Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children ( Dagher, R., and Helman, L, (1999) Oncologist 4, 34-44), whereas medulloblas toma, a highly malignant tumor of the cerebellum, accounts for 20% of child hood brain tumors (Goodrich, L, V,, and Scott, M. P. (1998) Neuron 21, 1243 -1257), Both tumors are associated with a deficiency in the tumor suppresso r Patched (PTCH) in Gorlin syndrome (Gorlin, R, J, (1987) Medicine (Baltimo re) 66, 98-113), and they are present in the corresponding murine models. R MS in Ptch mutant mice consistently contain elevated levels of the tumor gr owth-promoting insulin-like growth factor 2 (Igf2), We have investigated th e mechanism of Igf2 overexpression and its significance in medulloblastoma and RMS tumorigenesis, Here we report that Igf2 is indispensable for the fo rmation of medulloblastoma and RMS in Ptch mutants. Overexpression of Igf2 in RMS in these mice does not involve loss of imprinting, uniparental disom y, amplification of the Igf2 locus, or polyploidy, Since Igf2 is also overe xpressed in non-tumor tissue deficient in Ptch, these observations suggest that Ptch regulates Igf2 levels through a transcriptional mechanism. They a lso identify Igf2 as a potential target for medulloblastoma and RMS.