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Profiling of hereditary and solitary osteochondromas and peripheral chondrosarcomas on
genomic, gene expression and protein level.
Abstract 2005 MHE Conference
L. Hameetman, A.M. Cleton-Jansen, G. David, J.V.M.G. Bovee,
P.C.W. Hogendoorn. Department of Pathology Leiden University Medical Center,
Leiden The Netherlands and University of Leuven, Belgium
Osteochondroma is a cartilage capped benign bony neoplasm on the outer surface of bones
preformed by endochondral ossification. The cartilage cap of osteochondroma histologically
resembles the morphological organization of an epiphyseal growth plate. A small percentage
osteochondromas transform towards their malignant counter part, secondary peripheral
chondrosarcoma. For Multiple Osteochondromas EXT1 located at 8q24 was shown to act as tumor
suppressor gene in tumours of EXT1 mutant patients.
We demonstrate that in hereditary tumors EXT expression is correlated with mutation status of the
patient. Furthermore, EXT1, but not EXT2, is down-regulated in sporadic tumors, where 8q24 loss is
a frequent phenomenon, but mutations or promoter hypermethylation are not found till now.
EXT genes are involved in biosynthesis of heparan sulphate proteoglycans (HSPGs).
Immunohistochemical evaluation of a series (n=70) of both hereditary and solitary tumors revealed
intracellular accumulation of HSPG core proteins and of shorter or less complex HS chains, in
contrast to the extracellular expression of these molecules found in growth plates. HSPGs are
involved in several growth signaling pathways, including in the negative feedback loop of the Indian
Hedgehog (IHH) and parathyroid hormone–like hormone (PTHLH).PTHLH signaling is absent in
osteochondromas, but reactivated upon malignant transformation towards chondrosarcoma.
Disturbed expression of IHH signaling molecules has also been implicated in osteochondroma.
With quantitative RT-PCR we were able to demonstrate similar expression levels of IHH signaling in
osteochondromas as compared to the growth plate. A gradual decrease in expression of IHH
signaling molecules was observed with increasing malignancy, suggesting that IHH signaling is
inactived and PTHLH signaling is IHH-independent in chondrosarcomas. cDNA expression profiling
and immunohistochemical studies suggest that TGF--mediated proliferative signaling is upregulated
in high-grade chondrosarcomas. TGF- is a good candidate to regulate PTHLH signaling in high-
grade tumors.Chondrosarcoma progression is further accompanied by down-regulation of energy
metabolism-related genes and upregulation of the proto-oncogene jun B.
Dysplasia Epiphysealis Hemimelica (DEH, Trevor's disease) and metachondromatosis (MC) are
considered in the differential diagnosis of solitary and hereditary osteochondromas. In a comparative
study between DEH, MC and osteochondroma we were able to demonstrate that histologically DEH
differs from conventional osteochondroma, while MC-related lesions do not. With qPCR we show that
in contrast to osteochondroma, MC and DEH still express the EXT genes and immunohistochemical
analysis showed that EXT downstream pathways are active. These results indicate that DEH and MC
are indeed different entities and that so far unknown molecular defects in these lesions do not affect
EXT signaling.
genomic, gene expression and protein level.
Abstract 2005 MHE Conference
L. Hameetman, A.M. Cleton-Jansen, G. David, J.V.M.G. Bovee,
P.C.W. Hogendoorn. Department of Pathology Leiden University Medical Center,
Leiden The Netherlands and University of Leuven, Belgium
Osteochondroma is a cartilage capped benign bony neoplasm on the outer surface of bones
preformed by endochondral ossification. The cartilage cap of osteochondroma histologically
resembles the morphological organization of an epiphyseal growth plate. A small percentage
osteochondromas transform towards their malignant counter part, secondary peripheral
chondrosarcoma. For Multiple Osteochondromas EXT1 located at 8q24 was shown to act as tumor
suppressor gene in tumours of EXT1 mutant patients.
We demonstrate that in hereditary tumors EXT expression is correlated with mutation status of the
patient. Furthermore, EXT1, but not EXT2, is down-regulated in sporadic tumors, where 8q24 loss is
a frequent phenomenon, but mutations or promoter hypermethylation are not found till now.
EXT genes are involved in biosynthesis of heparan sulphate proteoglycans (HSPGs).
Immunohistochemical evaluation of a series (n=70) of both hereditary and solitary tumors revealed
intracellular accumulation of HSPG core proteins and of shorter or less complex HS chains, in
contrast to the extracellular expression of these molecules found in growth plates. HSPGs are
involved in several growth signaling pathways, including in the negative feedback loop of the Indian
Hedgehog (IHH) and parathyroid hormone–like hormone (PTHLH).PTHLH signaling is absent in
osteochondromas, but reactivated upon malignant transformation towards chondrosarcoma.
Disturbed expression of IHH signaling molecules has also been implicated in osteochondroma.
With quantitative RT-PCR we were able to demonstrate similar expression levels of IHH signaling in
osteochondromas as compared to the growth plate. A gradual decrease in expression of IHH
signaling molecules was observed with increasing malignancy, suggesting that IHH signaling is
inactived and PTHLH signaling is IHH-independent in chondrosarcomas. cDNA expression profiling
and immunohistochemical studies suggest that TGF--mediated proliferative signaling is upregulated
in high-grade chondrosarcomas. TGF- is a good candidate to regulate PTHLH signaling in high-
grade tumors.Chondrosarcoma progression is further accompanied by down-regulation of energy
metabolism-related genes and upregulation of the proto-oncogene jun B.
