d87288b136b9a6b83e7bba463c3a8155 pmc_33217932.pdf 3766142758449f735749f799b78edd2718df2e1f pmc_33217932.pdf 9c49a1f683b7bb9c2c6d4052d8f9b6adb70c4b81d759a7981fdbecd25de99060 pmc_33217932.pdf Title: Both Epimutations and Chromosome Aberrations Affect Multiple Imprinted Loci in Aggressive Wilms Tumors Subject: The embryonal renal cancer Wilms tumor (WT) accounts for 7% of all children’s malignancies. Its most frequent molecular defect is represented by DNA methylation abnormalities at the imprinted 11p15.5 region. Multiple imprinted methylation alterations dictated by chromosome copy-number variations have been recently demonstrated in adult cancers, raising the question of whether multiple imprinted loci were also affected in WT. To address this issue, we analyzed DNA methylation and chromosome profiles of 7 imprinted loci in 48 WT samples. The results demonstrated that methylation abnormalities of multiple imprinted loci occurred in 35% of the cases, but that they were associated with either chromosome aberrations or normal chromosome profiles. Multiple imprinted methylation changes were correlated with tumor stage and presence of metastasis, indicating that these epimutations were more frequent in highly aggressive tumors. When chromosome profiles were affected, these alterations were extended to flanking cancer driver genes. Overall, this study demonstrates the presence of multiple imprinted methylation defects in aggressive WTs and suggests that the mechanism by which they arise in embryonal and adult cancers is different. Keywords: nephroblastoma; genomic imprinting; DNA methylation; chromosome aberrations Author: Laura Pignata, Orazio Palumbo, Flavia Cerrato, Basilia Acurzio, Enrique de Álava, Josep Roma, Soledad Gallego, Jaume Mora, Massimo Carella, Andrea Riccio and Gaetano Verde Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Wed Nov 18 09:45:11 2020 CET ModDate: Thu Nov 19 12:36:36 2020 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 13 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2346179 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- VJWYXJ+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 MFWPRN+VnURWPalladioL Type 1 Custom yes yes no 15 0 QVQSTY+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 NCDIBZ+URWPalladioL-Bold Type 1 Custom yes yes no 24 0 LZDGTK+Rpxb Type 1 Builtin yes yes no 28 0 UEDDDG+URWPalladioL-Roma Type 1 Custom yes yes no 32 0 ASICFG+Rpxr Type 1 Builtin yes yes no 36 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 45 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 67 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 71 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 75 0 JNLIIF+Rpxi Type 1 Builtin yes yes no 82 0 PHINAC+PalatinoLinotype TrueType WinAnsi yes yes no 99 0 DNVXPV+Pxsy Type 1 Builtin yes yes no 107 0 PHINAC+PalatinoLinotype TrueType WinAnsi yes yes no 118 0 PHIOKK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 121 0 PHINAC+PalatinoLinotype TrueType WinAnsi yes yes no 136 0 PHIOKK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 139 0 CJAABN+Calibri CID TrueType Identity-H yes yes yes 154 0 CJAABO+Calibri,Bold CID TrueType Identity-H yes yes yes 160 0 CIPMPI+PalatinoLinotype TrueType WinAnsi yes yes no 166 0 CIPNCJ+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 169 0 CIPNCL+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 172 0 CIPODH+TimesNewRoman CID TrueType Identity-H yes yes yes 175 0 PHINAC+PalatinoLinotype TrueType WinAnsi yes yes no 191 0 PHIOKK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 194 0 OVNEXW+EURM10 Type 1 Builtin yes yes no 206 0 VSHNAE+Rpcxr Type 1 Builtin yes yes no 220 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2022-07-07 02:26:49 CEST RepresentationInformation: pmc_33217932.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2020-12-14 03:47:13 CET Size: 2346179 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 371 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4923ab24 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Children: Item: Title: DNA Methylation Defects Affect Multiple Imprinted Loci in WTs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: Epimutations at Multiple Imprinted Loci are Associated with Tumor Aggressiveness in WT Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: The Epimutations at Imprinted Loci are Associated with Different Chromosome Profiles Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Chromosome Alterations at Imprinted Loci Include Flanking Cancer Driver Genes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Children: Item: Title: Patients Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: DNA Methylation Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Chromosome Microarray Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Info: Title: Both Epimutations and Chromosome Aberrations Affect Multiple Imprinted Loci in Aggressive Wilms Tumors Author: Laura Pignata, Orazio Palumbo, Flavia Cerrato, Basilia Acurzio, Enrique de Álava, Josep Roma, Soledad Gallego, Jaume Mora, Massimo Carella, Andrea Riccio and Gaetano Verde Subject: The embryonal renal cancer Wilms tumor (WT) accounts for 7% of all children’s malignancies. Its most frequent molecular defect is represented by DNA methylation abnormalities at the imprinted 11p15.5 region. Multiple imprinted methylation alterations dictated by chromosome copy-number variations have been recently demonstrated in adult cancers, raising the question of whether multiple imprinted loci were also affected in WT. To address this issue, we analyzed DNA methylation and chromosome profiles of 7 imprinted loci in 48 WT samples. The results demonstrated that methylation abnormalities of multiple imprinted loci occurred in 35% of the cases, but that they were associated with either chromosome aberrations or normal chromosome profiles. Multiple imprinted methylation changes were correlated with tumor stage and presence of metastasis, indicating that these epimutations were more frequent in highly aggressive tumors. When chromosome profiles were affected, these alterations were extended to flanking cancer driver genes. Overall, this study demonstrates the presence of multiple imprinted methylation defects in aggressive WTs and suggests that the mechanism by which they arise in embryonal and adult cancers is different. 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