Decreased EXT expression and intracellular accumulation of heparan sulphate proteoglycan in osteochondromas and
peripheral chondrosarcomas
L Hameetman 1, G David 2, A Yavas 1, SJ White 3, AHM Taminiau 4, A-M Cleton-Jansen 1, PCW Hogendoorn 1, JVMG Bovée 1
*
1Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands
2Centre for Human Genetics, University of Leuven, Leuven, Belgium
3Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
4Department of Orthopaedic Surgery, Leiden University Medical Centre, Leiden, The Netherlands
Funded by:
Dutch Cancer Society; Grant Number: RUL2002-2738
Abstract
Mutational inactivation of EXT1 or EXT2 is the cause of hereditary multiple osteochondromas. These genes function in heparan
sulphate proteoglycan (HSPG) biosynthesis in the Golgi apparatus. Loss of heterozygosity of the EXT1 locus at 8q24 is
frequently found in solitary osteochondromas, whereas somatic mutations are rarely found. We investigated the expression of
EXT1 and EXT2 (quantitative RT-PCR) and of different HSPGs (immunohistochemistry) in solitary and hereditary
osteochondromas and in cases with malignant progression to secondary peripheral chondrosarcoma, in relation to possible
mutations and promoter methylation. The mutation status of patients with multiple osteochondromas correlated with decreased
EXT1 or EXT2 expression found in their resected tumours. We could not show somatic point mutations or promoter
hypermethylation in 17 solitary tumours; however, EXT1 expression was decreased in 15 cases, whereas EXT2 was not.
Intracellular accumulation of syndecan-2 and heparan sulphate-bearing isoforms of CD44 (CD44v3) was found in most tumours,
which concentrated in the Golgi apparatus as shown by confocal microscopy. This contrasted with the extracellular expression
found in normal growth plates. In conclusion, mutational inactivation of either EXT1 or EXT2 leads to loss of mRNA expression
of the corresponding gene. We hypothesize that loss of EXT expression disrupts the function of the EXT1/2 complex in HSPG
biosynthesis, resulting in the intracellular accumulation of HSPG core proteins that we found in these tumours.
Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
peripheral chondrosarcomas
L Hameetman 1, G David 2, A Yavas 1, SJ White 3, AHM Taminiau 4, A-M Cleton-Jansen 1, PCW Hogendoorn 1, JVMG Bovée 1
*
1Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands
2Centre for Human Genetics, University of Leuven, Leuven, Belgium
3Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
4Department of Orthopaedic Surgery, Leiden University Medical Centre, Leiden, The Netherlands
Funded by:
Dutch Cancer Society; Grant Number: RUL2002-2738
Abstract
Mutational inactivation of EXT1 or EXT2 is the cause of hereditary multiple osteochondromas. These genes function in heparan
sulphate proteoglycan (HSPG) biosynthesis in the Golgi apparatus. Loss of heterozygosity of the EXT1 locus at 8q24 is
frequently found in solitary osteochondromas, whereas somatic mutations are rarely found. We investigated the expression of
EXT1 and EXT2 (quantitative RT-PCR) and of different HSPGs (immunohistochemistry) in solitary and hereditary
osteochondromas and in cases with malignant progression to secondary peripheral chondrosarcoma, in relation to possible
mutations and promoter methylation. The mutation status of patients with multiple osteochondromas correlated with decreased
EXT1 or EXT2 expression found in their resected tumours. We could not show somatic point mutations or promoter
hypermethylation in 17 solitary tumours; however, EXT1 expression was decreased in 15 cases, whereas EXT2 was not.
Intracellular accumulation of syndecan-2 and heparan sulphate-bearing isoforms of CD44 (CD44v3) was found in most tumours,
which concentrated in the Golgi apparatus as shown by confocal microscopy. This contrasted with the extracellular expression
found in normal growth plates. In conclusion, mutational inactivation of either EXT1 or EXT2 leads to loss of mRNA expression
of the corresponding gene. We hypothesize that loss of EXT expression disrupts the function of the EXT1/2 complex in HSPG
biosynthesis, resulting in the intracellular accumulation of HSPG core proteins that we found in these tumours.
Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
| Judith V.M.G. Bovée M.D., Ph.D., research |
Research authored by Dr. Bovée
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List of Publications via PubMed
(NIH National Library of Medicine)
List of Publications via PubMed
(NIH National Library of Medicine)
The role of EXT1 in nonhereditary osteochondroma: identification of homozygous deletions.
Hameetman L, Szuhai K, Yavas A, Knijnenburg J, van Duin M, van Dekken H, Taminiau AH, Cleton-Jansen AM, Bovée JV,
Hogendoorn PC.
Department of Pathology, Leiden University Medical Center, PO Box 9600 L1-Q, 2300 RC Leiden, The Netherlands.
J Natl Cancer Inst. 2007 Mar 7;99(5):396-406.
BACKGROUND: Multiple osteochondromas is a hereditary syndrome that is characterized by the formation of cartilage-capped
bony neoplasms (osteochondromas), for which exostosis (multiple)-1 (EXT1) has been identified as a causative gene. However,
85% of all osteochondromas present as solitary (nonhereditary) lesions in which somatic mutations in EXT1 are extremely rare,
but loss of heterozygosity and clonal rearrangement of 8q24 (the chromosomal locus of EXT1) are common. We examined
whether EXT1 might act as a classical tumor suppressor gene for nonhereditary osteochondromas. METHODS: Eight
nonhereditary osteochondromas were subjected to high-resolution array-based comparative genomic hybridization (array-CGH)
analysis for chromosome 8q. The array-CGH results were validated by subjecting tumor DNA to multiple ligation-dependent
probe amplification (MLPA) analysis for EXT1. EXT1 locus-specific fluorescent in situ hybridization (FISH) was performed on
nuclei isolated from the three tissue components of osteochondroma (cartilage cap, perichondrium, bony stalk) to examine
which parts of the tumor are of clonal origin. RESULTS: Array-CGH analysis of tumor DNA revealed that all eight
osteochondromas had a large deletion of 8q; five tumors had an additional small deletion of the other allele of 8q that contained
the EXT1 gene. MLPA analysis of tumor DNA confirmed these findings and identified two additional deletions that were smaller
than the limit of resolution of array-CGH. FISH analysis of the cartilage cap, perichondrium, and bony stalk showed that these
homozygous EXT1 deletions were present only in the cartilage cap of osteochondroma. CONCLUSION: EXT1 functions as a
classical tumor suppressor gene in the cartilage cap of nonhereditary osteochondromas.
Hameetman L, Szuhai K, Yavas A, Knijnenburg J, van Duin M, van Dekken H, Taminiau AH, Cleton-Jansen AM, Bovée JV,
Hogendoorn PC.
Department of Pathology, Leiden University Medical Center, PO Box 9600 L1-Q, 2300 RC Leiden, The Netherlands.
J Natl Cancer Inst. 2007 Mar 7;99(5):396-406.
BACKGROUND: Multiple osteochondromas is a hereditary syndrome that is characterized by the formation of cartilage-capped
bony neoplasms (osteochondromas), for which exostosis (multiple)-1 (EXT1) has been identified as a causative gene. However,
85% of all osteochondromas present as solitary (nonhereditary) lesions in which somatic mutations in EXT1 are extremely rare,
but loss of heterozygosity and clonal rearrangement of 8q24 (the chromosomal locus of EXT1) are common. We examined
whether EXT1 might act as a classical tumor suppressor gene for nonhereditary osteochondromas. METHODS: Eight
nonhereditary osteochondromas were subjected to high-resolution array-based comparative genomic hybridization (array-CGH)
analysis for chromosome 8q. The array-CGH results were validated by subjecting tumor DNA to multiple ligation-dependent
probe amplification (MLPA) analysis for EXT1. EXT1 locus-specific fluorescent in situ hybridization (FISH) was performed on
nuclei isolated from the three tissue components of osteochondroma (cartilage cap, perichondrium, bony stalk) to examine
which parts of the tumor are of clonal origin. RESULTS: Array-CGH analysis of tumor DNA revealed that all eight
osteochondromas had a large deletion of 8q; five tumors had an additional small deletion of the other allele of 8q that contained
the EXT1 gene. MLPA analysis of tumor DNA confirmed these findings and identified two additional deletions that were smaller
than the limit of resolution of array-CGH. FISH analysis of the cartilage cap, perichondrium, and bony stalk showed that these
homozygous EXT1 deletions were present only in the cartilage cap of osteochondroma. CONCLUSION: EXT1 functions as a
classical tumor suppressor gene in the cartilage cap of nonhereditary osteochondromas.
