Repetitive DNA sequences comprise about 45% of the mammalian genome. Long Interspersed Elements (LINE-1), a class of non-Long Terminal Repeat (LTR) retrotransposons, are amplified to more than 500,000 copies in both truncated (~0.9 kb) form or active full-length elements (~6 kb)1. A full-length LIN E-1 contains a 5′ untranslated region (UTR}, two non-overlapping open reading frames (ORF1 and ORF2}, and a 3′ UTR that ends in a poly (A) tail2. The heavily methylated LINE-1 elements are among the host cell defense mechanisms to inhibit L 1-ribonucleoprotein (L 1 RNP) formation and prevent its mobilization throughout the human genome.
Hypomethylation of LINE-1 leads to genetic instability by LINE-1 transposition across the genome and disruption of gene expression3. Such increases in chromosomal instability contribute to cancer development and progression. Given that LINE-1 constitutes approximately 17% of the human genome, the extent of LINE-1 methylation is regarded as a surrogate marker of global DNA methylation. Therefore, LINE-1 methylation levels are an excellent pharmacodynamics (PD) marker for hypomethylating agent therapy.