requiring high-quality DNA extracted from unfixed tumour and nontumour tissues [31] and reverse transcription (RT)-PCR-based techniques to identify both specific RET rearrangements [95] and gene activation [104]. The latter methods are also suitable for the analysis of archival materials, and Williams et al have demonstrated that the use of a nested RT-PCR approach for the analysis of RET tyrosine kinase expression can significantly improve the sensitivity of their assay [104]. A third method of analysing RET overexpression in PTCs is the immunohistochemical detection of the RET gene product in tissue sections [100].…”

“…Wide differences (2.5-60%) in frequency of RET activation by RET/PTC in PTCs of different populations have been reported, and it is not clear whether these are due to environmental factors, racial differences or technical reasons [31,37,78,101,104,109]. However, several studies have shown an association between ionizing radiation and development of PTC [31,45,57].…”

Multiple endocrine neoplasia type 2: recent progress in diagnosis and management

“…A tissuespecific threshold effect may exist whereby C cells and adrenal cells are most and parathyroid cells are least vulnerable to the growth-promoting effects conferred by the RET oncogene (12,48,49). The fact that phenotypic differences between MEN-2A and FMTC exist although individuals with these disorders may have identical RET mutations, suggests that other genetic and/or environmental factors may modulate the development of phenotypes in MEN-2.…”