For years, many colleagues have suggested there are likely to be not only GENETIC FACTORS in the etiology of cancer, but also EPIGENETIC FACTORS. “Genetics” implies DNA sequence alterations. “Epigenetics” (chromosomal effects other than DNA sequence changes) is generally accepted to include: DNA methylations, RNA-interference (RNAi), histone modifications, and chromatin remodeling. DNA-methylation assays and, to some extent, RNAi assays, are now available as commercial kits––not that different from the procedures of whole-genome sequencing (WGS) and whole exon-sequencing (WES) being used to screen individuals or large cohorts for GENETIC differences in risk of cancer or other clinical disorders.
The [below publication is an example of epigenetic effects (histone modifications) influencing individual risk of developing sarcoma (cancers of connective tissue, derived from the mesoderm). Several types of pediatric cancers reportedly contain high-frequency missense mutations in leading to alterations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized.
Authors report herein that the H3 lysine 36–to–methionine (H3K36M) change impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in human chondroblast (cartilage) cells. H3K36M mutant nucleosomes inhibited the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, was sufficient to phenocopy the H3K36M mutation. Following loss of H3K36 methylation, a genome-wide gain in H3K27 methylation leads to a redistribution of polycomb repressive complex 1 and de-repression of its target genes known to block mesenchymal differentiation. These findings were found to be similar to those seen in human undifferentiated sarcomas in which novel K36M/I mutations in H3.1 have been identified.
Science 13 May 2o16; 352: 844 – 849