Recurrent DGCR8, DROSHA, and SIX Homeodomain Mutations in Favorable Histology Wilms Tumors

Walz, Amy L.; Ooms, Ariadne H.A.G.; Gadd, Samantha; Gerhard, Daniela S.; Smith, Malcolm A.; Auvil, Jaime M. Guidry; Meerzaman, Daoud; Chen, Qingrong; Hsu, Chih Hao; Yan, Chunhua; Nguyen, Cu; Hu, Ying; Bowlby, Reanne; Brooks, Denise; Ma, Yussanne; Mungall, Andrew J.; Moore, Richard A.; Schein, Jacqueline E.; Marra, Marco A.; Huff, Vicki; Dome, Jeffrey S.; Chi, Yueh‐Yun; Mullighan, Charles G.; Ma, Jing; Wheeler, David A.; Hampton, Oliver A.; Jafari, Nadereh; Ross, Nicole; Gastier‐Foster, Julie M.; Perlman, Elizabeth J.

doi:10.1016/j.ccell.2015.01.003

Cited by 237 publications

(193 citation statements)

References 62 publications

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“…Alternatively, absolute levels of SIX proteins might be important, and high levels are required for reprogramming and progenitor maintenance. SIX1/2 mutations have recently been associated with Wilms' tumors (Wegert et al, 2015;Walz et al, 2015). These data provide further evidence that the blastemal elements of the tumor reflect the characteristics of the nephron progenitor niche.…”

Section: Six1 Function In Mouse Versus Humansupporting

confidence: 53%

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Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators

et al. 2016

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Nephron endowment is determined by the self-renewal and induction of a nephron progenitor pool established at the onset of kidney development. In the mouse, the related transcriptional regulators Six1 and Six2 play non-overlapping roles in nephron progenitors. Transient Six1 activity prefigures, and is essential for, active nephrogenesis. By contrast, Six2 maintains later progenitor selfrenewal from the onset of nephrogenesis. We compared the regulatory actions of Six2 in mouse and human nephron progenitors by chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq). Surprisingly, SIX1 was identified as a SIX2 target unique to the human nephron progenitors. Furthermore, RNAseq and immunostaining revealed overlapping SIX1 and SIX2 activity in 16 week human fetal nephron progenitors. Comparative bioinformatic analysis of human SIX1 and SIX2 ChIP-seq showed each factor targeted a similar set of cis-regulatory modules binding an identical target recognition motif. In contrast to the mouse where Six2 binds its own enhancers but does not interact with DNA around Six1, both human SIX1 and SIX2 bind homologous SIX2 enhancers and putative enhancers positioned around SIX1. Transgenic analysis of a putative human SIX1 enhancer in the mouse revealed a transient, mouse-like, pre-nephrogenic, Six1 regulatory pattern. Together, these data demonstrate a divergence in SIX-factor regulation between mouse and human nephron progenitors. In the human, an auto/cross-regulatory loop drives continued SIX1 and SIX2 expression during active nephrogenesis. By contrast, the mouse establishes only an auto-regulatory Six2 loop. These data suggest differential SIX-factor regulation might have contributed to species differences in nephron progenitor programs such as the duration of nephrogenesis and the final nephron count.

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Section: Six1 Function In Mouse Versus Humansupporting

confidence: 53%

“…Furthermore, SIX1 and SIX2 mutations have also recently been associated with Wilms' tumor, a pediatric kidney cancer (Wegert et al, 2015;Walz et al, 2015). The tumors are characterized by blastemal, epithelial and stromal elements much like the developing kidney.…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators

et al. 2016

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“…These genome-wide mutation analyses also identified low-frequency somatic mutations in epigenetic remodelers SMARCA4 and ARID1A (Rakheja et al 2014). Very recently, mutations in DROSHA and DGCR8 were also identified in exome sequencing studies of highrisk blastemal Wilms' tumors and favorable histology Wilms' tumors (Walz et al 2015). These studies also identified a recurring Q177R missense mutation in both SIX1 and SIX2.…”

