Papillary ca is due to what mutation a.RET/PTC, b.RAS c.BRAF d. PAX8 ANS=ABCD Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, representing ~80% of all cases. In PTC, mutations of genes encoding effectors of the MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) PATHWAY are central to malignant transformation. In 70% of all cases rearrangements of the genes encoding the receptor tyrosine kinases RET or NTRK leading to expression of constitutively active fusion proteins, as well as activating-point mutations of RAS or BRAF, are found. In any given PTC, mutation only occurs in a single component of the MAPK pathway, supporting the idea that constitutive functional activation of any of these effectors alone is sufficient to foster development of PTC. The BRAF (T1799A) somatic mutation encodes the constitutively active kinase B-Raf (Val600Glu). Among differentiated thyroid neoplasms this mutation is found almost exclusively in PTC, accounting for approximately 44% of all cases. A recently reported intrachromosomal rearrangement between BRAF and AKAP9 also leads to expression of a constitutively active form of B-Raf, but is a rare event found mainly in a subset of radiation-induced PTC. BRAF mutations are probably involved in tumor initiation, as they are found in microscopic PTC. Targeted expression of B-Raf (Val600Glu) in thyroid cells of transgenic mice results in PTC, indicating that inappropriate expression of this oncogenic form of the kinase can recapitulate the disease phenotype. Prior exposure to ionizing radiation during childhood predisposes to development of PTC with RET rearrangements and, to a lesser extent, with NTRK or BRAF intrachromosomal inversions. These mutations are also found in children with PTC without known exposure to radiation. By contrast, point mutations of BRAF are exceedingly rare in this population, with an overall prevalence of 4–6%. Thus, somatic mutation of BRAF is the most common early genetic event causally associated with development of PTC in adult patients without a history of radiation exposure. There is a general consensus that PTCs with different mutations have distinct histopathologic appearance and biologic properties. Gene expression profiling of PTCs with RET/PTC, RAS and BRAF mutations accurately classified the mutational status of the cancers, further supporting the concept that each of these oncogenes induces specific phenotypic features. Tumors associated with RET/PTC1 rearrangements usually have the classical or conventional papillary histotype, whereas those with RET/PTC3 are associated with solid-variant PTC. Follicular-variant PTCs frequently harbor RAS mutations or PAX8/PPARG rearrangements or, less commonly, distinct B-Raf mutations (Lys601Glu, Gly474Arg) and have a comparatively low frequency of lymph-node metastases. Although most PTCs with BRAF mutations have a classical histology, almost 80% of tall-cell variant PTCs have the BRAF (T1799A) mutation; this histotype is believed to present more often at an advanced disease stage. Although the majority of PTCs, regardless of genotype, are surgically removed at an early stage of the disease, most studies indicate that PTCs with BRAF mutations are overrepresented among those cases presenting at an advanced stage. These tumors have a higher frequency of extrathyroidal invasion and a predisposition to neck-lymph-node and distant metastasis. PTCs with BRAF mutations also have a higher recurrence rate, and the metastatic recurrences have diminished radio-iodine avidity. A recent study describes a de novo BRAF mutation in lymphatic metastases in which the primary PTC did not seem to have this mutation. This finding suggests that late acquisition of BRAF mutations could confer predisposition to lymphatic spread; however, it is also conceivable that the lymph-node metastases arose from a discrete focus of the primary PTC harboring a BRAF mutation. Regardless, these findings support the concept that BRAF pre disposes to lymphatic involvement. Although most reports confirm the association of BRAF mutation with unfavorable clinicopathologic features, it should be noted that two studies from Italy and two from Asia did not find a statistically significant association between BRAF mutation and these negative prognostic markers. About 25% of undifferentiated thyroid cancers have BRAF mutations, and this proportion is probably higher in tumors with documented evidence of progression from a pre-existing well-differentiated PTC. In the latter case, the BRAF mutation is present in both components of the tumor–well-differentiated and undifferentiated–suggesting a role for oncogenic BRAF in disease progression. By contrast, RET/PTC rearrangements are rarely, if ever, found in poorly differentiated or anaplastic thyroid carcinomas. Data from mouse models of thyroid cancer are consistent with these observations. Thus, PTCs arising in B-Raf (Val600Glu) transgenic mice are invasive and undergo transition to poorly differentiated carcinomas, whereas those that develop in RET/PTC transgenic mice do not progress to this form. Taken together, multiple lines of evidence indicate that PTCs with BRAF mutations have a worse prognosis. It remains to be seen whether this information will be of practical value and alter diagnostic or therapeutic strategies.