Dysplasia Epiphysealis Hemimelica (DEH, Trevor's disease) and metachondromatosis (MC) are
considered in the differential diagnosis of solitary and hereditary osteochondromas. In a comparative
study between DEH, MC and osteochondroma we were able to demonstrate that histologically DEH
differs from conventional osteochondroma, while MC-related lesions do not. With qPCR we show that
in contrast to osteochondroma, MC and DEH still express the EXT genes and immunohistochemical
analysis showed that EXT downstream pathways are active. These results indicate that DEH and MC
are indeed different entities and that so far unknown molecular defects in these lesions do not affect
EXT signaling.
Research authored by Dr. Hogendoorn
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List of Publications via PubMed
(NIH National Library of Medicine)
List of Publications via PubMed
(NIH National Library of Medicine)
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Press Release 03 / 06 / 07 4pm Eastern time
JNCI Journal of the National Cancer Institute 2007 99(5):396-406; doi:10.1093
/jnci/djk067
To read the abstract from this research paper click here http://jnci.oxfordjournals.
org/cgi/content/abstract/99/5/396
EXT1 Gene Influences Formation of Nonhereditary Benign Bone Tumors
Mutations in a gene known as EXT1 cause Multiple Osteochondromas, a rare hereditary disorder that
results in the formation of benign cartilage-covered bone tumors. Now scientists have shown that
EXT1 is also involved in the development of nonhereditary osteochondromas, the more common
form of the disease.
Liesbeth Hameetman of Leiden University Medical Center in The Netherlands, and colleagues
examined eight nonhereditary osteochondromas to determine whether EXT1 acts as a tumor-
suppressing gene in nonhereditary osteochondromas in the same way it does in hereditary ones.
Mutations or deletions of tumor suppressor genes increased the likelihood of a cell becoming a tumor
cell, but both copies of the gene had to be affected for this to happen.
In seven of the eight osteochondromas, both copies of EXT1 were deleted; these deletions occurred
only in the cartilage cap of the one osteochondroma that was examined in detail. Previous studies
demonstrated that the cartilage cap was formed of tumor tissue, but it was unknown whether other
parts of the osteochondromas—the bony stalk and the connective tissue—were as well. The authors
conclude that EXT1 acts as a tumor suppressor gene in the cartilage of nonhereditary
osteochondromas.
“Our finding that the cartilage cap is the only [tumor] component of osteochondroma revives long-
standing debate about the cell origin of osteochondromas,” the authors write.
The MHE Research Foundation would like to thank Dr. Hogendoorn and his colleagues for all their
long standing research efforts. These research findings have paramount importance to the field of
MHE / MO / HME research. MHERF would also like to thank Dr. Hogendoorn for always staying in such
close contact with our organization and for all his support. Also for being given this opportunity to
be the first organization besides the JNCI Journal of the National Cancer Institute to help announce
these research findings.
Contact: Pancras Hogendoorn, Leiden University Medical Center
JNCI Journal of the National Cancer Institute 2007 99(5):396-406; doi:10.1093
/jnci/djk067
To read the abstract from this research paper click here http://jnci.oxfordjournals.
org/cgi/content/abstract/99/5/396
EXT1 Gene Influences Formation of Nonhereditary Benign Bone Tumors
Mutations in a gene known as EXT1 cause Multiple Osteochondromas, a rare hereditary disorder that
results in the formation of benign cartilage-covered bone tumors. Now scientists have shown that
EXT1 is also involved in the development of nonhereditary osteochondromas, the more common
form of the disease.
Liesbeth Hameetman of Leiden University Medical Center in The Netherlands, and colleagues
examined eight nonhereditary osteochondromas to determine whether EXT1 acts as a tumor-
suppressing gene in nonhereditary osteochondromas in the same way it does in hereditary ones.
Mutations or deletions of tumor suppressor genes increased the likelihood of a cell becoming a tumor
cell, but both copies of the gene had to be affected for this to happen.
In seven of the eight osteochondromas, both copies of EXT1 were deleted; these deletions occurred
only in the cartilage cap of the one osteochondroma that was examined in detail. Previous studies
demonstrated that the cartilage cap was formed of tumor tissue, but it was unknown whether other
parts of the osteochondromas—the bony stalk and the connective tissue—were as well. The authors
conclude that EXT1 acts as a tumor suppressor gene in the cartilage of nonhereditary
osteochondromas.
“Our finding that the cartilage cap is the only [tumor] component of osteochondroma revives long-
standing debate about the cell origin of osteochondromas,” the authors write.
The MHE Research Foundation would like to thank Dr. Hogendoorn and his colleagues for all their
long standing research efforts. These research findings have paramount importance to the field of
MHE / MO / HME research. MHERF would also like to thank Dr. Hogendoorn for always staying in such
close contact with our organization and for all his support. Also for being given this opportunity to
be the first organization besides the JNCI Journal of the National Cancer Institute to help announce
these research findings.
Contact: Pancras Hogendoorn, Leiden University Medical Center
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Dr. Hogendoorn's research
The MHE Research Foundation is proud to be working with the EuroBoNeT consortium, a European Commission
granted Network of Excellence for studying the pathology and genetics of bone tumors.
granted Network of Excellence for studying the pathology and genetics of bone tumors.
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Information on The Diseases Database a cross-referenced index of human disease, and the Intute: health & life
sciences a free online service providing access to the very best Web resources for education and research
located in the UK
By the Health On the Net Foundation. Click here to verify.# HON Conduct 282463 and is linked on the NIH
National Library of Medicine, Directory of Health Organizations (SIS) website, as well as the link for Patient
Information on The Diseases Database a cross-referenced index of human disease, and the Intute: health & life
sciences a free online service providing access to the very best Web resources for education and research
located in the UK
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This web page was updated last on 2/20/08, 4:00 pm Eastern time
