Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan.
Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka, 812-8582, Japan.
Nat Commun. 2018 Apr 24;9(1):1643. doi: 10.1038/s41467-018-03999-y.
The accumulations of different types of genetic alterations such as nucleotide substitutions, structural rearrangements and viral genome integrations and epigenetic alterations contribute to carcinogenesis. Here, we report correlation between the occurrence of epigenetic features and genetic aberrations by whole-genome bisulfite, whole-genome shotgun, long-read, and virus capture sequencing of 373 liver cancers. Somatic substitutions and rearrangement breakpoints are enriched in tumor-specific hypo-methylated regions with inactive chromatin marks and actively transcribed highly methylated regions in the cancer genome. Individual mutation signatures depend on chromatin status, especially, signatures with a higher transcriptional strand bias occur within active chromatic areas. Hepatitis B virus (HBV) integration sites are frequently detected within inactive chromatin regions in cancer cells, as a consequence of negative selection for integrations in active chromatin regions. Ultra-high structural instability and preserved unmethylation of integrated HBV genomes are observed. We conclude that both precancerous and somatic epigenetic features contribute to the cancer genome architecture.
不同类型的遗传改变（如核苷酸取代、结构重排和病毒基因组整合以及表观遗传改变）的积累导致了癌症的发生。在这里，我们通过对 373 例肝癌进行全基因组亚硫酸氢盐测序、全基因组鸟枪法测序、长读测序和病毒捕获测序，报告了表观遗传特征与遗传异常之间的相关性。体细胞替换和重排断点富集于具有无活性染色质标记和肿瘤基因组中活跃转录的高度甲基化区域的肿瘤特异性低甲基化区域。个体突变特征取决于染色质状态，特别是具有更高转录链偏向性的特征出现在活性染色质区域内。乙型肝炎病毒（HBV）整合位点经常在癌细胞中无活性染色质区域中检测到，这是由于在活性染色质区域中整合的负选择。观察到超高结构不稳定性和整合的 HBV 基因组的保留未甲基化。我们得出结论，癌前和体细胞表观遗传特征都有助于癌症基因组结构的形成。
