title: DNA secondary structures and epigenetic determinants of cancer genome evolution.
abstract: An unstable genome is a hallmark of many cancers. It is unclear, however, whether some mutagenic features driving somatic alterations in cancer are encoded in the genome sequence and whether they can operate in a tissue-specific manner. We performed a genome-wide analysis of 663,446 DNA breakpoints associated with somatic copy-number alterations (SCNAs) from 2,792 cancer samples classified into 26 cancer types. Many SCNA breakpoints are spatially clustered in cancer genomes. We observed a significant enrichment for G-quadruplex sequences (G4s) in the vicinity of SCNA breakpoints and established that SCNAs show a strand bias consistent with G4-mediated structural alterations. Notably, abnormal hypomethylation near G4s-rich regions is a common signature for many SCNA breakpoint hotspots. We propose a mechanistic hypothesis that abnormal hypomethylation in genomic regions enriched for G4s acts as a mutagenic factor driving tissue-specific mutational landscapes in cancer.
authors: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Subhajyoti
authors: S
authors: De
authors: Franziska
authors: F
authors: Michor
mesh_terms: D053960:DNA Breaks; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000737:chemistry*; D044127:Epigenesis, Genetic; D042822:Genomic Instability; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000235:genetics*; D009690:Nucleic Acid Conformation
chemical_list: D004273:DNA, Neoplasm