BRAF mutations are uncommon in papillary thyroid cancer of young patients.

Mortality is low for young patients (younger than 21 years) with papillary thyroid cancer (PTC), and different mutations might contribute to this. Previous studies detected ret/PTC rearrangements more frequently in PTC from children than adults, and recent reports describe a high incidence of BRAF T1796A transversion in adult PTC. However, BRAF mutations have not been adequately studied in PTC from young patients. We amplified and sequenced segments of the BRAF gene spanning the T1796A transversion site in 14 PTC from patients 10-21 years of age (mean, 17.5 +/- 3.5 years). The PTC (7 = class 1; 5 = class 2; 1 = class 3) ranged from 0.7-2.9 cm in diameter (mean, 1.4 +/- 0.75 cm). None of them (0/14) contained BRAF T1796A and none recurred (mean follow-up, 66 +/- 40 months). This incidence of BRAF T1796A is significantly less than that reported for adult PTC (270/699, 38.6%, p = 0.0015) in several series. None of our PTC (0/10) contained ras mutations, but 7/12 (58%) contained ret/PTC rearrangements. We conclude that BRAF mutations are less common in PTC from young patients, and ret/PTC rearrangements were the most common mutation found in these childhood PTC.

Erythropoietin and the erythropoietin receptor are expressed by papillary thyroid carcinoma from children and adolescents. Expression of erythropoietin receptor might be a favorable prognostic indicator.

Erythropoietin (EPO) and the EPO receptor (EPO-R) have been implicated in solid tumors of the brain, breast, kidney and female genital tract. Based on their expression by a variety of tumors, we hypothesized that EPO and/or EPO-R might be expressed by thyroid cancers. To test this, we determined EPO and EPO-R expression by immunohistochemistry in 17 papillary thyroid carcinomas (PTC) from children and adolescents. Only a minority of PTC (4/17, 24%) expressed EPO, and there were no significant differences between the PTC that did or did not express EPO. In contrast, EPO-R was detected in the majority of PTC (11/17, 65%). The average tumor size (1.5 +/- 0.8 cm), MACIS score (3.6 +/- 0.2) and risk of recurrence (0/11) for the EPO-R(+) PTC were significantly less than those for PTC that failed to express EPO-R (average tumor size = 3.6 +/- 2.4 cm, p = 0.021; average MACIS score = 4.3 +/- 0.7, p = 0.004; recurrence = 3/6, p = 0.029). We conclude that the majority of PTC from children and adolescents express EPO-R, a finding associated with favorable prognostic indicators and a lower risk of recurrence.

Angiogenesis inhibitors specific for methionine aminopeptidase 2 as drugs for malaria and leishmaniasis.

Methionine aminopeptidase 2 (MetAP2) is responsible for the hydrolysis of the initiator methionine molecule from the majority of newly synthesized proteins. We have cloned the MetAP2 gene from the malaria parasite Plasmodium falciparum (PfMetAP2; GenBank accession number AF348320). The cloned PfMetAP2 has no intron, consists of 1,544 bp and encodes a protein of 354 amino acids with a molecular mass of 40,537 D and an overall base composition of 72.54% A + T. PfMetAP2 has 40% sequence identity with human MetAP2 and 45% identity with yeast MetAP2, and is located in chromosome 14 of P. falciparum. The three-dimensional structure of Pf MetAP2 has been modeled based on the crystal structure of human MetAP2, and several amino acid side chains protruding into the binding pocket that differ between the plasmodial and human enzyme have been identified. The specific MetAP2 inhibitors, fumagillin and TNP-470, potently blocked in vitro growth of P. falciparum and Leishmania donavani, with IC(50) values similar to the prototype drugs. Furthermore, in the case of P. falciparum, the chloroquine-resistant strains are equally susceptible to these two compounds.