A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 07/2012; 122(8):2983-8. DOI: 10.1172/JCI64400
Source: PubMed


Cancer is principally considered a genetic disease, and numerous mutations are thought essential to drive its growth. However, the existence of genomically stable cancers and the emergence of mutations in genes that encode chromatin remodelers raise the possibility that perturbation of chromatin structure and epigenetic regulation are capable of driving cancer formation. Here we sequenced the exomes of 35 rhabdoid tumors, highly aggressive cancers of early childhood characterized by biallelic loss of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. We identified an extremely low rate of mutation, with loss of SMARCB1 being essentially the sole recurrent event. Indeed, in 2 of the cancers there were no other identified mutations. Our results demonstrate that high mutation rates are dispensable for the genesis of cancers driven by mutation of a chromatin remodeling complex. Consequently, cancer can be a remarkably genetically simple disease.

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Available from: Chip Stewart, Oct 05, 2015
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    • "However, other concomitant genomic aberrations are rarely found in MRTs. In fact, exome sequencing of a panel of 35 MRTs revealed that mutations or deletions of SNF5 are essentially the sole recurrent genomic alterations in MRTs [35]. Albeit, perturbation in SNF5 function causes genome-wide alterations in nucleosome positioning and global changes in transcription [14], [36]–[39]. "
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    ABSTRACT: Malignant rhabdoid tumors (MRTs) are aggressive pediatric cancers arising in brain, kidney and soft tissues, which are characterized by loss of the tumor suppressor SNF5/SMARCB1. MRTs are poorly responsive to chemotherapy and thus a high unmet clinical need exists for novel therapies for MRT patients. SNF5 is a core subunit of the SWI/SNF chromatin remodeling complex which affects gene expression by nucleosome remodeling. Here, we report that loss of SNF5 function correlates with increased expression of fibroblast growth factor receptors (FGFRs) in MRT cell lines and primary tumors and that re-expression of SNF5 in MRT cells causes a marked repression of FGFR expression. Conversely, siRNA-mediated impairment of SWI/SNF function leads to elevated levels of FGFR2 in human fibroblasts. In vivo, treatment with NVP-BGJ398, a selective FGFR inhibitor, blocks progression of a murine MRT model. Hence, we identify FGFR signaling as an aberrantly activated oncogenic pathway in MRTs and propose pharmacological inhibition of FGFRs as a potential novel clinical therapy for MRTs.
    PLoS ONE 10/2013; 8(10):e77652. DOI:10.1371/journal.pone.0077652 · 3.23 Impact Factor
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    • "Of note, other examples showed that tumors including malignant ones may rely on a unique mutation . Indeed, in rhabdoid child tumors, exome sequencing analysis indicated that biallelic loss of a subunit of the SWI/ SNF chromatin remodeling complex was solely responsible for this malignancy (Lee et al., 2012). Moreover, the recent demonstration that identical somatic codon 61 NRAS mutations were found in different CMN lesions, melanomas as well as in neurological lesions from the same patients, also supports the causative role of the NRAS mutation in CMN genesis (Kinsler et al., 2013). "
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    ABSTRACT: Congenital melanocytic nevus (CMN) is a particular melanocytic in utero proliferation characterized by an increased risk of melanoma transformation during infancy or adulthood. NRAS and BRAF mutations have consistently been reported in CMN samples, but until recently results have been contradictory. We therefore studied a series of large and giant CMN and compared them to small and medium CMN using Sanger sequencing, pyrosequencing, high resolution melting analysis and mutation enrichment by an enhanced version of ice-COLD-PCR. Large-giant CMN displayed NRAS mutations in 94.7% of cases (18/19). At that point, the role of additional mutations in CMN pathogenesis had to be asked. We therefore performed exome-sequencing on 5 specimens of large-giant nevi. The results showed that NRAS mutation was the sole recurrent somatic event found in such melanocytic proliferations. The genetic profile of small-medium CMN was significantly different with 70% of cases bearing NRAS mutations and 30% showing BRAF mutations. These findings strongly suggest that NRAS mutations are sufficient to drive melanocytic benign proliferations in utero.Journal of Investigative Dermatology accepted article preview online, 15 October 2013; doi:10.1038/jid.2013.429.
    Journal of Investigative Dermatology 10/2013; 134(4). DOI:10.1038/jid.2013.429 · 7.22 Impact Factor
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    • "Conventional chemotherapeutics remain disappointing in the treatment of rhabdoid tumors [35], making alternative approaches highly needed. Rhabdoid tumors seem to lack other mutations than those found in SMARCB1[15,36], suggesting epigenetic changes high likely in this tumor entity [15,37]. "
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    ABSTRACT: Background Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches. Methods Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines. Results HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy. Conclusion Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors.
    BMC Cancer 06/2013; 13(1):286. DOI:10.1186/1471-2407-13-286 · 3.36 Impact Factor
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