Abstract
About 70% of papillary thyroid carcinomas (PTC) present a mutation of BRAF gene (BRAF T1799A) or a rearrangement of RET gene (RET/PTC). In this study, we examined whether PTC without BRAF T1799A and without RET/PTC named PTC-ga(-) are distinguishable on the bases of molecular characteristics from PTC-ga(+), exhibiting one and/or the other of these two gene alterations, We determined the mutational status of 116 PTC and we analyzed their gene expression profiles using macroarray and quantitative PCR. Complementary analyses of gene expression were performed at the protein level by Western blot. Among the 116 PTC, 75 were PTC-ga(+) (61 BRAF T1799A and 14 RET/PTC) and 41 were PTC-ga(-). Expression data of 42 PTC “marker” genes (i.e. genes quoted in several studies) led to a complete segregation of PTC-ga(+), PTC-ga(-) and normal tissue (NT) by hierarchical clustering. Unexpectedly, the expression level of about half of these genes was comparable in PTC-ga(-) and NT; this was particularly evident for thyroid-specific genes, TPO, TG, DIO1, DIO2, FOXE1 and PAX8 which were markedly under-expressed in PTC-ga(+) but at a normal level in PTC-ga(-). Five genes including DUOX1&2 were found selectively dysregulated in PTC-ga(-).The increase in DUOX transcripts in PTC-ga(-) was confirmed at the protein level. Clinicopathological data support the distinction between PTC-ga(-) and PTC-ga(+). Tumor grade was lower in PTC-ga(-) than PTC-ga(+) and there was a highly statistically significant association between the mutational status and tumor histology: 81% of follicular variants of PTC corresponded to PTC-ga(-) whereas 84% of PTC of classical form were PTC-ga(+).
In conclusion, we show that PTC without the BRAF T1799A mutation and without a RET/PTC rearrangement maintain a higher level of expression of thyroid differentiation and appear to be of better prognosis than PTC with one and/or the other gene alteration.