Hu Xiaoju, Xu Zhuxuan, De Subhajyoti
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.
NAR Cancer. 2020 Sep;2(3):zcaa026. doi: 10.1093/narcan/zcaa026. Epub 2020 Sep 25.
Although not all somatic mutations are cancer drivers, their mutational signatures, i.e. the patterns of genomic alterations at a genome-wide scale, provide insights into past exposure to mutagens, DNA damage and repair processes. Computational deconvolution of somatic mutation patterns and expert curation pan-cancer studies have identified a number of mutational signatures associated with point mutations, dinucleotide substitutions, insertions and deletions, and rearrangements, and have established etiologies for a subset of these signatures. However, the mechanisms underlying nearly one-third of all mutational signatures are not yet understood. The signatures with established etiology and those with hitherto unknown origin appear to have some differences in strand bias, GC content and nucleotide context diversity. It is possible that some of the hitherto 'unknown' signatures predominantly occur outside gene regions. While nucleotide contexts might be adequate to establish etiologies of some mutational signatures, in other cases additional features, such as broader (epi)genomic contexts, including chromatin, replication timing, processivity and local mutational patterns, may help fully understand the underlying DNA damage and repair processes. Nonetheless, remarkable progress in characterization of mutational signatures has provided fundamental insights into the biology of cancer, informed disease etiology and opened up new opportunities for cancer prevention, risk management, and therapeutic decision making.
虽然并非所有体细胞突变都是癌症驱动因素，但其突变特征，即在全基因组范围内的基因组改变模式，能让人深入了解过去对诱变剂的暴露情况、DNA损伤及修复过程。对体细胞突变模式进行计算反卷积和开展泛癌专家策展研究，已经确定了一些与点突变、二核苷酸替换、插入和缺失以及重排相关的突变特征，并为其中一部分特征确定了病因。然而，所有突变特征中近三分之一的潜在机制仍不为人所知。已确定病因的特征与起源迄今不明的特征在链偏向性、GC含量和核苷酸上下文多样性方面似乎存在一些差异。有可能一些迄今“未知”的特征主要发生在基因区域之外。虽然核苷酸上下文可能足以确定某些突变特征的病因，但在其他情况下，诸如更广泛的（表观）基因组上下文，包括染色质、复制时间、持续合成能力和局部突变模式等额外特征，可能有助于全面理解潜在的DNA损伤和修复过程。尽管如此，突变特征表征方面的显著进展为癌症生物学提供了基本见解，为疾病病因提供了信息，并为癌症预防、风险管理和治疗决策开辟了新机会。