Multiple Osteochondromas: Clinicopathological and Genetic Spectrum and Suggestions for Clinical Management
Hereditary Cancer Clin Pract 2004; 2(4);161-173
authors: Liesbeth Hameetman, Liesbeth Hameetman, Judith V.M.G. Bovée, Antonie H.M. Taminiau,
Antonie H.M. Taminiau, Herman M. Kroon, Herman M. Kroon, Pancras C.W. Hogendoorn,
Pancras C.W. Hogendoorn
Multiple Osteochondromas is an autosomal dominant disorder characterised by the presence of multiple osteochondromas and
a variety of orthopaedic deformities. Two genes causative of Multiple Osteochondromas, Exostosin-1 (EXT1) and Exostosin-2
(EXT2), have been identified, which act as tumour suppressor genes. Osteochondroma can progress towards its malignant
counterpart, secondary peripheral chondrosarcoma and therefore adequate follow-up of Multiple Osteochondroma patients is
important in order to detect malignant transformation early.
This review summarizes the considerable recent basic scientific and clinical understanding resulting in a multi-step genetic model
for peripheral cartilaginous tumorigenesis. This enabled us to suggest guidelines for clinical management of Multiple
Osteochondroma patients. When a patient is suspected to have Multiple Osteochondroma, the radiologic documentation,
histology and patient history have to be carefully reviewed, preferably by experts and if indicated for Multiple Osteochondromas,
peripheral blood of the patient can be screened for germline mutations in either EXT1 or EXT2. After the Multiple
Osteochondroma diagnosis is established and all tumours are identified, a regular follow-up including plain radiographs and
base-line bone scan are recommended
Hereditary Cancer Clin Pract 2004; 2(4);161-173
authors: Liesbeth Hameetman, Liesbeth Hameetman, Judith V.M.G. Bovée, Antonie H.M. Taminiau,
Antonie H.M. Taminiau, Herman M. Kroon, Herman M. Kroon, Pancras C.W. Hogendoorn,
Pancras C.W. Hogendoorn
Multiple Osteochondromas is an autosomal dominant disorder characterised by the presence of multiple osteochondromas and
a variety of orthopaedic deformities. Two genes causative of Multiple Osteochondromas, Exostosin-1 (EXT1) and Exostosin-2
(EXT2), have been identified, which act as tumour suppressor genes. Osteochondroma can progress towards its malignant
counterpart, secondary peripheral chondrosarcoma and therefore adequate follow-up of Multiple Osteochondroma patients is
important in order to detect malignant transformation early.
This review summarizes the considerable recent basic scientific and clinical understanding resulting in a multi-step genetic model
for peripheral cartilaginous tumorigenesis. This enabled us to suggest guidelines for clinical management of Multiple
Osteochondroma patients. When a patient is suspected to have Multiple Osteochondroma, the radiologic documentation,
histology and patient history have to be carefully reviewed, preferably by experts and if indicated for Multiple Osteochondromas,
peripheral blood of the patient can be screened for germline mutations in either EXT1 or EXT2. After the Multiple
Osteochondroma diagnosis is established and all tumours are identified, a regular follow-up including plain radiographs and
base-line bone scan are recommended
Dr. Bovée is one of the team members of EuroBoNet pathologist specialised in the pathology of bone and soft tissue tumours.
She is part of the bone tumour research group. The main emphasis of her research is focused on enchondromas,
osteochondromas and chondrosarcomas.
She is part of the bone tumour research group. The main emphasis of her research is focused on enchondromas,
osteochondromas and chondrosarcomas.
