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

Abstract

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...

Genetic variation frequencies in Wilms' tumor: A meta‐analysis and systematic review

“…We used the descriptions "Caucasian" and "non-Caucasian" to explore the ethnicity influence. Random-effect meta-regression analyses were (20,21,28,30,42,51,52) 0.071 (0.041, 0.100) 4.710 0.000 68.5 0.004 1.000 0.092 Random DROSHA (27)(28)(29)(30) 0.082 (0.048, 0.116) 4.770 0.000 76.1 0.006 0.296 0.019 Random WT1 (13,15,27,30,31,38,42,46,(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65) 0.141 (0.104, 0.178) 7.480 0.000 77.9 0.000 0.007 0.001 Random WTX (13)(14)(15)27,31,38,42,46,(53)(54)(55)(56)(57)66) 0.147 (0.110, 0.184) 7.750 0.000 72.6 0.000 0.228 0.347 Random CTNNB1 (13,15,27,…”

Clinical, pathological and loss of heterozygosity differences in Wilms tumors between Asian and non‐Asian children

“…compared to Caucasians, Japanese children have been found to have a similar incidence of TP53, WT1, CTNNB1 and WTX abnormalities, as well as hyperdiploidy and nonrandom trisomies including 11p13 and 11p15 abnormalities, but IGF2 LOI is significantly lower. 5,6,19,22 Conversely, Wilms tumors from Kenyan patients have more frequent mutations of TP53 and LOH 16p-a locus rich in TP53 target genes 23,24 -but a similar incidence of 1q and 12p gain, as compared to Western cohorts. 24 With our adapted assay we determined the LOH profile in our multiracial cohort and found the incidence among our Asian patients to be similar to reported rates.…”

“…[1][2][3][4] Also, differences in the incidence of histological features of high risk disease such as nephrogenic rests and anaplasia, and molecular risk factors such as loss of imprinting (LOI) of the IGF2 locus, have been similarly reported. 2,5,6 This paucity of evidence to date stems from the lack of robust population data, and the lack of resources to study and profile pathological and molecular features of these tumors in many Asian countries. In addition, a key limiting factor in many resource-limited centers in Asia is the lack of frozen tumor specimens for such molecular tests.…”

Wilms Tumor

“…Under normal conditions, IGF2 is imprinted such that it is paternally expressed while only maternally inherited allele of H19 is expressed. 35,36 In addition to WT1 and WT2 genes, a range of additional genes have been implicated in the pathogenesis and biology of WT. In some cases, LOI may be associated with loss of the maternal allele with replacement by duplicated paternal allele (uniparental paternal duplication).…”