Upload
helki
View
42
Download
1
Tags:
Embed Size (px)
DESCRIPTION
Studies on Familial and Sporadic (Non-Familial) Chordoma. Dilys Parry, Ph.D Genetic 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. - PowerPoint PPT Presentation
Citation preview
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!
Family 1 Family 2
1
+
2
+
3
+
4
+
5
+
6
+
7
+
9 10
88
Family 7
8
+
3
6
+
7
+
1
+
2
+
4
+
5
+
3
1
+
2
+
Family 3 Family 6 Family 8Family 4
Chordoma
Astrocytoma
1
+
2
+
3
+
4
+
5
+
6
+
7
+
8
+
9
+
10
+
11
+
12
+
13
+
14
+
15
+
16
+
17
+
18
+
19
+
20
+
21
+
22
+
23 24
27
+
28
+
29
+
30
+
38 42
+
43
+
44
+
5
+
4 1
+
2
+
3
1
+
2
+
3
+
4
+
5
+
6
+
7
+
8
+
9 10
11 1213
14 15 16
+
17
+
18
+
19
+
1
+
2
+
3
+
4
+
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
Family 1I
II
III
IV
Chordoma in index cases
2 2
39 28 30
20
+
5567
44
Chordoma by MRI in examined relatives
35
8 16
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.
Family 1I
II
III
IV 2 2
39 28 30
20
+
5567
44 35
8 16
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
1
+
2
+
3
+
4
+
5
+
6
+
7
+
9 10
88
Family 7
8
+
3
6
+
7
+
1
+
2
+
4
+
5
+
3
1
+
2
+
Family 3 Family 6 Family 8Family 4
Chordoma
Astrocytoma
1
+
2
+
3
+
4
+
5
+
6
+
7
+
8
+
9
+
10
+
11
+
12
+
13
+
14
+
15
+
16
+
17
+
18
+
19
+
20
+
21
+
22
+
23 24
27
+
28
+
29
+
30
+
38 42
+
43
+
44
+
5
+
4 1
+
2
+
3
1
+
2
+
3
+
4
+
5
+
6
+
7
+
8
+
9 10
11 1213
14 15 16
+
17
+
18
+
19
+
1
+
2
+
3
+
4
+
5
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)