Involvement of MET/TWIST/APC combination or the potential role of ossification factors in pediatric high-grade osteosarcoma oncogenesis.
Dysregulated cell growth or differentiation due to misexpression of developmental critical factors seems to be a decisive event in oncogenesis. As osteosarcomas are histologically defined by malignant osteoblasts producing an osteoid component, we prospected in pediatric osteosarcomas treated with OS94 protocol the genomic status of several genes implied in ossification processes. In 91 osteosarcoma cases, we focused on the analysis of the fibroblast growth factor receptors (FGFRs) TWIST, APC, and MET by allelotyping, real-time quantitative polymerase chain reaction, gene sequencing, and protein polymorphism study. Our study supports the frequent role of TWIST, APC, and MET as osteosarcoma markers (50%, 62%, and 50%, respectively). TWIST and MET were mainly found to be deleted, and no additional APC mutation was identified. Surprisingly, FGFRs are abnormal in only < 30%. Most of these factors and their abnormalities seem to be linked more or less to one clinical subgroup, but the most significant correlation is the link of MET, TWIST, and APC abnormalities to a worse outcome and their combination within abnormal tumors. A wider cohort is mandatory to define more robust molecular conclusions, but these results are to be considered as the beginning of a more accurate basis for diagnosis, in search of targeted therapies, and to further characterize prognostic markers.
Entz-Werle
Natacha
N
Institut National de la Santé et de la Recherche Médicale U682, Strasbourg, France. natacha.entz-werle@chru-strasbourg.fr
Lavaux
Thomas
T
Metzger
Nadia
N
Stoetzel
Corinne
C
Lasthaus
Christelle
C
Marec
Perrine
P
Kalifa
Chantal
C
Brugieres
Laurence
L
Pacquement
Hélène
H
Schmitt
Claudine
C
Tabone
Marie-Dominique
MD
Gentet
Jean-Claude
JC
Lutz
Patrick
P
Babin
Annie
A
Oudet
Pierre
P
Gaub
Marie Pierre
MP
Perrin-Schmitt
Fabienne
F
D001779:Blood Coagulation Factors / Q000502:physiology*; D001859:Bone Neoplasms / Q000209:etiology* / Q000378:metabolism*; D002648:Child; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology*; D010012:Osteogenesis / Q000502:physiology*; D012516:Osteosarcoma / Q000209:etiology* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met; D011956:Receptors, Cell Surface / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000502:physiology*; D051879:Twist-Related Protein 1 / Q000502:physiology*