Bovée, Judith V M G

Chondrosarcomas are chemo- and radiotherapy resistant and frequently harbor mutations in isocitrate dehydrogenase (IDH1 or IDH2), causing increased levels of D-2-hydroxyglutarate (D-2-HG). DNA repair defects and synthetic lethality with poly(ADP-ribose) polymerase (PARP) inhibition occur in IDH mutant glioma and leukemia models. Here we evaluated DNA repair and PARP inhibition, alone or combined with chemo- or radiotherapy, in chondrosarcoma cell lines with or without endogenous IDH mutations. Chondrosarcoma cell lines treated with the PARP inhibitor talazoparib were examined for dose–response relationships, as well as underlying cell death mechanisms and DNA repair functionality. Talazoparib was combined with chemo- or radiotherapy to evaluate potential synergy. Cell lines treated long term with an inhibitor normalizing D-2-HG levels were investigated for synthetic lethality with talazoparib. We report that talazoparib sensitivity was variable and irrespective of IDH mutation status. All cell lines expressed Ataxia Telangiectasia Mutated (ATM), but a subset was impaired in poly(ADP-ribosyl)ation (PARylation) capacity, homologous recombination, and O-6-methylguanine-DNA methyltransferase (MGMT) expression. Talazoparib synergized with temozolomide or radiation, independent of IDH1 mutant inhibition. This study suggests that talazoparib combined with temozolomide or radiation are promising therapeutic strategies for chondrosarcoma, irrespective of IDH mutation status. A subset of chondrosarcomas may be deficient in nonclassical DNA repair pathways, suggesting that PARP inhibitor sensitivity is multifactorial in chondrosarcoma.

Nodular fasciitis is a benign self‐limited myofibroblastic neoplasm, which usually involves the upper extremities and trunk of young patients. These tumors have been shown to harbor a translocation involving the MYH9 and USP6 genes, leading to overexpression of the latter. We report seven cases of nodular fasciitis with cutaneous presentations. All cases involved the dermis, with six involving the superficial subcutis, and one auricular tumor extending into cartilage. All cases showed USP6 rearrangement by fluorescence in situ hybridization; in two of three cases, the characteristic MYH9‐USP6 fusion was shown by RT‐PCR. All patients underwent conservative resection. Nodular fasciitis is an uncommon mesenchymal neoplasm that can occasionally present in superficial locations and is sometimes mistaken for a malignant process. Molecular testing can be useful to distinguish this entity from other cutaneous spindle cell tumors.