H-Ras Protooncogene Mutations in Human Thyroid Neoplasms*

Abstract

Structural alterations of protooncogene sequences may be involved in the pathogenesis of human neoplasms. We screened 54 thyroid tumors (36 benign and 18 malignant) for gene rearrangements of the protooncogenes c-myc, c-myb, c-fos, c-erb-B1, c-erb-B2, c-erb-A, N-ras, K-ras, and H-ras. Only mutations of H-ras were observed. None of the 15 colloid adenomas examined had detectable H-ras rearrangements. Of the remaining tumors, we observed mutations of H-ras in 4 benign and 4 malignant neoplasms. Gene amplification was found in 5 tumors. An aggressive recurrent papillary carcinoma had a marked amplification of one of the H-ras alleles. The amplified allele was truncated, in that the 3' variable tandem repeat was not a part of the amplification unit, and contained a codon 12 point mutation leading to a valine for glycine substitution. We also observed the association of low copy gene amplification with a codon 12 valine for glycine mutation in a follicular adenoma. Two tumors contained H-ras EcoRI polymorphisms not present in the DNA of normal thyroid from the same individuals, and one follicular carcinoma showed loss of an H-ras allele. Ras protooncogenes may become transforming by quantitative mutations, leading to increased expression, or qualitative mechanisms, through activating point mutations. Both of these appear to coexist in thyroid neoplasms, and it may be that a combination of both mechanisms is capable of inducing a more complete spectrum of neoplastic phenotypes.

High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas.

“…They comprise a broad spectrum of neoplastic phenotypes, which include benign and nonprogressive macrofollicular adenomas, microfollicular adenomas, well-differentiated follicular and papillary carcinomas, and the invasive and always fatal anaplastic carcinomas (1). The sequence of somatic cell mutations which underlie these different tumor cell types is gradually becoming unraveled (2)(3)(4)(5)(6)(7)(8)(9). Activating point mutations of ras oncogenes are probably an early event in thyroid tumor formation, in that they occur with similar prevalence in benign and malignant thyroid tumors (3)(4)(5)(6).…”

“…The sequence of somatic cell mutations which underlie these different tumor cell types is gradually becoming unraveled (2)(3)(4)(5)(6)(7)(8)(9). Activating point mutations of ras oncogenes are probably an early event in thyroid tumor formation, in that they occur with similar prevalence in benign and malignant thyroid tumors (3)(4)(5)(6). Allelic losses ofchromosome 11 q 13, a region containing a number of genes involved in growth control, including the putative gene predisposing to multiple endocrine neoplasia type I, are found in follicular but not papillary thyroid tumors (7), suggesting that loss of a tumor suppressor gene at this locus may direct progression towards the follicular phenotype.…”

Towards Understanding the Molecular Basis of Thyroid Cancer

“…114 The predominance of EGF receptor expression in papillary carcinoma was extended to the transcripts of c-erbB1 and c-erbB2/neu oncogenes which encode EGF receptor or analogue respectively. 115,116 Aasland et al 116 reported a two-to threefold increase in c-erbB1 and c-erbB2/neu mRNA in papillary carcinomas and their lymph node metastases, as well as in one benign adenoma compared to thyroid tissue.…”

“…115,117 EGF expression was shown to be of prognostic value in that tumors with higher EGF expression were more likely to recur. 113 as was suggested by Aasland et al 116 earlier on the basis of c-erbB1 and c-erbB2/neu expression.…”

Enhanced sensitivity to apoptosis in Ras-transformed thyroid cells

“…Ras mutations are found at similar frequencies in benign adenomas and di erentiated carcinomas, suggesting that they are an initiating event in thyroid neoplasia (Lemoine et al, 1990;Namba et al, 1990;Suarez et al, 1990). The e ects of activated Ras on thyroid cells are exceedingly complex.…”