| Elena Pedrini, Ph.D., research |
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2009 Conference abstract
Osteochondroma Onset and Malignant Degeneration: Redefinition of EXT Gene Role
Monia Zuntini1*, Elena Pedrini1*, Alessandro Parra1, Marco Alberghini2, Federica Sgariglia1, and Luca Sangiorgi1
1Department of Medical Genetics and 2Anatomy and Pathological Histology Unit, Rizzoli Orthopaedic Institute, Bologna, Italy.
e-mail: elena.pedrini@ior.it
Osteochondroma is the most common of the benign tumors of the bone. It could presents as a single lesion, solitary
osteochondroma (SO) with an incidence of 1-2%, whereas it occurs as multiple lesions in the context of multiple
osteochondroma disease (MO, incidence of 1/50000). The most severe complication of osteochondroma is the malignant
transformation into secondary peripheral chondrosarcoma (CHS); it is estimated to be rare in SO (<1%) whereas it occurs in
1-5% of MO patients. Even if both conditions have been associated with mutations in EXT1 and EXT2 genes, the molecular
mechanism involved in osteochondroma onset and malignant progression is still contradictory.
To evaluate whether a second mutational hit is required for the development of solitary/multiple osteochondromas and/or their
malignant degenerations, we investigated 65 tissue samples, including 46 osteochondromas (35 MO and 11 SO) and 17
peripheral chondrosarcomas (12 derived from MO and 5 from SO) with 2 recurrences, for the presence of both point mutations
and big rearrangements in EXT1/EXT2 genes; mutational screening was performed with a combined DHPLC/MLPA protocol
including also direct sequencing of all abnormal profiles and quantitative Real Time qPCR to validate MLPA results. Analyses were
performed also on corresponding constitutional blood samples. For 5 patients we considered more resections from different
affected skeletal sites.
6 out of 11 SO samples showed the presence of point or big mutations in EXT1 gene whereas 5 showed no EXT mutations; no
samples with two mutational hit were observed. Mutational screening of 35 MO samples confirmed all the presence of the
germ-line mutation found in constitutional DNA; 30 samples (86%) showed only this heterozygous mutation, while a second
mutational hit was found in 5 tissues. Analyzing malignant degeneration, 3 out of 5 SO-related chondrosarcomas showed no
additional somatic mutation, while in 2 primary tumour resections the loss of one copy of EXT1 or EXT2 gene was detected; the
corresponding recurrence of this latter sample showed the loss of both EXT2 alleles. 5 out of 12 CHS resections derived from
MO showed the presence of a second EXT1/2 somatic mutational hit; in the only available recurrence the heterozygous germline
mutation was found at homozygous status due to the loss of the wt allele.
Our results show the absence of a second mutational hit in most of analyzed MO and SO samples suggesting that their growth
may not necessarily require two EXT1/2 genetic alterations, which seems to be a common prerequisite for malignant
transformation and tumour progression. All these evidences lead to the hypothesis of the presence of molecular mechanisms
alternative to EXT inactivation in MO pathogenesis, as mutations/polymorphisms in EXT regulatory sequences,
post-transcriptional regulation pathways or involvement of other genes not belonging to EXT family.
Osteochondroma Onset and Malignant Degeneration: Redefinition of EXT Gene Role
Monia Zuntini1*, Elena Pedrini1*, Alessandro Parra1, Marco Alberghini2, Federica Sgariglia1, and Luca Sangiorgi1
1Department of Medical Genetics and 2Anatomy and Pathological Histology Unit, Rizzoli Orthopaedic Institute, Bologna, Italy.
e-mail: elena.pedrini@ior.it
Osteochondroma is the most common of the benign tumors of the bone. It could presents as a single lesion, solitary
osteochondroma (SO) with an incidence of 1-2%, whereas it occurs as multiple lesions in the context of multiple
osteochondroma disease (MO, incidence of 1/50000). The most severe complication of osteochondroma is the malignant
transformation into secondary peripheral chondrosarcoma (CHS); it is estimated to be rare in SO (<1%) whereas it occurs in
1-5% of MO patients. Even if both conditions have been associated with mutations in EXT1 and EXT2 genes, the molecular
mechanism involved in osteochondroma onset and malignant progression is still contradictory.
To evaluate whether a second mutational hit is required for the development of solitary/multiple osteochondromas and/or their
malignant degenerations, we investigated 65 tissue samples, including 46 osteochondromas (35 MO and 11 SO) and 17
peripheral chondrosarcomas (12 derived from MO and 5 from SO) with 2 recurrences, for the presence of both point mutations
and big rearrangements in EXT1/EXT2 genes; mutational screening was performed with a combined DHPLC/MLPA protocol
including also direct sequencing of all abnormal profiles and quantitative Real Time qPCR to validate MLPA results. Analyses were
performed also on corresponding constitutional blood samples. For 5 patients we considered more resections from different
affected skeletal sites.
6 out of 11 SO samples showed the presence of point or big mutations in EXT1 gene whereas 5 showed no EXT mutations; no
samples with two mutational hit were observed. Mutational screening of 35 MO samples confirmed all the presence of the
germ-line mutation found in constitutional DNA; 30 samples (86%) showed only this heterozygous mutation, while a second
mutational hit was found in 5 tissues. Analyzing malignant degeneration, 3 out of 5 SO-related chondrosarcomas showed no
additional somatic mutation, while in 2 primary tumour resections the loss of one copy of EXT1 or EXT2 gene was detected; the
corresponding recurrence of this latter sample showed the loss of both EXT2 alleles. 5 out of 12 CHS resections derived from
MO showed the presence of a second EXT1/2 somatic mutational hit; in the only available recurrence the heterozygous germline
mutation was found at homozygous status due to the loss of the wt allele.
Our results show the absence of a second mutational hit in most of analyzed MO and SO samples suggesting that their growth
may not necessarily require two EXT1/2 genetic alterations, which seems to be a common prerequisite for malignant
transformation and tumour progression. All these evidences lead to the hypothesis of the presence of molecular mechanisms
alternative to EXT inactivation in MO pathogenesis, as mutations/polymorphisms in EXT regulatory sequences,
post-transcriptional regulation pathways or involvement of other genes not belonging to EXT family.
|
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Click here to verify.# HON Conduct 282463 and is the patient support link on the US Government Genetics Home Reference (http://ghr.nlm.nih.gov)
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Intute: health & life sciences a free online service providing access to the very best Web resources for education and research located in the UK
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.
studying the pathology and genetics of bone tumors.
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