Frequent activation of EGFR in advanced chordomas

Histopathological features of 42 chordoma specimens, 21 primary and 21 advanced, were assessed by immunohistochemistry and fluorescent in situ hybridization (FISH) using PDGFRB, CSF1R, and EGFR probes. Twenty-two of these cases, for which frozen material was available (nine primary and 13 advanced tumors), were selectively analyzed using the whole-genome 4.3 K TK-CGH-array, phospho-kinase antibody array or Western immunoblotting. The study was supplemented by direct sequencing of KIT, PDGFRB, CSF1R and EGFR.We demonstrated that EGFR is frequently and the most significantly activated RTK in chordomas. Furthermore, concurrent to EGFR activation, the tumors commonly reveal co-activation of alternative RTK. The consistent activation of AKT, the frequent loss of the tumor suppressor PTEN allele, the recurrent activation of upstream RTK and of downstream effectors like p70S6K and mTOR, all indicate the PI3K/AKT pathway as an important mediator of transformation in chordomas.Given the complexity of the signaling in chordomas, combined treatment regimens targeting multiple RTK and downstream effectors are likely to be the most effective in these tumors. Personalized therapy with careful selection of the patients, based on the molecular profile of the specific tumor, is anticipated.Chordomas are rare tumors. With an incidence of about 0.05/100000/year, they account for less than 5% of all primary malignant bone tumors. Mainly adults between 40 and 60 years are affected, but cases of children presenting with chordoma were also rarely reported (5% of cases). These bone tumors arise from remnants of the fetal notochord, and hence occur along the midline, and most often in the caudal spine or the base of the skull. They are slowly growing masses with the tendency to destroy the surrounding bone and to infiltrate adjacent soft tissue. Initial symptoms usually relate to local progression of the disease. Chordomas infrequently metastasize to lung, bone, soft tissue, lymph nodes and