Genome-Wide Profiles of Extra-cranial Malignant Rhabdoid Tumors Reveal Heterogeneity and Dysregulated Developmental Pathways

Chun, Hye Jung; Lim, Emilia L.; Heravi-Moussavi, Alireza; Saberi, Saeed; Mungall, Andrew J.; Bilenky, Mikhail; Carles, Annaïck; Tse, Kane; Shlafman, Inna; Zhu, Kelsey; Qian, Jenny Q.; Palmquist, Diana L.; He, An; Long, William D.; Goya, Rodrigo; Ng, Michelle; LeBlanc, Véronique G.; Pleasance, Erin; Thiessen, Nina; Wong, Tina; Chuah, Eric; Zhao, Yong; Schein, Jacquie; Gerhard, Daniela S.; Taylor, Michael D.; Moore, Richard A.; Ma, Yussanne; Jones, Steven J.M.; Perlman, Elizabeth J.; Hirst, Martin; Marra, Marco A.

doi:10.1016/j.ccell.2016.02.009

Cited by 114 publications

(151 citation statements)

References 88 publications

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“…These findings have significant implications for ATRT treatment as the safety and efficacy of dasatinib are established in adults and children. Interestingly, consistent with the reported enrichment of BMP signaling/mesenchymal lineage genes in non-CNS RTs (Birks et al, 2011; Chun et al, 2016; Gadd et al, 2010), we observed an overlap in the methylation profiles of non-CNS RTs and group 2 ATRTs (data not shown), which suggests that some group 2 ATRTs and non-CNS tumors characteristically seen in very young children with rhabdoid predisposition syndrome, may have common or closely related cellular origins. Indeed, we observed that dasatinib and nilotinib also robustly inhibited the growth of G401, a renal RT cell line (data not shown) and suggest potential roles for dasatinib and nilotinib in non-CNS RT treatment.…”

Section: Discussionsupporting

confidence: 87%

Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

et al. 2016

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SUMMARY We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

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Section: Discussionsupporting

confidence: 87%

Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

et al. 2016

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“…Aside from the loss of SMARCB1 in MRTs, prior studies that included SNP and exome analysis noted very little variation in MRT genomes[13, 23–25]. Recent studies by Chun et al found clustering of CG island promoter methylation into two groups that correlated with age at diagnosis, which may provide a biological reason for the apparent survival benefit among older patients[26]. Similar to non-CNS rhabdoid tumors, recent investigations in transcriptomic and epigenetic organization of CNS AT/RTs suggests that these tumors can be subclassified into three distinct molecular subgroups with different preferred locations in the brain, suggesting they may originate from different precursor cells while maintaining their common loss of SMARCB1 [27].…”

Section: Discussionmentioning

confidence: 99%

Prognostic factors and survival in non-central nervous system rhabdoid tumors

Farber

Shukla

Lim

et al. 2017

Journal of Pediatric Surgery

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Introduction Non-central nervous system (non-CNS) rhabdoid tumors tend to present at a young age and have an extremely aggressive course, with dismal overall survival rates. Inactivation of the tumor suppressor gene SMARCB1 has been shown in rhabdoid tumors regardless of anatomic location, suggesting a common genetic basis. We retrospectively analyzed our institutional experience with non-CNS rhabdoid tumors to determine overall survival and prognostic variables. Methods We reviewed records of pediatric patients (age <22y) with non-CNS rhabdoid tumor at our institution between 1980 and 2014. Variables evaluated for correlation with survival included: age > or <1.5 years (median) at diagnosis, M1 status, and radiation therapy. The log-rank test was used to compare Kaplan-Meier probability distributions with P values adjusted for multiple testing using the false discovery rate approach. Results Nineteen consecutive patients (10 female) with histologically verified rhabdoid tumor were identified. Mean age at diagnosis was 3.2 years (median 1.5y, range 1.3mo–21.8y). Primary tumors were located in the kidney (n=10), head and neck (n=5), and in the liver, thigh, mediastinum and retroperitoneum (n=1 each). SMARCB1 expression was absent in all 10 patients tested. Eight patients had distant metastases at diagnosis. Median overall survival was 1.2 years. Age greater than the median and radiation therapy were associated with better outcome, with a median overall survival of 2.7 years (P=0.049 and P=0.003, respectively). Conclusion Survival rates for rhabdoid tumor remain poor, but prognosis is better in older children, regardless of primary tumor location. Because of its rarity, clinical trials with present agents are difficult to conduct. Further progress will require a focus on therapies targeted at tumor biology rather than anatomic location for non-CNS rhabdoid tumors.

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“…The ongoing and detailed characterization of AT/RT and MRT (50,51) will likely lead to further biological insights that can better delineate molecular subtypes of these tumors and may lead to novel therapeutic avenues. Despite this progress, how best to approach early cancer surveillance for germline carriers at risk for these rare and aggressive tumors is likely to remain an area of significant clinical challenge.…”

Section: Discussionmentioning

confidence: 99%

Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome

Foulkes

Kamihara

Evans

et al. 2017

Clinical Cancer Research

153

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Gorlin syndrome and rhabdoid tumor predisposition syndrome (RTPS) are autosomal dominant syndromes associated with an increased risk of childhood-onset brain tumors. Individuals with Gorlin syndrome can manifest a wide range of phenotypic abnormalities, with about 5% of family members developing medulloblastoma, usually occurring in the first 3 years of life. Gorlin syndrome is associated with germline mutations in components of the Sonic Hedgehog pathway, including Patched1 (PTCH1) and Suppressor of fused (SUFU). SUFU mutation carriers appear to have an especially high risk of early-onset medulloblastoma. Surveillance MRI in the first years of life in SUFU mutation carriers is, therefore, recommended. Given the risk of basal cell carcinomas, regular dermatologic examinations and sun protection are also recommended. Rhabdoid tumors (RT) are tumors initially defined by the descriptive “rhabdoid” term, implying a phenotypic similarity with rhabdomyoblasts at the microscopic level. RTs usually present before the age of 3 and can arise within the cranium as atypical teratoid/rhabdoid tumors or extracranially, especially in the kidney, as malignant rhabdoid tumors. However, RTs of both types share germline and somatic mutations in SMARCB1 or, more rarely, SMARCA4, each of which encodes a chromatin remodeling family member. SMARCA4 mutations are particularly associated with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The outcome following a diagnosis of any of these tumors is often poor, and the value of surveillance is unknown. International efforts to determine surveillance protocols are underway, and preliminary recommendations are made for carriers of SMARCB1 and SMARCA4 mutations. Clin Cancer Res; 23(12); e62–e67. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

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Genome-Wide Profiles of Extra-cranial Malignant Rhabdoid Tumors Reveal Heterogeneity and Dysregulated Developmental Pathways

Cited by 114 publications

References 88 publications

Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

Prognostic factors and survival in non-central nervous system rhabdoid tumors

Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome

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