In the United States in 2018, an estimated 10,590 new cases of cancer will be diagnosed among children from birth to 14 years, and about 1,180 children are expected to die from the disease. Although cancer death rates for this age group have declined by 57 percent over the past four decades, cancer remains the leading cause of death from disease among children. The most common types of cancer diagnosed in children ages 0 to 14 years are
leukemias,
brain and other
central nervous system (CNS) tumors, and
lymphomas.
Although pediatric cancer is rare, it’s the leading cause of disease-related death among children who survive past infancy (in the Western world). Around 1 in 500 children will be diagnosed with cancer by age 15. Like most rare diseases, childhood cancer is difficult to study because so few patients are available. Even for the most common types — leukemia, brain/CNS tumors, and lymphomas — only a few hundred cases have been sequenced over the past decade. But we’re making progress.
DNA methylation in pediatric cancers
DNA methylation mechanism
Cytosine methylation is carried out by a family of DNA methyltransferases, including DNMT1, DNMT3A, and DNMT3B (Okano et al. 1998). DNMT1 is considered as the maintenance DNA methyltransferase that can bind hemimethylated DNA during cell division, result- ing in the inheritance of the methylated cytosine state in the daughter strand. DNMT3A and DNMT3B function as de novo DNA methyltransferases, which can methyl- ate the unmethylated cytosines during embryogenesis (Fig. 4A; Stein et al. 1982; Okano et al. 1998; Jones and Liang 2009).
DNA methylation was long considered to be an irre-versible epigenetic modification that could be removed only by the passive mechanism of cell division. This view was reversed by the discovery of the TET (ten-elev- en translocation) family of dioxygenases that use oxygen, Fe(II), and a-ketoglutarate as substrates in a sequential enzymatic reaction to convert 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and subsequently into 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) (Iyer et al. 2009; Tahiliani et al. 2009). In the active demethylation pathway,5mC is successively oxidized by members of theTET family to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5- carboxylcytosine (5caC).
From: Epigenetic changes in pediatric solid tumors: promising new targets
More recent studies have identified DNA demethylases (TET1,2) which hydroxylate 5-Methylcytosine(5mC) in CpG dinucleotides to 5- Hydroxymethylcytosine(5-hC). Evidence proposes that TET enzymes are capable of iterative oxidation on substrates to 5-formylmethylcytosine (5-fC) or 5- carboxymethylcytosine(5-caC) (23, 24). This leads to substrates upon which base excision repair mechanisms mediated by thymine-DNA glycosylase (TDG) excise a modified C and replace with an unmodified C, allowing for rapid re-activation (gene ON) of previously silenced genes (24).