Neoplasms

All Conditions

Musculoskeletal Diseases

Symptoms and General Pathology

Rare Diseases

Osteosarcoma

Bone Neoplasms

Disease Susceptibility

Chordoma

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

NCI Family Study Referrals

Alisa M Goldstein, Ph.D.

Sara Glashofer

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. Reports of a small number of families worldwide with two or more relatives with chordoma support a role for susceptibility genes in chordoma etiology. Recently we determined that duplications of the T gene co-segregated with disease in four multiplex chordoma families. The T gene encodes brachyury, a tissue-specific transcription factor that is expressed in notochord cells and is essential for formation and maintenance of the notochord. Some of the other chordoma families that we studied did not have T-gene duplications; the aggregation of chordomas in these families may result from changes in other susceptibility genes or other types of mutations targeting the T gene. We are continuing gene identification studies of multiplex chordoma families at the NIH Clinical Center under 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 population.

Objectives:

The major goal of this protocol is to identify sporadic chordoma patients willing to provide germline and tumor DNA for studies to determine the frequency of alterations in chordoma susceptibility genes. Our previous protocols with SEER and Massachusetts General Hospital to identify chordoma patients were limited to residents of specific geographic regions in the U.S. (2 states and 2 metropolitan areas) or to patients with pediatric skull base tumors. This protocol will enroll patients who more broadly represent the age, site and gender distributions of sporadic chordoma in the general U.S. population.

Eligibility:

Eligible patients are males and females in the U.S. with chordoma 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 greater than or equal to age 6 years at the time of enrollment.

Design:

The study description and contacting information including an e-mail link to the study contact person will be posted on web sites of two chordoma support groups. We will mail study information to be given to patients to colleagues at major medical centers that treat chordoma.

The components of the study will be carried out in subjects' homes using materials mailed to them. Up to 100 participants will: 1) complete a self-administered Personal and Family Medical History Questionnaire, 2) collect saliva using a saliva collection kit, and 3) provide permission to obtain medical/pathology records, and paraffin blocks or slides on each primary chordoma. Parents will serve as proxies for minor children.

We will recontact patients who report chordoma in at least one blood relative. If we confirm the relative's chordoma diagnosis, we will invite the study subject and selected family members to participate in clinical and gene mapping studies under protocol 78-C-0039. We may also recontact study participants to tell them about any new studies on chordoma etiology. They can decide at that time whether they want to participate in them.

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.

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

- Susceptibility genes for Chordoma - Association between age at dx/Chordoma subtype and genetic risk factors

National Cancer Institute (NCI)

Population-based sampling of individuals affected with Chordoma

Mary L McMaster, M.D.

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.

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.

In 1996, we have identified and studied one large family in which 8 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 tentatively mapped this gene to the long arm of chromosome 7. To confirm this finding, and to fine map and clone the gene, we needed 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 included 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 carried out all the data collection activities for the study subjects identified through the Detroit registry. NCI also conducted 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 sent 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.

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

To determine if any unusual patterns of cancers other than chordoma or other medical conditions appear to cluster in families of the chordoma patients with the ultimate, long-term goal fine-mappingthe gene(s) involved in chordoma.

Study title	NCT ID	Conditions	Eligibility	Organization
Genetic Clues to Chordoma Etiology: A Protocol to Identify Sporadic Chordoma Patients for Studies of Cancer-Susceptibility Genes	NCT01200680	Genes Sporadic Chordo...	6 Years -	National Institutes of Health Clinical Center (CC)
Genetic Clues to Chordoma Etiology: A Protocol to Identify Sporadic Chordoma Patients for Studies of Cancer-Susceptibility Genes	NCT01200680	Genes Sporadic Chordo...	6 Years -	National Institutes of Health Clinical Center (CC)
Genetic Aspects of Chordoma: A Collaboration With SEER Registries to Identify Chordoma Families	NCT00341627	Chordoma	- 110 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for sporadic chordoma