Uwe Kordes

Germline Nonsense Mutation and Somatic Inactivation of SMARCA4/BRG1 in a Family with Rhabdoid Tumor Predisposition Syndrome

Rhabdoid tumors of early infancy are highly aggressive with consequent poor prognosis. Most cases show inactivation of the SMARCB1 (also known as INI1 and hSNF5) tumor suppressor, a core member of the ATP-dependent SWI/SNF chromatin-remodeling complex. Familial cases, described as rhabdoid tumor predisposition syndrome (RTPS), have been linked to heterozygous SMARCB1 germline mutations. We identified inactivation of another member of the SWI/SNF chromatin-remodeling complex, its ATPase subunit SMARCA4 (also known as BRG1), due to a SMARCA4/BRG1 germline mutation and loss of heterozygosity by uniparental disomy in the tumor cells of two sisters with rhabdoid tumors lacking SMARCB1 mutations. SMARCA4 is thus a second member of the SWI/SNF complex involved in cancer predisposition. Its general involvement in other tumor entities remains to be established.

High-resolution genomic analysis suggests the absence of recurrent genomic alterations other than SMARCB1 aberrations in atypical teratoid/rhabdoid tumors.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare malignant pediatric brain tumor characterized by genetic alterations affecting the SMARCB1 (hSNF5/INI1) locus in chromosome band 22q11.2. To identify potential additional genetic alterations, high‐resolution genome‐wide analysis was performed using a molecular inversion probe single‐nucleotide polymorphism (MIP SNP) assay (Affymetrix OncoScan formalin‐fixed paraffin‐embedded express) on DNA isolated from 18 formalin‐fixed paraffin‐embedded archival samples. Alterations affecting the SMARCB1 locus could be demonstrated by MIP SNP in 15 out of 16 evaluable cases (94%). These comprised five tumors with homozygous deletions, six tumors with heterozygous deletions, and four tumors with copy number neutral loss of heterozygosity (LOH) involving chromosome band 22q11.2. Remarkably, MIB SNP analysis did not yield any further recurrent chromosomal gains, losses, or copy neutral LOH. On MIP SNP screening for somatic mutations, the presence of a SMARCB1 mutation (c.472C>T p.R158X) was confirmed, but no recurrent mutations of other cancer relevant genes could be identified. Results of fluorescence in situ hybridization, multiplex ligation‐dependent probe amplification, and SMARCB1 sequencing were highly congruent with that of the MIP SNP assay. In conclusion, these data further suggest the absence of recurrent genomic alterations other than SMARCB1 in AT/RT.

Clinical and molecular features in patients with atypical teratoid rhabdoid tumor or malignant rhabdoid tumor.

The SMARCB1 gene status in 50 patients with atypical teratoid rhabdoid tumor and/or malignant rhabdoid tumor recruited to a German registry was prospectively analyzed with FISH and PCR. Altogether we found 40 SMARCB1 mutations in 28 patients. Two patients were positive for SMARCB1 staining at immunochemistry. Germline mutations were identified in 10 of 41 patients with CNS disease, including three large heterozygous deletions, six truncating mutations and one donor splice site mutation. No missense mutation was identified. Analysis of first degree relatives did not detect any carriers. Mutations were distributed over the SMARCB1‐gene without particular clustering. No germline mutation was found in nine patients without CNS disease. Patients with germline mutation had a lower median age at diagnosis in comparison to those without detectable germline mutation (5.5 vs. 13 months, P = 0.001), a higher rate of primary multicentric CNS disease (5/10 vs. 5/36) and synchronous or metachronous mixed CNS and extracranial disease (4/10 vs. 1/36). Two year overall survival was 0% in patients with germline mutation and 48% in those without detectable germline mutation (P < 0.001). Patients with germline mutation of SMARCB1 manifest at an early age and have a very high risk for progression which has to be considered with respect to the outcome of further treatment studies.

Cribriform neuroepithelial tumor (CRINET): a nonrhabdoid ventricular tumor with INI1 loss and relatively favorable prognosis.

Atypical teratoid/rhabdoid tumors are malignant embryonal tumors characterized by the presence of rhabdoid cells, genetic alterations affecting the SMARCB1 gene (hSNF5/INI1), and a poor prognosis. Whether INI1 plays a role in the pathogenesis of other central nervous system tumors is uncertain. We report on cases of 2 young children with unusual intracranial nonrhabdoid neuroectodermal tumors within and around the third or fourth ventricle that are characterized by cribriform strands and trabeculae and well-defined epithelial membrane antigen-immunopositive surfaces and show INI1 protein loss. Histological and immunohistochemical features did not correspond to established tumor types, including atypical teratoid/rhabdoid tumors, medulloepithelioma, choroid plexus carcinoma, and ependymoma. Fluorescence in situ hybridization analyses failed to identify chromosomal alterations affecting the SMARCB1 locus, but sequencing revealed a homozygous 4-bp duplication in exon 4 (492duplCCTT) in one of the tumors. Both children responded well to conventional adjuvant therapy protocols and are alive and in complete remission longer than 5 years postoperatively. We suggest that cribriform neuroepithelial tumor (CRINET) is a nonrhabdoid ventricular tumor that shows loss of tumoral INI1 protein and has a relatively favorable prognosis.

Ovarian small cell carcinoma of the hypercalcemic type in children and adolescents: a prognostically unfavorable but curable disease.

