Stratification of Wilms tumor by genetic and epigenetic analysis

Abstract

Somatic defects at five loci, WT1, CTNNB1, WTX, TP53 and the imprinted 11p15 region, are implicated in Wilms tumor, the commonest childhood kidney cancer. In this study we analysed all five loci in 120 Wilms tumors. We identified epigenetic 11p15 abnormalities in 69% of tumors, 37% were H19 epimutations and 32% were paternal uniparental disomy (pUPD). We identified mutations of WTX in 32%, CTNNB1 in 15%, WT1 in 12% and TP53 in 5% of tumors. We identified several significant associations: between 11p15 and WTX (P=0.007), between WT1 and CTNNB1 (P<0.001), between WT1 and pUPD 11p15 (P=0.01), and a strong negative association between WT1 and H19 epimutation (P<0.001). We next used these data to stratify Wilms tumor into three molecular Groups, based on the status at 11p15 and WT1. Group 1 tumors (63%) were defined as 11p15-mutant and WT1-normal; a third also had WTX mutations. Group 2 tumors (13%) were WT1-mutant. They either had 11p15 pUPD or were 11p15-normal. Almost all had CTNNB1 mutations but none had H19 epimutation. Group 3 tumors (25%) were defined as 11p15-normal and WT1-normal and were typically normal at all five loci (P<0.001). We also identified a novel clinical association between H19 epimutation and bilateral disease (P<0.001). These data provide new insights into the pattern, order, interactions and clinical associations of molecular events in Wilms tumor.

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

“…CTNNB1 alterations in sinonasal HPC have been consistently reported in exon 3, with missense mutations [4,5]; mutations affecting positions 32-45 of the amino-terminal region disrupt phosphorylation-dependent degradation of b-catenin [6]. Numerous other tumor types harbor CTNNB1 mutations, most frequently desmoid-type fibromatosis [7,8] as well as salivary basal cell adenoma [9], pilomatricoma and pilomatrix carcinoma [10], hepatocellular carcinoma [11], colorectal carcinoma [12], medulloblastoma [13], endometrial adenocarcinoma [14], Wilms tumor [15], and adrenocortical carcinoma [16]. Sinonasal HPC shares the features of a uniform spindle and ovoid cell population and HPC-like vessels with SFT, Fig.…”

Methylome analysis identifies a Wilms tumor epigenetic biomarker detectable in blood

“…In WT, the few genes that are recurrently mutated show low mutation frequencies -WTX (18%) [7], CTNNB1 (15%) [8] and WT1 (12%) [8] -and do not account for the majority of WTs. However, epimutation affecting the IGF2/ H19 locus at 11p15.5 is much more common (69%) [8].…”

“…In WT, the few genes that are recurrently mutated show low mutation frequencies -WTX (18%) [7], CTNNB1 (15%) [8] and WT1 (12%) [8] -and do not account for the majority of WTs. However, epimutation affecting the IGF2/ H19 locus at 11p15.5 is much more common (69%) [8]. Additional genes and regions known to be affected by methylation in WT include GLIPR1 [9], imprinted genes NNAT [10] and the WT1-antisense region [11], various satellite regions [12,13], HACE1 [14], RASSF1A [15], P16 and the protocadherin cluster at 5q31 [16].…”

Caveolin-1 Expression is Associated with Tumor Size and Therapy Response in Wilms Tumor

“…5 At the current time, high cure rates can be achieved and multimodality treatment has resulted in a significant improvement in outcome. [5][6][7] Hitherto, many parameters were suggested as relevant markers for assessing the proliferative activity and tumor cell dynamics of the WT. [6][7][8][9] But the presence of Cav-1 expression in WT has not been investigated widely.…”

“…[5][6][7] Hitherto, many parameters were suggested as relevant markers for assessing the proliferative activity and tumor cell dynamics of the WT. [6][7][8][9] But the presence of Cav-1 expression in WT has not been investigated widely. The aim of this study was both to explore the importance of Cav-1 expression in Wilms tumor and also investigate the relationships between them, and some clinical prognostic factors such as tumor size, stage and histological features.…”