Genetic Aspects of Chordoma: A Collaboration With SEER Registries to Identify Chordoma Families

Chordoma is an uncommon (400 case/year in the U.S.) and potentially fatal bone tumor derived
from remnants of embryonic notochord. It occurs primarily in the axial skeleton and has a
mean age at diagnosis of 55 years, with a range from early childhood to over 70 years. This
tumor usually presents at an advanced stage and the associated mortality is high due to local
destruction and distant metastases. Chordoma is rare in African-Americans and is typically
sporadic; there are few reports of these tumors arising congenitally or within members of the
same family.

Recently, we have identified and studied one large family in which 10 relatives in three
generations have chordoma; the inheritance pattern suggests transmission of a mutation in an
autosomal dominant gene. Using information from this family, we have tentatively napped this
gene to the long arm of chromosome 7. To confirm this finding, and to fine map and clone the
gene, we need to study additional chordoma families. In an effort to identify such families,
we have developed collaborations with four SEER registries covering the populations of
Detroit, Los Angeles, Iowa, and New Mexico. Each registry will identify all chordoma cases
diagnosed since 1988 and invite them (or the next of kin of deceased cases) to participate in
our study. Through 1997, the registries have identified a total of 140 chordoma cases, 96 of
whom are living. The registries will invite these patients (or their next of kin) to
participate in the study. The study components include completion of a self-administered
personal and family medical history questionnaire, retrieval of medical records and pathology
reports pertaining to chordoma, and collection of paraffin-embedded chordoma tissue and
buccal mucosal cells for genetic studies. NCI will carry out all the data collection
activities for the study subjects identified through the Detroit registry. NCI will also
conduct the buccal cell collection component of the study for all patients identified by the
other three registries. These three registries will carry out all other study activities on
these patients/next of kin and will send the data and slides prepared from the paraffin
blocks to NCI. NCI will analyze the questionnaire data to determine if any unusual patterns
of cancers other than chordoma or other medical conditions appear to cluster in families of
the chordoma patients. Selected members of any families with two or more relatives with
chordoma will be invited to participate in a separate clinical and molecular study conducted
at NIH to try to identify the chordoma gene. DNA from the buccal cells and tumor blocks from
all other patients with "sporadic" chordoma identified through the registries (likely to
comprise most patients) will not be studied until we or others have identified such a gene.