Ovarian small cell carcinoma of the hypercalcemic type is a rare neoplasm that is associated with a poor prognosis. The objective of the current study was to investigate the clinicopathologic features of this tumor and to develop preliminary diagnostic and therapeutic guidelines.

Expression of SOX9 and SOX10 in central neuroepithelial tumor

The SOX group E transcription factors play an integral role in the specification and differentiation of astrocytes and oligodendrocytes. We have examined the pattern of expression for SOX9 and SOX10 in primary brain tumors by immunohistochemistry. Pediatric and adult high grade tumors display strong nuclear staining for both SOX9 and SOX10 (astrocytic, oligodendroglial and primitive neuroectodermal tumors). In comparison pediatric pilocytic astrocytoma express much less SOX9 and SOX10. Reactive astrogliosis is characterized by an increase of SOX9 only.

High-dose chemotherapy (HDCT) with auto-SCT in children with atypical teratoid/rhabdoid tumors (AT/RT): a report from the European Rhabdoid Registry (EU-RHAB).

A retrospective analysis of data from the European Rhabdoid Registry (EU-RHAB) was performed to describe the outcome of children with atypical teratoid/rhabdoid tumors (AT/RT) who underwent high-dose chemotherapy (HDCT) with auto-SCT. Nineteen patients (male, n=15; median age at diagnosis 21 months) were identified. Nine patients presented with metastatic disease at diagnosis. A partial or subtotal resection was achieved in 11, a total resection in five and a biopsy in three patients. Patients received a median of six chemotherapy cycles prior to HDCT. Additional radiotherapy was performed in 14 patients (first-line, n=9; following progression, n=5). Six patients underwent tandem auto-SCT. Disease status before HDCT was CR in six, PR in eight, stable disease in two and progressive disease (PD) in two patients (data missing, n=1). With a median follow-up of 16 months, 14 patients progressed. Estimated progression-free and OS at 2 years were 29% (±11%) and 50% (±12%), respectively. At last follow-up, eight patients were alive (first CR, n=4; second CR, n=2; PR, n=1; PD, n=1). Eleven patients died of PD. Median time-to-progression was 14 months. Selected patients with AT/RT might benefit from HDCT with radiotherapy. The definitive impact of this treatment modality has to be evaluated prospectively in a randomized trial.

Favorable outcome of patients affected by rhabdoid tumors due to rhabdoid tumor predisposition syndrome (RTPS).

Rhabdoid tumor predisposition syndrome is usually associated with shorter survival in patients with malignant rhabdoid tumors regardless of anatomical origin. Here we present four children harboring truncating heterozygous SMARCB1/INI1 germline mutations with favorable outcome. All four patients received multi‐modality treatment, three according to therapeutic recommendations by the EU‐RHAB registry, two without radiotherapy, and mean event‐free survival accounts for 7 years. In conclusion, intensive treatment with curative intent is justified for children with rhabdoid tumors even if an underlying rhabdoid predisposition syndrome is demonstrated. Pediatr Blood Cancer 2014;61:919–921.

Choroid plexus carcinomas are characterized by complex chromosomal alterations related to patient age and prognosis

Choroid plexus carcinoma is a malignant brain tumor predominantly occurring in young children. Only limited data are available regarding the underlying molecular genetic alterations. Therefore, molecular inversion probe single nucleotide polymorphism (MIP SNP) arrays were performed on a series of 26 neuropathologically well‐characterized choroid plexus carcinomas. Recurrent copy number losses of chromosomes 5, 6, 16, 18, 19, and 22 as well as gains of chromosomes 1, 2, 4, 12, and 20 were identified. Furthermore, GISTIC analysis identified significant recurrent gains of 17 genes in 9 regions, and recurrent losses of 96 genes in 14 regions. Clustering analysis separated choroid plexus carcinomas into two groups: one characterized by marked losses and the other characterized by gains across the chromosomes. Chromosomal losses of 9, 19p, and 22q were significantly more frequent in younger children (<36 months), whereas gains on chromosomes 7 and 19, and chromosome arms 8q, 14q, and 21q prevailed in older patients. Multivariate analysis revealed that loss of 12q was associated with shorter survival [12 ± 5 months vs. 86 ± 8 months; (mean ± SD; P = 0.001)] and, in addition, 45 smaller chromosomal regions showing genetic alterations significantly associated with survival could be identified. The MIP SNP array profiles also contributed to the diagnosis of two difficult SMARCB1‐negative tumors as choroid plexus carcinoma and cribriform neuroepithelial tumor (CRINET), respectively. In conclusion, choroid plexus carcinomas are characterized by complex genetic alterations, which are related to patient age and may have prognostic and diagnostic value.

Childhood cancer predisposition syndromes—A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology

Heritable predisposition is an important cause of cancer in children and adolescents. Although a large number of cancer predisposition genes and their associated syndromes and malignancies have already been described, it appears likely that there are more pediatric cancer patients in whom heritable cancer predisposition syndromes have yet to be recognized. In a consensus meeting in the beginning of 2016, we convened experts in Human Genetics and Pediatric Hematology/Oncology to review the available data, to categorize the large amount of information, and to develop recommendations regarding when a cancer predisposition syndrome should be suspected in a young oncology patient. This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer predisposition syndrome should be suspected.