Genetic Clues to Chordoma Etiology: A Protocol to Identify Sporadic Chordoma Patients for Studies of Cancer-Susceptibility Genes

Synopsis Background: Chordoma is a rare, slow growing, often fatal bone cancer derived from remnants of the embryonic notochord. It occurs mostly in the axial skeleton (skull base, vertebrae, sacrum and coccyx), is more frequent in males than females, 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. Although most chordomas are sporadic, we previously identified germline duplication of the T gene (T-dup+), now designated TBXT, which encodes brachyury, a transcription factor that plays an important role in embryonic development, as a major susceptibility mechanism in familial chordoma. A common polymorphism in TBXT is also associated with an increased risk for both familial and sporadic chordoma. Although chordomas are slow-growing, local recurrences are common and treatment options are limited particularly for those with advanced disease. Thus, a better understanding of predisposing factors and molecular processes in chordoma is critically needed. Objectives: * To identify loci that cause susceptibility to chordoma and related tumors * To determine the functional significance of mutations or other genetic changes at these loci * To determine the frequency of alterations in chordoma susceptibility genes * To identify genetic determinants conferring chordoma and related tumors risk in individuals * To evaluate the natural history of disease in chordoma and related tumors, including evaluation of survival Endpoints: Primary Endpoint: All cancers that occur in individuals and families at high risk of chordoma Secondary Endpoints: Markers of pre-malignant conditions such as benign notochordal cell tumors (BCNT), notochordal remnants Study Population: Eligible patients are males and females in the U.S. or Canada with chordoma or related tumors diagnosed at any age and at any primary site. Because we want to obtain saliva from all participants, eligibility is limited to patients who will be \> age 6 years at the time of enrolment. Design of Sites/Facilities Enrolling Participants: The components of the study will be carried out in subjects homes using materials mailed to them. The components include: 1) a self-administered Personal and Family Medical History Questionnaire, 2) saliva collected as a source of germline DNA using a saliva collection kit; 3) providing permission to obtain medical/pathology records, and paraffin blocks or slides on each primary ch ordoma and related tumors; 4) a self-administered Follow-Up Questionnaire to collect information about treatment, additional chordomas, and changes in health status since initial chordoma diagnosis. Study Duration: Start Date: 01/22/2011 End Date: 12/31/2051 This study is designed to be an open-ended natural history study with anticipated enrollment of 10-40 patients per year, with an accrual ceiling of 400. Participant Duration: Study participants may be reevaluated every few years to document changes in their history of chordoma over time and to collect information on treatment and survival. This is essential for establishing the natural history of chordoma and related tumors and to investigate the clinical significance of molecular subtypes.