Genomic Profiling Maps Loss of Heterozygosity and Defines the Timing and Stage Dependence of Epigenetic and Genetic Events in Wilms' Tumors

Yuan, Eric; Li, Chi Ming; Yamashiro, Darrell J.; Kandel, Jessica J.; Thaker, Harshwardhan M.; Murty, Vundavalli V.; Tycko, Benjamin

doi:10.1158/1541-7786.mcr-05-0082

Cited by 63 publications

(74 citation statements)

References 43 publications

(53 reference statements)

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“…Interestingly, most cases of 11p LOH in WT involve both the 11p13 and 11p15 regions (19), and although it was originally shown that the WT1 gene at 11p13 was not imprinted in kidney (20), we have subsequently shown that paternally expressed imprinted transcripts are transcribed from the WT1 locus. These imprinted transcripts are the noncoding antisense RNA WT1-AS (21) and the alternate coding transcript AWT1, which gives rise to NH 2 -terminally truncated WT1 proteins (22).…”

Section: Introductionmentioning

confidence: 75%

Frequency and Timing of Loss of Imprinting at 11p13 and 11p15 in Wilms' Tumor Development

Brown

Power

Moore

et al. 2008

Molecular Cancer Research

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Epigenetic changes occur frequently in Wilms' tumor (WT), especially loss of imprinting (LOI) of IGF2/H19 at 11p15. Our previous results have identified imprinted transcripts (WT1-AS and AWT1) from the WT1 locus at 11p13 and showed LOI of these in some WTs. In this article, we set out to test the relationship between LOI at 11p13 and 11p15 and their timing in WT progression relative to other genetic changes. We found a higher level (83%) of 11p13 LOI in WT than of 11p15 LOI (71%). There was no correlation between methylation levels at the 11p13 and 11p15 differentially methylated regions or between allelic expression of WT1-AS/AWT1 and IGF2. Interestingly, retention of normal imprinting at 11p13 was associated with a small group of relatively late-onset, high-stage WTs. An examination of genetic and epigenetic alterations in nephrogenic rests, which are premalignant WT precursors, showed that LOI at both 11p13 and 11p15 occurred before either 16q loss of heterozygosity (LOH) or 7p LOH. This suggests that these LOH events are very unlikely to be a cause of LOI but that LOH may act by potentiating the effects of overexpression of IGF2 and/or WT1-AS/AWT1 that

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Section: Introductionmentioning

confidence: 75%

Frequency and Timing of Loss of Imprinting at 11p13 and 11p15 in Wilms' Tumor Development

Brown

Power

Moore

et al. 2008

Molecular Cancer Research

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“…Both methods detected similar incidence of IGF2 LOI. Yuan et al (28) used IGF2 LOI with methylation analysis of H19 DMR and SNP arrays. In contrast, Fukuzawa et al used a methylation analysis of two imprinted regions of 11p15.5, H19 DMR and KvDMR1, to detect it.…”

Section: Discussionmentioning

confidence: 99%

“…The ranges of each abnormality in Caucasians indicate the lowest and highest values reported in the previous studies. (5,7,8,18,28) …”

Section: Discussionmentioning

confidence: 99%

Different incidences of epigenetic but not genetic abnormalities between Wilms tumors in Japanese and Caucasian children

