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



Status:Recruiting
Conditions:Cancer, Other Indications
Therapuetic Areas:Oncology, Other
Healthy:No
Age Range:6 - 100
Updated:4/6/2019
Start Date:October 1, 2010
Contact:Alisa M Goldstein, Ph.D.
Email:goldstea@mail.nih.gov
Phone:(240) 276-7233

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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.

Background:

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.

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 regions (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 population.

Eligibility:

Eligible patients are males and females 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 time of enrollment.

Design:

The study description and contact 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 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.

- ELIGIBILITY CRITERIA:

- To be eligible subjects must be at least 6 years old at the time of enrollment, be the
only person in their family ever diagnosed with chordoma, and reside in the U.S or
Canada.

- Chordoma in the patients can have been diagnosed at any age and any primary site.
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