Somatic Hypomethylation of Pericentromeric SST1 Repeats and Tetraploidization in Human Colorectal Cancer Cells
Somatic DNA hypomethylation and aneuploidy are hallmarks of cancer, and there is evidence for a causal relationship between them in knockout mice but not in human cancer. The non-mobile pericentromeric repetitive elements SST1 are hypomethylated in about 17% of human colorectal cancers (CRC) with so...
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| Auteurs principaux: | , , , , , , |
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| Format: | article |
| Langue: | EN |
| Publié: |
MDPI AG
2021
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| Accès en ligne: | https://doaj.org/article/1273cbe6e959447fbfd2d9c82c722e6c |
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| Résumé: | Somatic DNA hypomethylation and aneuploidy are hallmarks of cancer, and there is evidence for a causal relationship between them in knockout mice but not in human cancer. The non-mobile pericentromeric repetitive elements SST1 are hypomethylated in about 17% of human colorectal cancers (CRC) with some 5–7% exhibiting strong age-independent demethylation. We studied the frequency of genome doubling, a common event in solid tumors linked to aneuploidy, in randomly selected single cell clones of near-diploid LS174T human CRC cells differing in their level of SST1 demethylation. Near-diploid LS174T cells underwent frequent genome-doubling events generating near-tetraploid clones with lower levels of SST1 methylation. In primary CRC, strong SST1 hypomethylation was significantly associated with global genomic hypomethylation and mutations in <i>TP53</i>. This work uncovers the association of the naturally occurring demethylation of the SST1 pericentromeric repeat with the onset of spontaneous tetraploidization in human CRC cells in culture and with <i>TP53</i> mutations in primary CRCs. Altogether, our findings provide further support for an oncogenic pathway linking somatic hypomethylation and genetic copy number alterations in a subset of human CRC. |
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