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H-Ras Protooncogene Mutations in Human Thyroid Neoplasms^*

Department of Medicine, Cedars-Sinai Medical Center, University of California School of Medicine (H.N., K.M., J.A.F.) Los Angeles, California 90048
The Division of Endocrinology, Hospital Italiano (R.A.G., A.A.) Buenos Aires, Argentina

Address all correspondence and requests for reprints to: James A. Fagin, M.D., Division of Endocrinology, Cedars-Sinai Medical Center, Becker Building 131, 8700 Beverly Boulevard, Los Angeles, California 90048.

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-Bl, 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.

^* This work was supported in part by NIH Grants CA-50706 and DK-41906.

Received January 4, 1990.

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