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Simple Summary  Cancer cells frequently exhibit an abnormal number of chromosomes, termed aneuploidy, often preceded by an aberrant genome duplication resulting in cells with double the number of chromosomes (tetraploidy). The cause of the aberrant genome-doubling remains unknown. Loss of DNA methylation is also frequent in cancer cells and has been found to be associated with aneuploidy. The mechanisms linking these alterations remain unclear. In this report, we describe the association between loss of methylation in a family of pericentromeric DNA sequences and sporadic genome-doubling in colorectal cancer cells cultured in vitro. These sequences are also hypomethylated in primary colorectal tumors, associated with inactivating mutations on genes of the main pathway controlling proper genome duplication. Our data suggest that the demethylation of these sequences might be associated with genome-doubling as early events in a subset of colorectal cancers, providing novel clues on the link between genome demethylation and aneuploidy in cancer.    Abstract  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  TP53 . 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  TP53  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.

Somatic Hypomethylation of Pericentromeric SST1 Repeats and Tetraploidization in Human Colorectal Cancer Cells