A genome-wide association study identifies susceptibility loci for Wilms tumor

Turnbull, Clare; Perdeaux, Elizabeth R; Pernet, David; Naranjo, Arlene; Renwick, Anthony; Seal, Sheila; Munoz-Xicola, Rosa Maria; Hanks, Sandra; Slade, Ingrid; Zachariou, Anna; Warren-Perry, Margaret; Ruark, Elise; Gerrard, Mary; Hale, Juliet; Hewitt, Martin; Kohler, Janice A.; Lane, Sheila; Levitt, Gill; Madi, Mabrook; Morland, Bruce; Neefjes, Veronica; Nicholson, James C.; Picton, Susan; Pizer, Barry; Ronghe, Milind; Stevens, Michael; Traunecker, Heidi; Stiller, Charles; Pritchard‐Jones, Kathy; Dome, Jeffrey S.; Grundy, Paul E.; Rahman, Nazneen

doi:10.1038/ng.2251

Cited by 72 publications

(58 citation statements)

References 14 publications

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“…Recently, a similar region of germline gain encompassing both genes was detected in a patient with bilateral nephroblastomatosis and a family history of WT [39]. A genome-wide association study has also identified potential WT susceptibility loci in this commonly gained region, mapping to SNPs that flank DDX1 [40]. We cannot therefore rule out a significant role for DDX1 in Wilms tumour.…”

Section: Discussionmentioning

confidence: 97%

Multiple mechanisms of MYCN dysregulation in Wilms tumour

Williams¹,

Chagtai²,

Alcaide-German³

et al. 2015

Oncotarget

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Genomic gain of the proto-oncogene transcription factor gene MYCN is associated with poor prognosis in several childhood cancers. Here we present a comprehensive copy number analysis of MYCN in Wilms tumour (WT), demonstrating that gain of this gene is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. Using whole exome and gene-specific sequencing, together with methylation and expression profiling, we show that MYCN is targeted by other mechanisms, including a recurrent somatic mutation, P44L, and specific DNA hypomethylation events associated with MYCN overexpression in tumours with high risk histologies. We describe parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumours of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolve over time. We report a second bilateral case in which MYCN gain is a germline aberration. Our results suggest a significant role for MYCN dysregulation in the molecular biology of Wilms tumour. We conclude that MYCN gain is prognostically significant, and suggest that the novel P44L somatic variant is likely to be an activating mutation.

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Section: Discussionmentioning

confidence: 97%

Multiple mechanisms of MYCN dysregulation in Wilms tumour

Williams¹,

Chagtai²,

Alcaide-German³

et al. 2015

Oncotarget

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“…Point mutations in WT1, WTX, b-catenin, and abnormalities involving translocations in chromosome 6 have been linked to Wilms tumor (Knudson and Strong 1972;Rivera and Haber 2005;Hu et al 2011), and several susceptibility loci for Wilms tumor were recently identified by a genome-wide association study (Turnbull et al 2012). However, the underlying genetic basis of most cases of Wilms tumor remains unknown (Turnbull et al 2012).…”

Section: Discussionmentioning

confidence: 99%

“…However, the underlying genetic basis of most cases of Wilms tumor remains unknown (Turnbull et al 2012). Here we report that up to a third of human Wilms tumors overexpress LIN28B.…”

Section: Discussionmentioning

confidence: 99%

Lin28 sustains early renal progenitors and induces Wilms tumor

et al. 2014

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Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differentiation of the embryonic kidney. Here we show that overexpression of the heterochronic regulator Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation, ultimately resulting in a pathology highly reminiscent of Wilms tumor. Using lineage-specific promoters to target Lin28 to specific cell types, we observed Wilms tumor only when Lin28 is aberrantly expressed in multiple derivatives of the intermediate mesoderm, implicating the cell of origin as a multipotential renal progenitor. We show that withdrawal of Lin28 expression reverts tumorigenesis and markedly expands the numbers of glomerulus-like structures and that tumor formation is suppressed by enforced expression of Let-7 microRNA. Finally, we demonstrate overexpression of the LIN28B paralog in a significant percentage of human Wilms tumor. Our data thus implicate the Lin28/Let-7 pathway in kidney development and tumorigenesis. Wilms tumor, a pediatric kidney cancer affecting one in 10,000 children in North America, arises from the failure of embryonic nephrogenic cells to undergo terminal differentiation (Rivera and Haber 2005). The development of the kidney is a complex process that requires reciprocal inductive interactions between the ureteric bud (UB) and metanephric mesenchyme (MM), which leads to proliferation and expansion of the primitive cap mesenchyme (CM) (Grobstein 1955(Grobstein , 1956Hatini et al. 1996;Davidson 2009). The CM cells differentiate into mature nephrons by a mesenchymal-to-epithelial transition (MET). As they also possess self-renewal capacity, CM cells represent embryonic kidney stem cells (Kobayashi et al. 2008;Pleniceanu et al. 2010). CM cells proliferate and differentiate in the outer nephrogenic zone of the kidney until the second postnatal day in mice (Hartman et al. 2007) and the 36th week of gestation in humans (Hinchliffe et al. 1991), after which time all remaining CM cells synchronously differentiate to establish the final number of nephrons in the adult kidney (Hartman et al. 2007). Wilms tumor shares histological features with the developing kidney and is frequently associated with persistent areas of embryonic tissue known as nephrogenic rests, which contain blastemal cells with varying degrees of differentiation (Rivera and Haber 2005).Lin28 is an RNA-binding protein that regulates gene expression via two different mechanisms: one that blocks the processing of the Let-7 family of microRNAs (miRNAs) (Heo et al. 2008;Newman et al. 2008;Rybak et al. 2008;Viswanathan et al. 2008)

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“…This requires large sample sizes not readily achievable for rare diseases. Yet, despite the a priori presumption that the GWAS design could not be successfully applied to childhood cancers investigations of ALL(58-64), neuroblastoma(65-74), Wilm's tumor(75), osteosarcoma(76), and Ewing's sarcoma (77), each have identified multiple variants associated with each disease (Table 2). The unexpected success of GWAS to studies of these rare cancers appears to be due to the larger magnitude of SNV-disease association among young onset cancers compared to those with adult onset, which was recently formally quantified (Figure 4) (78).…”

Section: Introductionmentioning

confidence: 99%

Genetic and Nongenetic Risk Factors for Childhood Cancer

Spector

Pankratz

Marcotte

2015

Pediatric Clinics of North America

162

169

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Summary The causes of childhood cancer have been systematically studied for several decades, but apart from high-dose radiation and prior chemotherapy there are few or no strong external risk factors. On the other hand, inherent risk factors including birth weight, parental age, and congenital anomalies are consistently associated with most types of pediatric cancer. Rare, highly-penetrant syndromes have long been known to cause a small proportion of cancers but recently the contribution of common genetic variation to etiology has come into focus through genome wide association studies. These have highlighted genes not previously implicated in childhood cancers and, surprisingly, have suggested that common variation explains a larger proportion of childhood cancers than adult. Rare variation and non-Mendelian inheritance, such as through maternal genetic effects or de novo germline mutations, may also contribute to childhood cancer risk but have not been widely examined to date.

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A genome-wide association study identifies susceptibility loci for Wilms tumor

Cited by 72 publications

References 14 publications

Multiple mechanisms of MYCN dysregulation in Wilms tumour

Multiple mechanisms of MYCN dysregulation in Wilms tumour

Lin28 sustains early renal progenitors and induces Wilms tumor

Genetic and Nongenetic Risk Factors for Childhood Cancer

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