To identify the genetic events that must be involved in thyroid
tumor progression, we initially investigated p53 gene alterations in 10
papillary adenocarcinomas, 4
follicular adenocarcinomas, and 8
undifferentiated carcinomas. Base substitutional mutations in exons 5 to 8 and loss of heterozygosity (LOH) of the p53 gene were not detected in papillary or
follicular adenocarcinomas. However, 7 of 8
undifferentiated carcinomas were carrying base substitutional mutations, and LOH was detected in 3 of 5 informative cases. Furthermore, to verify that the p53 gene alterations are truly involved in
tumor progression,
DNA from individual foci of the four
undifferentiated carcinomas coexisting with a differentiated focus and from one
follicular adenocarcinoma with an undifferentiated focus was analyzed by direct sequencing and polymerase-chain-reaction-restriction-fragment-length polymorphism (PCR-RFLP). Base substitutional mutations in the p53 gene from exons 5 to 8 were identified exclusively in the undifferentiated foci, but not in the differentiated foci. LOH was observed in 3 of 4 informative undifferentiated foci. In one of these positive cases, LOH was observed in both
papillary adenocarcinoma and
undifferentiated carcinoma. However, a p53 gene mutation at
codon 248 was detected in the
undifferentiated carcinoma but not in the
papillary adenocarcinoma. The results imply that LOH occurs first in
papillary adenocarcinoma followed by a p53 mutation during the transition from
papillary adenocarcinoma to
undifferentiated carcinoma. Maintenance of LOH during
tumor progression excludes the possibility that these different histological foci are derived from different origins and represents molecular evidence that
undifferentiated carcinoma is very likely derived from preexisting
papillary adenocarcinoma. Furthermore, these results strongly suggest that the mutated p53 gene plays a crucial role in de-differentiation during the progression of thyroid
tumors.