Press Release 2 / 13 / 08
Multiple osteochondromas
Judith V.M.G. Bovée
Orphanet Journal of Rare Diseases 2008, 3:3 (13 February 2008)
To Read this publication Click Here
Multiple osteochondromas
Judith V.M.G. Bovée
Orphanet Journal of Rare Diseases 2008, 3:3 (13 February 2008)
To Read this publication Click Here
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2009 Conference abstract
On the Clinical Manifestation and the Genetics of Ollier Disease
T.C. Pansuriya, S.H.M. Verdegaal, P.C.W. Hogendoorn, A.H.M. Taminiau, and J.V.M.G. Bovee
Leiden University Medical Center, P.O. 9600, 2300 RC Leiden, The Netherlands
Enchondromatosis is a non-hereditary disease, characterised by the presence of multiple enchondromas with a marked unilateral
predominance mainly affecting medulla of the metaphyses and diaphyses of short and long tubular bones of the limbs, especially
the hands and feet. The risk of malignant transformation is suggested to be up to 35%. Due to the rarity of these diseases,
systematic studies on clinical behaviour providing information how to treat patients are lacking. Also, studies to the genetic
cause of Ollier disease are sparse and hampered by low numbers. PTHR1 mutations can be found in only a small proportion (so
far 5 of 62) of cases.
We performed a descriptive retrospective EMSOS (European Musculoskeletal oncology Society)-study in which 12 institutes in
eight countries participated. 118 patients with Ollier Disease and 15 patients with Maffucci Syndrome were included. Unilateral
localization of disease was found in 60% of Ollier patients and 40% of patients with Maffucci Syndrome. One of the predictive
factors for developing chondrosarcoma is the location of the enchondromas; the risk increases especially when enchondromas
are located in the scapula (33%), humerus (18%), pelvis (26%) or femur (15%). For the phalanges, this risk is 14% in the hand
and 16% in the feet. The decision whether or not to perform extensive surgery is difficult, especially in patients who suffer
multiple chondrosarcomas. Malignant transformation was found in forty-four patients with Ollier Disease (37%) and eight
patients with Maffucci Syndrome (53%). Dedifferentiated chondrosarcoma was not found. Multiple synchronous or metachronous
chondrosarcomas were found in 15 patients. Nine patients died (range 21-54 yrs). Seven of them died disease related due to
pulmonary metastasis (2 humerus, 2 pelvis, 3 femur). Two patients died from glioma of the brain.
To study the genetic background of Ollier disease we performed SNP analysis using Affymetrix SNP6.0 on 15 enchondromas and
24 chondrosarcomas of different grades from 30 Ollier patients and normal DNA from 12 Ollier patients for paired comparison.
We studied tumour tissue since we hypothesized that Ollier disease is a mosaic condition, since it affects multiple bones with an
often unilateral predominance. All samples were divided into three groups: normals, enchondromas and chondrosarcomas. The
number of numerical genomic changes in the chromosomes were not different for the enchondromas (p=0.36) while large
genomic aberrations were seen in chondrosarcomas as compared to normals (p=0.01). Results are analyzed using R, Partek and
Nexus. No common region of Loss of Heterozygosity (LOH) was shared between all enchondromas. LOH at 6p, 9q and 13q is
shared by a proportion of chondrosarcomas. A list with candidate genes was generated combining the SNP data with expression
profiles generated using Illumina Bead Array and these genes are currently being validated. Enchondromas located in the
phalangeal bones of the hands were genetically different from enchondromas located in the long bones. In summary the absence
of common copy number variations or loss of heterozygosity suggests that instead point mutations or epigenetic mechanisms
seem to play a role in the origin of Olllier disease. Mutation analysis revealed absence of the reported G121E, A122T, R150C and
R255H variations in PTHR1 in our series. In addition, mutations in NDST1, the first modification enzyme of the HS polymer which
was recently suggested to compete with EXT1 for binding to EXT2, were also absent.
On the Clinical Manifestation and the Genetics of Ollier Disease
T.C. Pansuriya, S.H.M. Verdegaal, P.C.W. Hogendoorn, A.H.M. Taminiau, and J.V.M.G. Bovee
Leiden University Medical Center, P.O. 9600, 2300 RC Leiden, The Netherlands
Enchondromatosis is a non-hereditary disease, characterised by the presence of multiple enchondromas with a marked unilateral
predominance mainly affecting medulla of the metaphyses and diaphyses of short and long tubular bones of the limbs, especially
the hands and feet. The risk of malignant transformation is suggested to be up to 35%. Due to the rarity of these diseases,
systematic studies on clinical behaviour providing information how to treat patients are lacking. Also, studies to the genetic
cause of Ollier disease are sparse and hampered by low numbers. PTHR1 mutations can be found in only a small proportion (so
far 5 of 62) of cases.
