Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations

Abstract

BACKGROUND Anaplastic thyroid carcinoma (ATC) is the most lethal form of thyroid neoplasia and represents the end stage of thyroid tumor progression. In the current study, genetic alterations in a panel of ATC were profiled to determine the origins of ATC. METHODS Eight ATC were analyzed for BRAF mutation at codon 599 by using mutant‐allele‐specific polymerase chain reaction (PCR) and DNA sequencing of the PCR‐amplified exon 15. RAS mutation (HRAS, KRAS, and NRAS) at codons 12, 13, and 61 was analyzed by direct sequencing of PCR‐amplified exons 1 and 2 of the RAS gene. RET/PTC rearrangements and p53 mutation were monitored by immunohistochemical (IHC) staining by anti‐RET antibodies and an anti‐p53 mAb, respectively. RESULTS BRAF was mutated in 5 of the 8 ATCs tested. Histologic examination revealed that 4 of these 5 BRAF‐mutated ATCs contained a PTC component, suggesting that they may be derived from BRAF‐mutated PTC. Of the 3 ATCs with wild‐type BRAF, 2 had spindle cell features; one had follicular neoplastic characteristics mixed with papillary structures. Analysis of RAS mutation revealed only an HRAS mutation at codon 11, due to the transversion of GCC to TCC in one ATC with wild‐type BRAF. This leads to the substitution of valine to serine. IHC analysis of RET/PTC rearrangements revealed no positive staining of RET in any of 8 ATCs, suggesting that these ATCs are not derived from RET/PTC‐ rearranged PTC. In contrast, IHC analysis of p53 mutation revealed that p53 was detected in the nuclei of 5 of 5 BRAF‐mutated ATCs and 2 of 3 ATCs with wild‐type BRAF. p53 staining was present only in anaplastic thyroid tumor cells but not in neighboring papillary thyroid tumor cells. CONCLUSIONS These results suggest that many ATCs with papillary components are derived from BRAF‐mutated PTC, because of the addition of p53 mutation. Cancer 2005. © 2005 American Cancer Society.

BRAFV600E mutation in anaplastic thyroid carcinomas and their accompanying differentiated carcinomas

“…When multi-step carcinogenesis is taken into account, a considerable number of anaplastic carcinomas with BRAF mutations should be found. In previous reports, however, the frequency of the BRAF mutation was only about 10% on average and ranged from 0 to 63% (Fukushima et al, 2003;Namba et al, 2003;Nikiforova et al, 2003;Begum et al, 2004;Soares et al, 2004;Xing et al, 2004;Quiros et al, 2005). Among these studies, some reported that the BRAF mutation is found frequently only in anaplastic carcinomas with a papillary carcinoma component, although these studies have examined only four or five cases.…”

Differential proteomic and phenotypic behaviour of papillary and anaplastic thyroid cell lines

“…Several studies have suggested that BRAF (V600E) mutation (90% of all BRAF mutations) plays an important role in the early steps of the thyroid carcinogenesis leading to the progression towards the anaplastic forms [7][8][9][10], but some controversies about its significance still remain. Therefore, the biological mechanisms of thyroid cancerogenesis are still unclear.…”

Mutant p53 (G199V) Gains Antiapoptotic Function through Signal Transducer and Activator of Transcription 3 in Anaplastic Thyroid Cancer Cells

“…Molecular genetic studies have shown that p53 is rarely mutated in well-differentiated thyroid carcinomas, occasionally mutated in poorly differentiated thyroid carcinoma, and frequently mutated in ATC. Thus, p53 mutations are thought to be a late step in thyroid tumor progression and seem to play an important role in the dedifferentiation of thyroid carcinomas to ATC (9)(10)(11)(12)(13). In addition, p53 mutations are thought to be associated with reduced chemosensitivity and radiosensitivity of cancer cells.…”