Rhabdoid tumour predisposition syndrome (RTPS) is a rare syndrome caused by inheritance of a mutated INI1 gene for which only two multigeneration families have been reported. To further characterise the genotype and phenotype of RTPS, we present a third family in which at least three cousins developed an atypical teratoid/rhabdoid tumour (AT/RT) at a young age. Two of these patients showed unusual long survival, and one of these developed an intracranial meningioma and a myoepithelioma of the lip in adulthood. Mutation analysis of INI1 revealed a germline G4A mutation in the donor splice site of exon 4 (c.500 þ 1G4A) in the patients and in their unaffected fathers. This mutation prevents normal splicing and concomitantly generates a stop codon, resulting in nonsensemediated mRNA decay. Biallelic inactivation of INI1 in the tumours, except for the meningioma, was confirmed by absence of nuclear INI1-protein staining. The myoepithelioma of one of the patients carried an identical somatic rearrangement in the NF2 gene as the AT/RT, indicating that both tumours originated from a common precursor cell. In conclusion, this study demonstrates for the first time transmission of a germline INI1-mutation in a RTPS family via nonpenetrant males, long-term survival of two members of this family with an AT/RT, and involvement of INI1 in the pathogenesis of myoepithelioma.
This Phase I study investigated the recommended Phase II dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple-relapsed/refractory (R/R) CD22-positive acute lymphoblastic leukemia (ALL). Patients (≥1-<18 years) received three InO doses (Days 1, 8, 15) per course. Dose-escalation was based on dose-limiting toxicities (DLT) during Course 1 . Dose level 1 (DL1)=1.4 mg/m2 (0.6-0.4-0.4 mg/m2); DL2=1.8 mg/m2 (0.8-0.5-0.5 mg/m2). Secondary endpoints included safety, anti-leukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLT) were enrolled. In Course 1, first cohort, 1/6 (DL1) and 2/5 (DL2) patients experienced DLTs; subsequent review considered DL2 DLTs to be non-dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, where 0/6 (DL1) and 1/6 (DL2) patients had a DLT. Twenty-three patients experienced Grade 3-4 adverse events; hepatic sinusoidal obstruction syndrome was reported in two patients after subsequent chemotherapy. Overall response rate after Course 1 was 80% [95% CI: 59-93%] (20/25 patients; DL1=75% [43-95%], DL2=85% [55-98%]); 84% [60-97%] of responders obtained minimal residual disease-negative CR; 12-month overall survival was 40% [95% CI: 25-66%]. Nine patients received hematopoietic stem cell transplant or chimeric-antigen receptor T-cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating anti-leukemic activity in heavily pre-treated children with CD22-positive R/R ALL. RP2D was established as 1.8 mg/m2/course, as in adults.
Ependymomas frequently display allelic loss of chromosome 22 in the absence of mutations in the known tumor-suppressor genes on chromosome 22, suggesting the role of an alternative predisposing gene or genes from this chromosome. In an effort to localize these genes, 37 ependymomas derived from 33 patients were analyzed for the presence of copy number changes by use of a high-resolution chromosome 22 genomic microarray. Eighteen ependymomas (49%) displayed an array-CGH profile consistent with monosomy of chromosome 22. However, in 10 of these tumors, the fluorescence ratios for 22q clones scored as deleted were different from those at the single gene copy level. This suggests either analysis of mixed populations of tumor and normal stromal cells or analysis of mixed tumor cell populations with different genetic profiles. Four ependymomas derived from two patients showed overlapping interstitial deletions of 2.2 Mb and approximately 510 kb. Further analyses revealed that these deletions were present in the constitutional DNA of these two patients as well as in some of their unaffected relatives. Detailed microsatellite analysis of these families refined the commonly deleted segment to a region of 320 kb between markers RH13801 and D22S419. Our results provide additional evidence for the involvement of genes on chromosome 22 in the development of ependymoma and suggest the presence of a low-penetrance ependymoma susceptibility locus at 22q11.
Objective We report on a patient who developed a meningioma more than two decades after removal at a young age of an atypical teratoid/rhabdoid tumour (AT/RT), which was due to a germline INI1 mutation, and radio-and chemotherapy. Materials and methods We present genetic evidence that the meningioma is not a recurrence or metastasis of the AT/ RT and not due to the INI1 mutation, but is a radiationinduced tumour. Conclusion This is the first case illustrating that improved survival of young patients with an AT/RT after aggressive treatment may be gained at the cost of an increased risk for the development of radiation-induced, non-INI1-related tumours.
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