Twenty children with CNS AT/RT were diagnosed between January 1989 and June 2009. Twelve patients from six families had positive family histories and/or proven germline mutations in a parent, while eight appeared to be sporadic. Treatment following diagnosis varied and included supportive care measures only, chemotherapy, radiation therapy, and high-dose chemotherapy with hematopoietic stem cell rescue, depending on the age of the patient when diagnosed, parental decisions, and available therapeutic options when diagnosed ( and ).
Age at Diagnosis
The median age at diagnosis 4.8 months for children with FAT/RT (range 0–46 months), considerably younger than the median age of children diagnosed with sporadic tumors, which was 13 months (range 2.5–42 months). However, considerable overlap between age ranges in these two groups existed. For example, one infant with a sporadic tumor was diagnosed at only 2.5 months of age, while in Family 1, three siblings with familial CNSAT/RT were not diagnosed until 46, 18, and 42 months of age ().
Outcome of Evaluable Treated Patients With CNS AT/RT
Tumor Location at Diagnosis
Children with S-AT/RT usually had localized disease at diagnosis. Seven patients presented with supratentorial tumors, four had posterior fossa (PF) tumors, and one had a spinal primary tumor. In contrast, children with F-AT/RT usually had PF tumors, although one had a supratentorial tumor, and one had a localized spine tumor, but had widespread CNS disease at diagnosis.
Sixteen of the 20 patients diagnosed with AT/RT were treated with systemic chemotherapy and 11 were also treated with radiation. Chemotherapy and radiation therapy were associated with prolongation of overall survival (OS) and disease-free survival (DFS). Four patients, eventually determined to have F-AT/RT, were treated with supportive care measures only, and all expired within 2 months following presentation. Two additional patients in the familial cohort expired of infectious complications during chemotherapy, one during the first month from overwhelming sepsis associated with neutropenia (7-F1), and one from pneumonia 4 months into chemotherapy (14-F3). These two patients are thus not evaluable for tumor response. Data describing the treatment and outcome for the 14 treated and evaluable patients are summarized in .
Death from tumor progression occurred very rapidly in children who were not treated at the time of diagnosis. Once progression occurred in patients being treated, death occurred rapidly. However, there were three noteworthy exceptions. Patient 1 experienced PD following five courses of Headstart II, prior to planned HDC-SCR and radiation. She was treated with craniospinal radiation and temozolomide during radiation, followed by temozolomide, irinotecan, and bevacuzimab and had disease stabilization for 6 months, before her death from tumor cell dissemination within the cerebrospinal fluid. Patient 12-F2 survived 3.5 months following palliative involved field radiation administered after PD. Finally, Patient 6 experienced PD after chemotherapy, HDC-SCR, and radiation. He was treated with temozolomide for 4 months prior to PD again, and then with oxaliplatin for 3 months but expired 5 months after initial PD.
In the sporadic tumor cohort, tumors from two patients were not tested. One was negative by FISH, MLPA, and PCR-based coding sequence analysis. However, there was no additional material remaining for subsequent SNP array analysis. One tumor showed two common single base deletions in exon 9; and three cases had mutations in exon 5. The final tumor had an exon 7 deletion in one allele and loss of the second allele.
In the familial cohort, five of the six families had material available for genetic analysis. A germline splice site mutation in intron 7 was present in the blood samples from the affected children and the father in Family 1. There was an exon 4,5 duplication in the three siblings from Family 2. Family 3 demonstrated a germline duplication of exon 6 [23
]. Material from the two children in Family 4 was not available for testing. In Family 5, exon 7 was deleted in the patient and his biologic mother. Patient 20-F6 had a germline mutation in exon 5. The pedigrees from three families available for more complete evaluation are shown in , and the analyses descriptions are presented below. The pedigree from family F3 has previously been published [23
Pedigrees for Families F1, F2, and F5.
Three siblings, all of whom developed AT/RT, and their father showed a splice site mutation, c.986 + 1G > C, in intron 7 in their blood which was not found in their mother or unaffected sib. RNA from tumor in the proband, Patient 9-F1 showed a deletion of exon 7 as a result of the mutation. The tumor had a loss of most of the long arm of chromosome 22 as a result of a copy number neutral loss of heterozygosity event, as determined by Illumina 610K SNP array analysis. Cytogenetic analysis of blood and tumor samples in his brother, Patient 10-F1, showed a large deletion of chromosome 22 in 65% of tumor cells (46,XY,del(22)(q11.2q12)[13
]). FISH using the BCR/ABL and EWSR1 probes showed loss of BCR in 54.5% of cells (22q11.2(BCRx1)[109/200]), but retention of EWSR1, indicating an interstitial deletion involving chromosome 22q11.2. This was also confirmed by MLPA in his tumor sample. Patient 11-F1 was found to harbor the same germline mutation and had a supratentorial mass on surveillance brain MRI. She underwent gross total resection of the tumor, which demonstrated copy number neutral loss of heterozygosity of the wild-type allele by SNP array. She died from Clostridium septicum
sepsis associated with fever and neutropenia following her initial course of chemotherapy. On physical examination, the carrier-father was found to have multiple, mobile, soft nodules on the trunk and extremities. Biopsy of one of these lesions was characterized as a “dermatofibroma.” IHC staining for S100 was negative. IHC for SMARCB1
was not done ().
All three siblings presented with symptoms: Patient 12-F2, the proband, at birth; Patient 13-F2 at 5 months of age; and Patient 14-F2 at 0.5 months of age. Exons 1–9 of parental blood, and the tumors from the two patients tested exhibited wild-type SMARCB1 sequence and interphase FISH studies were normal. However, both harbored the same exon 4,5 duplication when analyzed with MLPA. Results were confirmed using a quantitative TaqMan assay. The mutation was not detected in either of the parents, suggesting gonadal mosaicism. Parental paternity was confirmed for the two affected children ().
The proband, Patient 19-F5, presented with symptoms at age 4.5 months. Tumor analysis showed no coding sequence mutations detectable by PCR analysis. By MLPA, the tumor tissue showed a heterozygous deletion of exons 1–6 and 8–9 in SMARCB1, and a homozygous deletion of exon 7. The peripheral blood of the patient and his mother showed a heterozygous deletion of exon 7 of SMARCB1 by MLPA. Maternal grandmother and grandfather, and two maternal aunts tested negative. The paternal uncle refused testing. The mutation in the patient’s mother is believed to have arisen de novo although germline mosaicism is a possibility ().