Genetic and epigenetic alterations on the short arm of chromosome 11 are involved in a majority of sporadic Wilms' tumours

Abstract

Wilms' tumour is one of the most common solid tumours of childhood. 11p13 (WT1 locus) and 11p15.5 (WT2 locus) are known to have genetic or epigenetic aberrations in these tumours. In Wilms' tumours, mutation of the Wilms tumour 1 (WT1) gene at the WT1 locus has been reported, and the WT2 locus, comprising the two independent imprinted domains IGF2/H19 and KIP2/LIT1, can undergo maternal deletion or alterations associated with imprinting. Although these alterations have been identified in many studies, it is still not clear how frequently combined genetic and epigenetic alterations of these loci are involved in Wilms' tumours or how these alterations occur. To answer both questions, we performed genetic and epigenetic analyses of these loci, together with an additional gene, CTNNB1, in 35 sporadic Wilms' tumours. Loss of heterozygosity of 11p15.5 and loss of imprinting of IGF2 were the most frequent genetic (29%) and epigenetic (40%) alterations in Wilms' tumours, respectively. In total, 83% of the tumours had at least one alteration at 11p15.5 and/or 11p13. One-third of the tumours had alterations at multiple loci. Our results suggest that chromosome 11p is not only genetically but also epigenetically critical for the majority of Wilms' tumours.

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

“…WTs that retain normal imprinting at 11p13 form a small group of tumors, which seem to have a distinct phenotype of high stage and relatively late age of onset (Table 1), although, clearly, this result needs replicating in a larger series. Overall therefore, these results show that LOI at the WT1 locus, associated with hypomethylation of the ARR DMR, is a frequent event in WT, in contrast to the very infrequent hypermethylation of the WT1 sense promoter reported in WT (30,31). Our results, together with previous reports of methylation changes at or close to the WT1 ARR in human breast cancer (32), acute myeloid leukemia (33), ovarian clear cell adenocarcinoma (34), and rat mesothelioma and renal cell carcinoma (35), pinpoint the WT1 ARR as a target for epigenetic deregulation in a range of cancers.…”

“…S5). Others have also shown that the Kv DMR is not often hypomethylated in non-LOH WTs but is hypomethylated in heterozygous tumors (30,41). Thus, a possible explanation for the late-onset phenotype in 11p15 LOI WTs might be that they lack the alerted expression of imprinted genes in the IC2 domain such as CDKN1C that should occur in 11p15 LOH WTs.…”

Japanese and North American/European patients with Beckwith–Wiedemann syndrome have different frequencies of some epigenetic and genetic alterations

“…Combined bisulfite restriction analyses (COBRA) using the hot-stop method were employed as described previously. 3,4 For H19-DMR, bisulfite sequencing was performed using the same primers as used for COBRA. PCR primers and conditions are shown in Supplementary Table 1.…”

-thalassemia major evolution from -thalassemia minor is associated with paternal uniparental isodisomy of chromosome 11p15

“…Because the acquired chromosome 11p15.5 deletion is frequently observed in a variety of malignancies, 8 and acquired deletion of the HBB gene is also described by Badens and by Galanello et al, 9,10 we suspected that the patient may have a hemizygosity caused by acquired deletion of chromosome 11p15.5 harboring the HBB gene. However, FISH analysis showed that both chromosome 11s had positive hybridization signals with all three probes studied (β-LCR, HBG and HBB gene probes), indicating that the HBB gene cluster was probably intact ( Figure 1B).…”