Studies on Familial and Sporadic (Non-Familial) Chordoma

1. Studies on Familial and Sporadic (Non-Familial) Chordoma Dilys Parry, Ph.D Genetic Epidemiology Branch, DCEG National Cancer Institute, National Institutes of Health, DHHS

2. 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.

3. Familial Chordoma Study • Research based on families with chordoma in 2or more blood relatives -- “ChordomaFamilies” • These families have an inheritedpredispositionto 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!

4. + 5 4 + + + 1 2 3 Family 1 Family 2 9 10 + 13 8 11 12 + + + + + + + 14 15 16 17 1 2 5 19 6 + + + + 7 3 4 18 Family 3 Family 4 Family 6 Family 7 Family 8 Chordoma Astrocytoma

5. 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

6. Family 1 I II 67 55 III 44 39 28 30 + 2 IV 20 2 Chordoma in index cases Chordoma by MRI in examined relatives 35 16 8

7. 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.

8. Family 1 I II 67 55 III 44 39 28 30 + 2 IV 20 2 35 8 16 All relatives with chordoma had the same DNA markers in a region on chromosome 6.

9. Familial Chordoma Study • The region with shared markers on chromosome 6 should contain the chordomagene in this family. • Study all genes in this region in family members with chordoma. • The chordomagene should be: • Changed in the same way in all family members with chordoma, BUT • Normal (unchanged) in unaffected relatives.

10. 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!!

11. Types of Large Genes Changes Normal Deletion Duplication

12. Duplications on chromosome 6q27 in 4 chordoma families

13. + 5 4 + + + 1 2 3 Family 1 Family 2 9 10 + 13 8 11 12 + + + + + + + 14 15 16 17 1 2 5 19 6 + + + + 7 3 4 18 Family 3 Family 4 Family 6 Family 7 Family 8 Chordoma Astrocytoma

15. 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

16. 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

17. Sporadic Chordoma The 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 sporadicchordomas 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.

18. 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.

19. 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

20. 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

21. 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)