Structural alterations to proto-oncogene sequences may be involved in the pathogenesis of human thyroid neoplasms. We studied 128 thyroid tumours (35 benign and 93 malignant) for ras gene point mutations in three different codons (12, 13 and 61) using a restriction fragment length polymorphism technique and direct sequencing of double-stranded DNA on polymerase chain-reaction-amplified tumour DNA. We found a high frequency of ras mutation for the Ha-ras codon 12 in follicular adenomas (7 of

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... particularly in atypical adenomas (5 of 17), in follicular carcinomas (6 of 19) , with a high percentage for Hü rthle cell carcinomas (6 of 11), and in papillary carcinomas (4 of 66). Point mutations for other ras genes in different codons studied were weak to absent. No mutation was found in undifferentiated carcinomas (n ¼ 8). The predominant amino acid substitution both in the adenomas and in the differentiated tumours was glycine to valine (GGC to GTC) at position 12 of the Ha-ras gene. Our results obtained on a large series confirm the frequent occurrence of Ha-ras codon 12 gene mutations both in adenomas and in carcinomas. The frequency of ras mutations is linked to the geographical origin of the population studied, and varies (0-85%) from one cancer type to another according to published data. Therefore, these mutations are merely an expression of cellular transformation.