Chordoma is a rare, slow growing, often fatal bone cancer derived from notochord remnants. It occurs in the axial skeleton (skull base, vertebrae, sacrum, coccyx), is more frequent in males, and has a median age at diagnosis of 58.5 years, with a wide age range. This typically sporadic tumor is often advanced at presentation, and mortality is high due to local recurrence or distant metastases. The usual treatment is surgery, followed by adjuvant radiation therapy. Chemotherapy has not had a significant treatment role. Reports of a few families with two or more relatives with chordoma support an etiologic role for chordoma susceptibility genes. We determined that T-gene duplications co-segregated with disease in four multiplex chordoma families. The T gene encodes brachyury, a tissue-specific transcription factor expressed in notochord cells that is essential for notochord formation and maintenance. The other chordoma families that we studied did not have T-gene duplications; chordomas in these families may result from changes in other susceptibility genes or other types of T-gene mutations. We are continuing gene identification studies of multiplex chordoma families under NIH protocol 78-C-0039. We also want to determine whether alterations in any identified chordoma susceptibility genes are associated with sporadic chordoma in the general populations.