11p15 Epimutations in Pediatric Embryonic Tumors: Insights from a Methylome Analysis
Embryonic tumors share few recurrent mutations, suggesting that other mechanisms, such as aberrant DNA methylation, play a prominent role in their development. The loss of imprinting (LOI) at the chromosome region 11p15 is the germline alteration behind Beckwith–Wiedemann syndrome that results in an...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/17/4256 |
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| author | Felipe Luz Torres Silva Juliana Silveira Ruas Mayara Ferreira Euzébio Iva Loureiro Hoffmann Thais Junqueira Helder Tedeschi Luiz Henrique Pereira Alejandro Enzo Cassone Izilda Aparecida Cardinalli Ana Luiza Seidinger Patricia Yoshioka Jotta Mariana Maschietto |
| author_facet | Felipe Luz Torres Silva Juliana Silveira Ruas Mayara Ferreira Euzébio Iva Loureiro Hoffmann Thais Junqueira Helder Tedeschi Luiz Henrique Pereira Alejandro Enzo Cassone Izilda Aparecida Cardinalli Ana Luiza Seidinger Patricia Yoshioka Jotta Mariana Maschietto |
| author_sort | Felipe Luz Torres Silva |
| collection | DOAJ |
| description | Embryonic tumors share few recurrent mutations, suggesting that other mechanisms, such as aberrant DNA methylation, play a prominent role in their development. The loss of imprinting (LOI) at the chromosome region 11p15 is the germline alteration behind Beckwith–Wiedemann syndrome that results in an increased risk of developing several embryonic tumors. This study analyzed the methylome, using EPIC Beadchip arrays from 99 sporadic embryonic tumors. Among these tumors, 46.5% and 14.6% presented alterations at imprinted control regions (ICRs) 1 and 2, respectively. Based on the methylation levels of ICR1 and ICR2, four clusters formed with distinct methylation patterns, mostly for medulloblastomas (ICR1 loss of methylation (LOM)), Wilms tumors, and hepatoblastomas (ICR1 gain of methylation (GOM), with or without ICR2 LOM). To validate the results, the methylation status of 29 cases was assessed with MS-MLPA, and a high level of agreement was found between both methodologies: 93% for ICR1 and 79% for ICR2. The MS-MLPA results indicate that 15 (51.7%) had ICR1 GOM and 11 (37.9%) had ICR2 LOM. To further validate our findings, the ICR1 methylation status was characterized via digital PCR (dPCR) in cell-free DNA (cfDNA) extracted from peripheral blood. At diagnosis, we detected alterations in the methylation levels of ICR1 in 62% of the cases, with an agreement of 76% between the tumor tissue (MS-MLPA) and cfDNA methods. Among the disagreements, the dPCR was able to detect ICR1 methylation level changes presented at heterogeneous levels in the tumor tissue, which were detected only in the methylome analysis. This study highlights the prevalence of 11p15 methylation status in sporadic embryonic tumors, with differences relating to methylation levels (gain or loss), location (ICR1 or ICR2), and tumor types (medulloblastomas, Wilms tumors, and hepatoblastomas). |
| first_indexed | 2024-03-10T23:26:52Z |
| format | Article |
| id | doaj.art-8b46904769ce415997fa8fed54fbab3c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T23:26:52Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-8b46904769ce415997fa8fed54fbab3c2023-11-19T07:55:18ZengMDPI AGCancers2072-66942023-08-011517425610.3390/cancers1517425611p15 Epimutations in Pediatric Embryonic Tumors: Insights from a Methylome AnalysisFelipe Luz Torres Silva0Juliana Silveira Ruas1Mayara Ferreira Euzébio2Iva Loureiro Hoffmann3Thais Junqueira4Helder Tedeschi5Luiz Henrique Pereira6Alejandro Enzo Cassone7Izilda Aparecida Cardinalli8Ana Luiza Seidinger9Patricia Yoshioka Jotta10Mariana Maschietto11Research Center, Boldrini Children’s Hospital, Campinas 13083-884, SP, BrazilResearch Center, Boldrini Children’s Hospital, Campinas 13083-884, SP, BrazilResearch