studies on familial and sporadic (non-familial) chordoma
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Studies on Familial and Sporadic (Non-Familial) Chordoma
Dilys Parry, Ph.DGenetic Epidemiology Branch, DCEG
National Cancer Institute, National Institutes of Health, DHHS
Familial Chordoma Study
Hypothesis: The first event that starts a chordoma is a change in a specific gene/s.
• Research goal: to identify the specific gene/s and then gene changes that cause chordoma
• Finding these genes/gene changes also identifies the cellular pathway(s) in which the genes act.
• Genes in pathways may be targets for new molecular treatments for chordoma.
Familial Chordoma Study• Research based on families with chordoma in 2 or more
blood relatives -- “Chordoma Families”
• These families have an inherited predisposition to developing chordoma.
• Family members with chordoma:– Have a change in a specific chordoma gene in ALL of
their cells – May develop more than 1 chordoma– Can pass the changed chordoma gene to their children
•Research began in 1996!
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Familial Chordoma Study• Clinical component at NIH Clinical Center includes:
– Family members with chordoma, their parent(s), sibs and children
– Personal and family medical history– MR imaging from skull base to tail bone– Blood for DNA– Medical records and pathology reports– Slides or blocks from any chordoma
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Chordoma in index cases
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Chordoma by MRI in examined relatives
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Familial Chordoma Study• Clinical component:
– Which family members have chordoma.
• Laboratory component:– Which DNA markers from all 23 pairs of
chromosomes are present in each family member.
• Combine clinical and lab results– Look at DNA to find a region on any chromosome for
which all relatives with chordoma have the same markers.
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All relatives with chordoma had the same DNA markers in a region on chromosome 6.
Familial Chordoma Study • The region with shared markers on chromosome 6
should contain the chordoma gene in this family.
• Study all genes in this region in family members with chordoma.
• The chordoma gene should be: – Changed in the same way in all family members with
chordoma, BUT– Normal (unchanged) in unaffected relatives.
T Gene• One of 20 genes in region of interest on chromosome 6
• Encodes brachyury: – Transcription factor– Important in regulating the development of the
notochord – Specifically expressed in notochord cells and
chordomas
• No sequence changes found in T gene or 20 other genes!!
Normal
Deletion
Duplication
Types of Large Genes Changes
Duplications on chromosome 6q27 in 4 chordoma families
Family 1 Family 2
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Summary so far!• Identified the T gene as a major susceptibility gene for
familial chordoma.• Three chordoma families did not have T- gene
duplications:– Are smaller (only 2 family members with chordoma)– May have other types of changes in the T gene, or
changes in other genes in the same pathway.
• Still studying these 3 families
• Still searching for new chordoma families
The T gene is a major susceptibility gene for familial chordoma!!!
• What are the implications of this finding for people with sporadic chordoma????
• People with sporadic chordoma are: – The only person in their family with chordoma (non-
familial chordoma)– Not expected to have any children with chordoma– Not expected to develop more than 1 chordoma
Sporadic ChordomaThe T gene is relevant for people with sporadic chordoma
because:• Changes in the T gene may be present in their chordoma.
– DNA from ~50% of studied sporadic chordomas had extra copies of the T gene, BUT
– DNA from the paired non-tumor tissue (blood, saliva) had the normal number of T genes.
• Gene changes present in chordomas but not in non-tumor tissues are SOMATIC changes.
• Somatic gene changes may be what caused the chordomas to develop, but they are not inherited.
Sporadic Chordoma On the other hand:
• In rare “sporadic” chordoma patients, the T gene may be duplicated in both chordoma tissue and all non-tumor tissues.
– No good data yet, but expect the T gene to be duplicated in both tumor and non-tumor cells in less than 1% of patients.
• Gene changes present in both chordoma and non-tumor tissue of the same person are GERMLINE changes.
• Germline gene changes can be inherited.
Sporadic Chordoma Study• Goal: To determine the frequency of changes in chordoma
susceptibility genes in chordoma and non-tumor tissue (saliva) from people with sporadic/non-familial chordoma.
• Eligibility:– Males and females with chordoma diagnosed at any age and
primary site– Be at least 6 years old – Be in the U.S. or Canada
• Number of participants:– Set at 100, but will be increased
• Length study open: 4 years
Sporadic Chordoma Study• Study done using materials mailed to each home
• Study activities:– Complete personal/family medical history questionnaire– Collect saliva sample– Provide permission to obtain copies of medical
records/pathology reports and slides/blocks of chordoma tissue
– Mail all back in envelope provided
• ~ 77 people have contacted us about study; more than 30 have completed study
• All
Acknowledgement• NCI Collaborators
– Alisa Goldstein– Rose Yang– David Ng– Mary Lou McMaster– Gladys Glenn– Deborah Zametkin– Stephanie Steinbart
• Duke University– Michael Kelley– David Alcorta– Sufeng Li
• Other Institutions– Norbert Liebsch (MGH,
Boston)– Eamonn Sheridan (St.
James University, UK)
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