Francis Hornicek, MD, PhD Overview of Chordoma and Review of NCCN Guidelines for Clinical Management Massachusetts General Hospital, Boston, MA The presentation will be a review of the NCCN guidelines for chordoma

The presentation will be a review of the NCCN guidelines for chordoma management. This review will include the rationale and an overview of chordoma. Characterization of genetic variants in the T gene in familial and sporadic chordoma Chordoma is a rare bone tumor that is believed to originate from notochordal remnants. T gene, which encodes Brachyury, is essential for the proper development and maintenance of the notochord and has been implicated in the pathogenesis of chordoma. Germline duplication of the T gene was reported to confer major susceptibility of familial chordoma. A common genetic variant in T was recently associated with the increased risk of sporadic chordoma. To further investigate the role of T variants in chordoma susceptibility, we sequenced all exons in the T gene in germline DNA from 112 individuals from chordoma families (40 chordoma cases and 72 unaffected members) and 91sporadic chordoma cases. We also conducted qPCR for T duplication in these individuals. Results from these analyses will be presented at the chordoma conference. Identification of somatically acquired mutations in chordoma exomes We are interested in exploring the genomes of tumours to better understand the genes and pathways which become disrupted during cancer progression. To do this, we search for somatically acquired mutations in large numbers of samples from specific cancer types, and perform analyses to recognize the patterns of mutation indicative of dominant or recessive cancer genes. One of the cancer-types we study is bone cancer, including osteosarcoma, chondrosarcoma, and rarer bone tumours such as chordoma. To kick-start these investigations we have analysed the coding sequence (exomes) of bone tumours including 25 chordoma tumour/normal pairs. We identified driver variants in several known cancer genes including PIK3CA, PBRM1, ARID1A and PTEN, however we did not identify any likely novel cancer genes. Our future aims are to sequence the full genomes of several chordomas to unravel the full spectrum of variation underlying these cancers. Chordoma is a tumour marked by dichotomy between histological appearance and biological behaviour. The relatively innocent histology of chordoma is easily recognizable and consists of a lobulated tumour populated by cells with vacuolated cytoplasm, a unique feature of chordoma also known as physaliferous appearance, in a mucinous background. This however doesn't translate to the rather insidious and malignant behaviour of the tumour that is characterized by local infiltration, destruction and is often recalcitrant to treatment. Results of ongoing whole genome sequencing of primary chordoma …