Center, Boldrini Children’s Hospital, Campinas 13083-884, SP, BrazilBoldrini Children’s Hospital, Campinas 13083-210, SP, BrazilBoldrini Children’s Hospital, Campinas 13083-210, SP, BrazilBoldrini Children’s Hospital, Campinas 13083-210, SP, BrazilBoldrini Children’s Hospital, Campinas 13083-210, SP, BrazilBoldrini Children’s Hospital, Campinas 13083-210, SP, BrazilBoldrini Children’s Hospital, Campinas 13083-210, SP, BrazilResearch Center, Boldrini Children’s Hospital, Campinas 13083-884, SP, BrazilResearch Center, Boldrini Children’s Hospital, Campinas 13083-884, SP, BrazilResearch Center, Boldrini Children’s Hospital, Campinas 13083-884, SP, BrazilEmbryonic tumors share few recurrent mutations, suggesting that other mechanisms, such as aberrant DNA methylation, play a prominent role in their development. The loss of imprinting (LOI) at the chromosome region 11p15 is the germline alteration behind Beckwith–Wiedemann syndrome that results in an increased risk of developing several embryonic tumors. This study analyzed the methylome, using EPIC Beadchip arrays from 99 sporadic embryonic tumors. Among these tumors, 46.5% and 14.6% presented alterations at imprinted control regions (ICRs) 1 and 2, respectively. Based on the methylation levels of ICR1 and ICR2, four clusters formed with distinct methylation patterns, mostly for medulloblastomas (ICR1 loss of methylation (LOM)), Wilms tumors, and hepatoblastomas (ICR1 gain of methylation (GOM), with or without ICR2 LOM). To validate the results, the methylation status of 29 cases was assessed with MS-MLPA, and a high level of agreement was found between both methodologies: 93% for ICR1 and 79% for ICR2. The MS-MLPA results indicate that 15 (51.7%) had ICR1 GOM and 11 (37.9%) had ICR2 LOM. To further validate our findings, the ICR1 methylation status was characterized via digital PCR (dPCR) in cell-free DNA (cfDNA) extracted from peripheral blood. At diagnosis, we detected alterations in the methylation levels of ICR1 in 62% of the cases, with an agreement of 76% between the tumor tissue (MS-MLPA) and cfDNA methods. Among the disagreements, the dPCR was able to detect ICR1 methylation level changes presented at heterogeneous levels in the tumor tissue, which were detected only in the methylome analysis. This study highlights the prevalence of 11p15 methylation status in sporadic embryonic tumors, with differences relating to methylation levels (gain or loss), location (ICR1 or ICR2), and tumor types (medulloblastomas, Wilms tumors, and hepatoblastomas).https://www.mdpi.com/2072-6694/15/17/425611p15ICR1ICR2DNA methylationembryonic tumorsmedulloblastoma |
| spellingShingle | Felipe Luz Torres Silva Juliana Silveira Ruas Mayara Ferreira Euzébio Iva Loureiro Hoffmann Thais Junqueira Helder Tedeschi Luiz Henrique Pereira Alejandro Enzo Cassone Izilda Aparecida Cardinalli Ana Luiza Seidinger Patricia Yoshioka Jotta Mariana Maschietto 11p15 Epimutations in Pediatric Embryonic Tumors: Insights from a Methylome Analysis Cancers 11p15 ICR1 ICR2 DNA methylation embryonic tumors medulloblastoma |
| title | 11p15 Epimutations in Pediatric Embryonic Tumors: Insights from a Methylome Analysis |
| title_full | 11p15 Epimutations in Pediatric Embryonic Tumors: Insights from a Methylome Analysis |
| title_fullStr | 11p15 Epimutations in Pediatric Embryonic Tumors: Insights from a Methylome Analysis |
| title_full_unstemmed | 11p15 Epimutations in Pediatric Embryonic Tumors: Insights from a Methylome Analysis |
| title_short | 11p15 Epimutations in Pediatric Embryonic Tumors: Insights from a Methylome Analysis |
| title_sort | 11p15 epimutations in pediatric embryonic tumors insights from a methylome analysis |
| topic | 11p15 ICR1 ICR2 DNA methylation embryonic tumors medulloblastoma |
| url | https://www.mdpi.com/2072-6694/15/17/4256 |
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