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Mutations of the INI1 Rhabdoid Tumor Suppressor Gene in Medulloblastomas and Primitive Neuroectodermal Tumors of the Central Nervous System¹

Divisions of Human Genetics and Molecular Biology [J. A. B., B. F., J-Y. Z.] and Oncology [A. J. J.], and Department of Pathology [L. B. R.], The Children’s Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine [J. A. B., A. J. J.], Philadelphia, Pennsylvania 19104; Departments of Experimental Pathology [C. D. J.] and Neurosurgery [C. R.] Mayo Clinic, Rochester, Minnesota 55905; Department of Neurology, Beth Israel Medical Center, North Division, New York, New York 10128 [J. C. A.]; and Department of Pathology, Kaplan Cancer Center, New York, New York 10016 [D. Z.]

Germ-line and somatic mutations of the hSNF5/INI1 gene have been reported in atypical teratoid/rhabdoid tumors (AT/RTs) of the brain, consistent with its role as a tumor suppressor gene. In the present study, we determined the frequency of deletions and mutations of INI1 in 52 children whose original diagnosis was medulloblastoma (MB) or primitive neuroectodermal tumor (PNET) of the central nervous system. Mutations were detected in DNA isolated from four tumors, all from children less than 3 years of age at diagnosis. Two of the four were reviewed and reclassified as atypical teratoid tumor, whereas there was insufficient material to establish this diagnosis in the two remaining cases. The relatively low frequency of mutations, even in a large series of infants, suggests that loss of sequences from chromosome 22 and/or mutations of INI1 do not account for the poor prognosis of children with MB or PNET who are less than 3 years of age at diagnosis. Nevertheless, chromosome 22 deletion and INI1-mutation analysis of infants with MB/PNET should be considered for all children who are less than 1 year of age. Detection of these mutations suggests that the child has an AT/RT, rather than a MB/PNET, a finding with important prognostic value.

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