Association of 11q loss, trisomy 12, and possible 16q loss with loss of imprinting of insulin‐like growth factor–II in Wilms tumor

Watanabe, Naoki; Nakadate, Hisaya; Haruta, Masayuki; Sugawara, Waka; Sasaki, Fumio; Tsunematsu, Yukiko; Kikuta, Atsushi; Fukuzawa, Masahiro; Okita, Hajime; Hata, Jun Ichi; Soejima, Hidenobu; Kaneko, Yasuhiko

doi:10.1002/gcc.20321

Cited by 20 publications

(34 citation statements)

References 24 publications

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“…Interestingly, we found a very significantly average older age of diagnosis in WT patients with LOI, compared with both normally imprinted and LOH patients (Table 2), similar to previous reports (15,39). When we analyzed 11p15 LOI tumors with respect to their 11p13 LOI status, we found no significant difference in age of onset between WTs with and without 11p13 LOI.…”

Section: Loi At 11p15supporting

confidence: 90%

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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: Loi At 11p15supporting

confidence: 90%

“…Other studies have not consistently found an association between 11p15 LOI and 16q LOH (19,39,49), and in our results we saw an increased incidence of 16q LOH in 11p15 LOI WTs but this did not reach statistical significance (Table 2). Clearly, our comparison of the timing of LOH and LOI in WT progression (Fig.…”

Section: Loi In Wt Progressioncontrasting

confidence: 80%

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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“…(5,6) To detect IGF2 LOI, we used allelic expression analysis and/or a combination of COBRA of H19 DMR and SNP arrays. Both methods detected similar incidence of IGF2 LOI.…”

Section: Discussionmentioning

confidence: 99%

“…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 the WT1 gene have been found in 13.0-17.6% of sporadic WTs. (7,8) WT1 is predominantly expressed in the embryonic kidney, and has a pivotal role in its development.…”

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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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Duplication of the paternal IGF2 allele in trisomy 11 and elevated expression levels of IGF2 mRNA in congenital mesoblastic nephroma of the cellular or mixed type

Watanabe

Haruta

Soejima

et al. 2007

Genes Chromosomes & Cancer

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In a metaphase comparative genomic hybridization and fluorescence in situ hybridization study of 13 congenital mesoblastic nephroma (CMN) tumors, trisomy 11 was found in seven cellular or mixed type tumors, disomy 11 with other chromosome changes in two cellular type tumors, and no chromosome changes in four classical type tumors. Reverse-transcription (RT)-PCR analysis detected the ETV6-NTRK3 fusion transcript in all eight cellular or mixed type tumors examined, but not in four classical type tumors. All seven tumors with trisomy 11 showed duplication of the paternal IGF2 allele, and six cellular or classical type tumors with disomy 11 showed one paternal and one maternal allele of IGF2, analyzing the methylation status of the sixth CTCF site of the H19-differentially methylated region. Allelic expression study using the ApaI/AvaII polymorphism site at exon 9 of IGF2 showed retention of imprinting in all seven tumors examined. Quantitative real-time RT-PCR analysis showed higher expression levels of IGF2 mRNA in three of three cellular type tumors with trisomy 11, in one cellular type tumor with disomy 11, and in three of four classical tumors than in fetal kidneys or normal kidney tissues. Thus, duplicated paternal IGF2 resulted in elevated IGF2 mRNA levels, and may provide CMN or its precursor cells with a proliferative advantage. The mechanism explaining that some cellular or classical type tumors with disomy 11 also showed elevated IGF2 mRNA levels remains unresolved. IGF2 clearly plays an important role in the tumorigenic process of CMN, although it is difficult to assess its exact role.

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Association of 11q loss, trisomy 12, and possible 16q loss with loss of imprinting of insulin‐like growth factor–II in Wilms tumor

Cited by 20 publications

References 24 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

Duplication of the paternal IGF2 allele in trisomy 11 and elevated expression levels of IGF2 mRNA in congenital mesoblastic nephroma of the cellular or mixed type

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