Age-Related DNA Methylation in Normal Kidney Tissue Identifies Epigenetic Cancer Risk Susceptibility Loci in the ANKRD34B and ZIC1 Genes
Both age-dependent and age-independent alteration of DNA methylation in human tissues are functionally associated with the development of many malignant and non-malignant human diseases. TCGA-KIRC data were biometrically analyzed to identify new loci with age-dependent DNA methylation that may contr...
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MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/10/5327 |
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| author | Jürgen Serth Inga Peters Bastian Hill Tatjana Hübscher Jörg Hennenlotter Michael Klintschar Markus Antonius Kuczyk |
| author_facet | Jürgen Serth Inga Peters Bastian Hill Tatjana Hübscher Jörg Hennenlotter Michael Klintschar Markus Antonius Kuczyk |
| author_sort | Jürgen Serth |
| collection | DOAJ |
| description | Both age-dependent and age-independent alteration of DNA methylation in human tissues are functionally associated with the development of many malignant and non-malignant human diseases. TCGA-KIRC data were biometrically analyzed to identify new loci with age-dependent DNA methylation that may contribute to tumor risk in normal kidney tissue. <i>ANKRD34B</i> and <i>ZIC1</i> were evaluated as candidate genes by pyrosequencing of 539 tissues, including 239 normal autopsy, 157 histopathologically tumor-adjacent normal, and 143 paired tumor kidney samples. All candidate CpG loci demonstrated a strong correlation between relative methylation levels and age (R = 0.70–0.88, <i>p</i> < 2 × 10<sup>−16</sup>) and seven out of 10 loci were capable of predicting chronological age in normal kidney tissues, explaining 84% of the variance (R = 0.92). Moreover, significantly increased age-independent methylation was found for 9 out of 10 CpG loci in tumor-adjacent tissues, compared to normal autopsy tissues (<i>p</i> = 0.001–0.028). Comparing tumor and paired tumor-adjacent tissues revealed two patient clusters showing hypermethylation, one cluster without significant changes in methylation, and a smaller cluster demonstrating hypomethylation in the tumors (<i>p</i> < 1 × 10<sup>−10</sup>). Taken together, our results show the presence of additional methylation risk factors besides age for renal cancer in normal kidney tissue. Concurrent tumor-specific hypermethylation suggests a subset of these loci are candidates for epigenetic renal cancer susceptibility. |
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| language | English |
| last_indexed | 2024-03-10T03:45:37Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-aacf71071d314b08b40beef3d5b3543b2023-11-23T11:20:45ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-012310532710.3390/ijms23105327Age-Related DNA Methylation in Normal Kidney Tissue Identifies Epigenetic Cancer Risk Susceptibility Loci in the ANKRD34B and ZIC1 GenesJürgen Serth0Inga Peters1Bastian Hill2Tatjana Hübscher3Jörg Hennenlotter4Michael Klintschar5Markus Antonius Kuczyk6Department of Urology and Urologic Oncology, Hannover Medical School, 30625 Hannover, GermanyDepartment of Urology and Urologic Oncology, Hannover Medical School, 30625 Hannover, GermanyDepartment of Urology and Urologic Oncology, Hannover Medical School, 30625 Hannover, GermanyDepartment of Urology and Urologic Oncology, Hannover Medical School, 30625 Hannover, GermanyDepartment of Urology, Eberhard Karls University of Tuebingen, 72076 Tuebingen, GermanyDepartment of Legal Medicine, Hannover Medical School, 30625 Hannover, GermanyDepartment of Urology and Urologic Oncology, Hannover Medical School, 30625 Hannover, GermanyBoth age-dependent and age-independent alteration of DNA methylation in human tissues are functionally associated with the development of many malignant and non-malignant human diseases. TCGA-KIRC data were biometrically analyzed to identify new loci with age-dependent DNA methylation that may contribute to tumor risk in normal kidney tissue. <i>ANKRD34B</i> and <i>ZIC1</i> were evaluated as candidate genes by pyrosequencing of 539 tissues, including 239 normal autopsy, 157 histopathologically tumor-adjacent normal, and 143 paired tumor kidney samples. All candidate CpG loci demonstrated a strong correlation between relative methylation levels and age (R = 0.70–0.88, <i>p</i> < 2 × 10<sup>−16</sup>) and seven out of 10 loci were capable of predicting chronological age in normal kidney tissues, explaining 84% of the variance (R = 0.92). Moreover, significantly increased age-independent methylation was found for 9 out of 10 CpG loci in tumor-adjacent tissues, compared to normal autopsy tissues (<i>p</i> = 0.001–0.028). Comparing tumor and paired tumor-adjacent tissues revealed two patient clusters showing hypermethylation, one cluster without significant changes in methylation, and a smaller cluster demonstrating hypomethylation in the tumors (<i>p</i> < 1 × 10<sup>−10</sup>). Taken together, our results show the presence of additional methylation risk factors besides age for renal cancer in normal kidney tissue. Concurrent tumor-specific hypermethylation suggests a subset of these loci are candidates for epigenetic renal cancer susceptibility.https://www.mdpi.com/1422-0067/23/10/5327age-related methylationage-dependent methylationrenal cell cancerepigeneticcancer susceptibility locuscancer development |
| spellingShingle | Jürgen Serth Inga Peters Bastian Hill Tatjana Hübscher Jörg Hennenlotter Michael Klintschar Markus Antonius Kuczyk Age-Related DNA Methylation in Normal Kidney Tissue Identifies Epigenetic Cancer Risk Susceptibility Loci in the ANKRD34B and ZIC1 Genes International Journal of Molecular Sciences age-related methylation age-dependent methylation renal cell cancer epigenetic cancer susceptibility locus cancer development |
| title | Age-Related DNA Methylation in Normal Kidney Tissue Identifies Epigenetic Cancer Risk Susceptibility Loci in the ANKRD34B and ZIC1 Genes |
| title_full | Age-Related DNA Methylation in Normal Kidney Tissue Identifies Epigenetic Cancer Risk Susceptibility Loci in the ANKRD34B and ZIC1 Genes |
| title_fullStr | Age-Related DNA Methylation in Normal Kidney Tissue Identifies Epigenetic Cancer Risk Susceptibility Loci in the ANKRD34B and ZIC1 Genes |
| title_full_unstemmed | Age-Related DNA Methylation in Normal Kidney Tissue Identifies Epigenetic Cancer Risk Susceptibility Loci in the ANKRD34B and ZIC1 Genes |
| title_short | Age-Related DNA Methylation in Normal Kidney Tissue Identifies Epigenetic Cancer Risk Susceptibility Loci in the ANKRD34B and ZIC1 Genes |
| title_sort | age related dna methylation in normal kidney tissue identifies epigenetic cancer risk susceptibility loci in the ankrd34b and zic1 genes |
| topic | age-related methylation age-dependent methylation renal cell cancer epigenetic cancer susceptibility locus cancer development |
| url | https://www.mdpi.com/1422-0067/23/10/5327 |
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