et al. 2012

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Epidemiological studies show that the incidence of Wilms tumor (WT) in East-Asian children is half of that in Caucasian children. Abnormalities of WT1, CTNNB1, WTX, and IGF2 were reported to be involved in Wilms tumorigenesis in Caucasians, although none of the studies simultaneously evaluated the four genes. WTX forms the b-catenin degradation complex; however, the relationship between WTX abnormality and CTNNB1 mutation was uncertain in WTs. We examined abnormalities of the four genes in 114 Japanese with WTs to clarify the relationship between genetic and epigenetic factors and the incidence of WTs. We found that abnormalities of WTX and CTNNB1 were mutually exclusive, and that although CTNNB1 mutation was frequent in WTs with WT1 abnormality, but rare in WTs without, the incidences of WTX abnormality were similar between WTs with or without WT1 abnormality. These findings were consistent with those reported in Caucasian populations, and indicate multiple roles of WTX abnormality. Abnormalities of WT1, WTX and CTNNB1, and loss of IGF2 imprinting (LOI) were detected in 31.6%, 22.8%, 26.3%, and 21.1% of the 114 WTs, respectively. When we selected 101 sporadic WTs, the incidences of WT1, CTNNB1, or WTX abnormality were generally comparable between the two populations, whereas the incidence of IGF2 LOI was lower in Japanese than that of IGF2 LOI reported in Caucasians (P = 0.04). This is the first comprehensive study of the four genes, and the results supported the hypothesis that the lower incidence of IGF2 LOI contributes to the lower incidence of WTs in Japanese children. (Cancer Sci 2012; 103: 1129-1135 T he rates of various types of adult cancers, including prostate, lung, breast, liver and gastric cancers, differ among ethnic populations, which are thought to be caused by different environmental factors. (1) In contrast, most pediatric tumors such as neuroblastomas and retinoblastomas show similar rates among ethnic populations. An exception is Wilms tumor (WT), a common pediatric tumor of the kidney, which is known to have different incidence rates between East-Asian and Caucasian populations. (2) Wilms tumor accounts for 8% of childhood cancers and occurs in 1 in 10 000 Caucasian children, though its incidence in East-Asian populations is half of that. (2) In Hawaii and Britain, the incidence of WT in people of Asian descent is about half to two-thirds of that in Caucasians, (3,4) suggesting that environmental factors play little part in the lower incidence.IGF2 is an imprinting gene expressed from the paternally inherited allele, and encodes a fetal polypeptide growth factor. Loss of imprinting (LOI) of IGF2 has been reported in various tumors, including pediatric tumors. There have been conflicting reports on the rates of IGF2 LOI in Japanese with WTs; one study reported IGF2 LOI in none of 21 tumors, whereas we previously reported it in seven of 27 tumors. (5,6) These results prompted us to analyze the IGF2 imprinting status in a substantial number of Japanese children with WTs.Various abnormalities of...

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“…Several additional studies of RCC have also indicated that the loss of 4q is associated with sarcomatoid transformation and high-grade tumors (Jiang et al, 1998;Yoshimoto et al, 2007). In Wilms' tumors, a 2.4-Mb minimal region of loss of heterozygosity has been detected at 4q24-q25 by 10K SNP array, which is a CXXC4 and progression of RCC T Kojima et al region that includes the CXXC4 gene (Yuan et al, 2005). Interestingly, loss of 4q has been detected in 46-77% of colon, cervix and hepatocellular carcinomas (Mitra et al, 1994;Ried et al, 1996;Yeh et al, 1996) suggesting that aberrant Wnt signaling may be implicated in the formation of several cancer types.…”

Section: Discussionmentioning

confidence: 99%

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

et al. 2008

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The Wnt signaling pathway is involved in normal embryonic development and controls the homeostatic self-renewal of stem cells in adult tissues. Constitutive activation of Wnt signaling contributes to cancer development and progression. We identified a CXXC4 homozygous deletion at 4q24 in an aggressive renal cell carcinoma (RCC) using single-nucleotide polymorphism (SNP) arrays. CXXC4 encodes Idax, which negatively regulates Wnt signaling by binding to the PDZ domain of Dishevelled. CXXC4 mRNA levels in tumor samples were significantly lower in patients with metastases compared with those without (P ¼ 0.0016). Patients whose tumors had lower CXXC4 expression than normal kidney showed a poorer cause-specific survival outcome than those with higher expression (P ¼ 0.0095). Decreased expression of CXXC4 also correlated with cytoplasmic staining of b-catenin. Knockdown of CXXC4 induced the nuclear translocation of b-catenin and altered expression of a set of genes involved in cell proliferation, invasion and survival. Furthermore, reduced expression of CXXC4 by small interfering RNAs promoted cell proliferation and inhibited apoptosis after 5-FU and doxorubicin treatment in RCC cells. These data suggest that CXXC4 plays a critical role in tumor progression of RCC through Wnt signaling. Wnt signaling could thus be a potential molecular target in RCC indicating decreased CXXC4 expression.

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Genomic Profiling Maps Loss of Heterozygosity and Defines the Timing and Stage Dependence of Epigenetic and Genetic Events in Wilms' Tumors

Cited by 63 publications

References 43 publications

Frequency and Timing of Loss of Imprinting at 11p13 and 11p15 in Wilms' Tumor Development

Frequency and Timing of Loss of Imprinting at 11p13 and 11p15 in Wilms' Tumor Development

Different incidences of epigenetic but not genetic abnormalities between Wilms tumors in Japanese and Caucasian children

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

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