Spectrum of IDH-mutant tumors in Ollier-Maffucci disease: the triple interaction theory.

We propose to refine our understanding of the pathophysiology underlying the tumor spectrum observed in patients with Ollier disease (OD) and Maffucci syndrome (MS). On one hand, assuming that all IDH-mutated tumors (as well as enchondromas) observed in OD-MS patients derive from one IDH-mutant cell giving rise to different lineages, the observation of different tumors arising in organs deriving from the neuroectoderm, mesoderm and endoderm points towards a very early post-zygotic event for the IDH mutation. To explain then that the spectrum of IDH-mutated tumors is restricted to some types of tumors, we propose the following hypothesis: - First, we posit that not every mutated cell of the lineage will "express" the IDH mutant phenotype. This can be due i/ to the disappearance in some tissue of the IDH-mutated clone due to negative selection pressure later in embryo development ii/ to the lack of expression of the IDH1 protein in specific cell types iii/ to a functional cell state not leading to the accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) in that tissue/organ. - Second, generalizing the recent understanding of the gliomagenesis in the general population bearing the rs55705857 G-allele variant at 8q24.21, we postulate that OD-MS patients with an inheritable predisposing single nucleotide polymorphism (SNP) are more likely to develop a malignancy, with a specific SNP for each kind of tumor/organ. In summary, our theory provides a new understanding of IDH-mutated tumors in OD-MS patients, as arising from the triple interaction within the same cell of a developmental defect (the somatic mutation that occurs early during the embryogenesis), an organ-specific functional state "expressing" the IDH mutation and leading to an accumulation of D-2HG, and an inheritable predisposing factor (a risky SNP, also specific to each organ). We discuss how this theory could guide future research in OD-MS patients and, more generally, in patients harboring sporadic IDH-mutated tumors.