We performed a descriptive retrospective EMSOS (European Musculoskeletal oncology Society)-study in which 12 institutes in
eight countries participated. 118 patients with Ollier Disease and 15 patients with Maffucci Syndrome were included. Unilateral
localization of disease was found in 60% of Ollier patients and 40% of patients with Maffucci Syndrome. One of the predictive
factors for developing chondrosarcoma is the location of the enchondromas; the risk increases especially when enchondromas
are located in the scapula (33%), humerus (18%), pelvis (26%) or femur (15%). For the phalanges, this risk is 14% in the hand
and 16% in the feet. The decision whether or not to perform extensive surgery is difficult, especially in patients who suffer
multiple chondrosarcomas. Malignant transformation was found in forty-four patients with Ollier Disease (37%) and eight
patients with Maffucci Syndrome (53%). Dedifferentiated chondrosarcoma was not found. Multiple synchronous or metachronous
chondrosarcomas were found in 15 patients. Nine patients died (range 21-54 yrs). Seven of them died disease related due to
pulmonary metastasis (2 humerus, 2 pelvis, 3 femur). Two patients died from glioma of the brain.
To study the genetic background of Ollier disease we performed SNP analysis using Affymetrix SNP6.0 on 15 enchondromas and
24 chondrosarcomas of different grades from 30 Ollier patients and normal DNA from 12 Ollier patients for paired comparison.
We studied tumour tissue since we hypothesized that Ollier disease is a mosaic condition, since it affects multiple bones with an
often unilateral predominance. All samples were divided into three groups: normals, enchondromas and chondrosarcomas. The
number of numerical genomic changes in the chromosomes were not different for the enchondromas (p=0.36) while large
genomic aberrations were seen in chondrosarcomas as compared to normals (p=0.01). Results are analyzed using R, Partek and
Nexus. No common region of Loss of Heterozygosity (LOH) was shared between all enchondromas. LOH at 6p, 9q and 13q is
shared by a proportion of chondrosarcomas. A list with candidate genes was generated combining the SNP data with expression
profiles generated using Illumina Bead Array and these genes are currently being validated. Enchondromas located in the
phalangeal bones of the hands were genetically different from enchondromas located in the long bones. In summary the absence
of common copy number variations or loss of heterozygosity suggests that instead point mutations or epigenetic mechanisms
seem to play a role in the origin of Olllier disease. Mutation analysis revealed absence of the reported G121E, A122T, R150C and
R255H variations in PTHR1 in our series. In addition, mutations in NDST1, the first modification enzyme of the HS polymer which
was recently suggested to compete with EXT1 for binding to EXT2, were also absent.
2009 Conference abstract
Osteochondroma Formation: Haploinsufficiency or Two Hits?
Christianne MA Reijnders 1, Cathelijn JF Waaijer1, Andrew Hamilton7, Sander Dijkstra2, John Ham5, Egbert Bakker3, Karoly
Szuhai4, Marcel Karperien6, Pancras CW Hogendoorn1, Sally E Stringer7, Judith VMG Bovée1
Departments of 1Pathology, 2Orthopedic Surgery, 3Human and Clinical Genetics, and 4Molecular Cell Biology, Leiden University
Medical Center, Leiden, The Netherlands; 5Department of Orthopedics, OLVG, Amsterdam, The Netherlands; 6Department of
Tissue Regeneration, University of Twente, Enschede, The Netherlands; 7Cardiovascular Group, School of Clinical and Laboratory
Sciences, Faculty of Human and Medical Sciences, University of Manchester, Manchester, United Kingdom
Background
Multiple osteochondromas (MO) is an autosomal dominant disorder caused by germline mutations in EXT1 and/or EXT2, whereas
solitary osteochondroma is a non-hereditary lesion. EXT is involved in heparan sulfate biosynthesis. We investigated the
controversial issue whether osteochondromas arise via the classical two-hit model for tumor suppressor genes or via
haploinsufficiency.
Design
An in vitro 3D chondrogenic pellet model was used to compare heterozygous mesenchymal stem cells (MSCs)(EXTwt/-) of MO
patients with normal MSCs and the corresponding tumor specimens (presumed EXT-/-). EXT mutations and mRNA expression
levels were assessed. HS chain length and structure of normal and heterozygous MSCs in monolayer culture was determined.