Section: Wilms' Tumor Geneticsmentioning

confidence: 82%

“…The recent identification of Q177R missense mutations in SIX1 and SIX2 (Walz et al 2015;Wegert et al 2015) fit neatly with a central role for disturbed control of nephron progenitors in Wilms' tumors. The mutations are somatic, and the majority was found to be in a heterozygous state, in which case wild-type and mutant alleles showed equal expression.…”

Section: Wilms' Tumors and The Control Of Nephron Progenitor Cellsmentioning

confidence: 99%

The yin and yang of kidney development and Wilms’ tumors

2015

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Wilms’ tumor, or nephroblastoma, is the most common pediatric renal cancer. The tumors morphologically resemble embryonic kidneys with a disrupted architecture and are associated with undifferentiated metanephric precursors. Here, we discuss genetic and epigenetic findings in Wilms’ tumor in the context of renal development. Many of the genes implicated in Wilms’ tumorigenesis are involved in the control of nephron progenitors or the microRNA (miRNA) processing pathway. Whereas the first group of genes has been extensively studied in normal development, the second finding suggests important roles for miRNAs in general—and specific miRNAs in particular—in normal kidney development that still await further analysis. The recent identification of Wilms’ tumor cancer stem cells could provide a framework to integrate these pathways and translate them into new or improved therapeutic interventions.

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“…First, a number of childhood cancers occur exclusively in children and adolescents. The genomic landscape of such tumors, including medulloblastoma, neuroblastoma, and Wilms tumors, have been the focus of several recent large-scale research projects, such as the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) (17), the Pediatric Cancer Genome Project (PCGP) (18), the Peds-MiOncoSeq (19) and the BASIC3 (20) projects, and have been found to harbor not only shared but several novel recurrent alterations when compared to the most common genomic alterations seen in adult epithelial malignancies. Such alterations include, in addition to SNVs and indels, a higher preponderance of gene fusions and copy number alterations.…”

Section: Pediatric Somatic Taskforcementioning

confidence: 99%

ClinGen Cancer Somatic Working Group – standardizing and democratizing access to cancer molecular diagnostic data to drive translational research

et al. 2017

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A growing number of academic and community clinics are conducting genomic testing to inform treatment decisions for cancer patients (1). In the last 3-5 years, there has been a rapid increase in clinical use of next generation sequencing (NGS) based cancer molecular diagnostic (MolDx) testing (2). The increasing availability and decreasing cost of tumor genomic profiling means that physicians can now make treatment decisions armed with patient-specific genetic information. Accumulating research in the cancer biology field indicates that there is significant potential to improve cancer patient outcomes by effectively leveraging this rich source of genomic data in treatment planning (3). To achieve truly personalized medicine in oncology, it is critical to catalog cancer sequence variants from MolDx testing for their clinical relevance along with treatment information and patient outcomes, and to do so in a way that supports large-scale data aggregation and new hypothesis generation. One critical challenge to encoding variant data is adopting a standard of annotation of those variants that are clinically actionable. Through the NIH-funded Clinical Genome Resource (ClinGen) (4), in collaboration with NLM's ClinVar database and >50 academic and industry based cancer research organizations, we developed the Minimal Variant Level Data (MVLD) framework to standardize reporting and interpretation of drug associated alterations (5). We are currently involved in collaborative efforts to align the MVLD framework with parallel, complementary sequence variants interpretation clinical guidelines from the Association of Molecular Pathologists (AMP) for clinical labs (6). In order to truly democratize access to MolDx data for care and research needs, these standards must be harmonized to support sharing of clinical cancer variants. Here we describe the processes and methods developed within the ClinGen's Somatic WG in collaboration with over 60 cancer care and research organizations as well as CLIA-certified, CAP-accredited clinical testing labs to develop standards for cancer variant interpretation and sharing.

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Recurrent DGCR8, DROSHA, and SIX Homeodomain Mutations in Favorable Histology Wilms Tumors

Cited by 237 publications

References 62 publications

Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators

Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators

The yin and yang of kidney development and Wilms’ tumors

ClinGen Cancer Somatic Working Group – standardizing and democratizing access to cancer molecular diagnostic data to drive translational research

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