Immunohistochemistry was performed on heparan sulfate (HS), heparan sulfate proteoglycans (HSPGs)(SDC2-4, perlecan,
CD44v3), and HS dependent signaling pathways: TGFbeta/BMP (phosphosmad-1, phosphosmad-2, PAI-1), Wnt (beta-catenin)
and PTHLH (PTHR1, bcl2).
Results
Germline EXT1 and EXT2 mutations were present in MO patients (6/8). We demonstrated a second hit in the EXT genes in 5 out
of 8 osteochondromas (both solitary and hereditary). MSCs with a heterozygous EXT mutation are identical to wildtype MSCs
with regard to HS chain length and structure, in vitro chondrogenesis and the expression of EXT and EXT downstream signaling
molecules.
Conclusion
In conclusion, since I) a heterozygous EXT mutation does not affect chondrogenesis, heparan sulfate and downstream signaling
pathways and II) we show a second hit in the majority of osteochondromas our results refute the haploinsufficiency theory and
strongly support the two-hit model for osteochondroma formation.
Osteochondroma Formation: Haploinsufficiency or Two Hits?
Christianne MA Reijnders 1, Cathelijn JF Waaijer1, Andrew Hamilton7, Sander Dijkstra2, John Ham5, Egbert Bakker3, Karoly
Szuhai4, Marcel Karperien6, Pancras CW Hogendoorn1, Sally E Stringer7, Judith VMG Bovée1
Departments of 1Pathology, 2Orthopedic Surgery, 3Human and Clinical Genetics, and 4Molecular Cell Biology, Leiden University
Medical Center, Leiden, The Netherlands; 5Department of Orthopedics, OLVG, Amsterdam, The Netherlands; 6Department of
Tissue Regeneration, University of Twente, Enschede, The Netherlands; 7Cardiovascular Group, School of Clinical and Laboratory
Sciences, Faculty of Human and Medical Sciences, University of Manchester, Manchester, United Kingdom
Background
Multiple osteochondromas (MO) is an autosomal dominant disorder caused by germline mutations in EXT1 and/or EXT2, whereas
solitary osteochondroma is a non-hereditary lesion. EXT is involved in heparan sulfate biosynthesis. We investigated the
controversial issue whether osteochondromas arise via the classical two-hit model for tumor suppressor genes or via
haploinsufficiency.
Design
An in vitro 3D chondrogenic pellet model was used to compare heterozygous mesenchymal stem cells (MSCs)(EXTwt/-) of MO
patients with normal MSCs and the corresponding tumor specimens (presumed EXT-/-). EXT mutations and mRNA expression
levels were assessed. HS chain length and structure of normal and heterozygous MSCs in monolayer culture was determined.
Immunohistochemistry was performed on heparan sulfate (HS), heparan sulfate proteoglycans (HSPGs)(SDC2-4, perlecan,
CD44v3), and HS dependent signaling pathways: TGFbeta/BMP (phosphosmad-1, phosphosmad-2, PAI-1), Wnt (beta-catenin)
and PTHLH (PTHR1, bcl2).
Results
Germline EXT1 and EXT2 mutations were present in MO patients (6/8). We demonstrated a second hit in the EXT genes in 5 out
of 8 osteochondromas (both solitary and hereditary). MSCs with a heterozygous EXT mutation are identical to wildtype MSCs
with regard to HS chain length and structure, in vitro chondrogenesis and the expression of EXT and EXT downstream signaling
molecules.
Conclusion
In conclusion, since I) a heterozygous EXT mutation does not affect chondrogenesis, heparan sulfate and downstream signaling
pathways and II) we show a second hit in the majority of osteochondromas our results refute the haploinsufficiency theory and
strongly support the two-hit model for osteochondroma formation.
New Publication
EXTra hit for mouse osteochondroma
Judith V. M. G. Bovée
10.1073/pnas.0914431107 PNAS published February 2, 2010 vol. 107 no. 5 1813-1814
EXTra hit for mouse osteochondroma
Judith V. M. G. Bovée
10.1073/pnas.0914431107 PNAS published February 2, 2010 vol. 107 no. 5 1813-1814
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