癌症突变通过复制错误和DNA损伤以及不完全的修复累积。个体突变过程通常显示核苷酸序列和功能区域的偏好。因此，一些序列上下文的突变率要比其他上下文高得多，而在功能区域之间还存在额外的变异。突变热点是指在癌症样本中出现反复突变的基因组位置，其突变率升高，通常是由高度局部化的突变过程引起的。我们计算了整个基因组的11-mer基因组序列，并使用PCA代表2583个全癌症整个基因组的11-mer与突变标志、单核苷酸变异的热点和特定的基因组区域相关联。我们评估了单个和组合的11-mer突变率，并推导出突变序列模式。我们表明热点通常可以识别高度可变的序列上下文。利用这些，我们展示了一些突变标志在热点序列上下文中富集，对应于潜在的局部化突变过程的明确定义的序列偏好。其中包括未知病因的17b标志和62标志（POLE缺陷）、7a标志（紫外线）和72标志（与淋巴瘤相关）。在某些情况下，当关注特定的基因组区域时，突变率和序列偏好进一步增加，比如在转录区域中的62标志，其突变率相较于癌症类型和突变标志平均值增加了9倍。我们总结了我们的研究发现，包括局部突变过程，它们的序列偏好和估计的突变率的目录。© 2023. BioMed Central Ltd., part of Springer Nature.

Cancer mutations accumulate through replication errors and DNA damage coupled with incomplete repair. Individual mutational processes often show nucleotide sequence and functional region preferences. As a result, some sequence contexts mutate at much higher rates than others, with additional variation found between functional regions. Mutational hotspots, with recurrent mutations across cancer samples, represent genomic positions with elevated mutation rates, often caused by highly localized mutational processes.We count the 11-mer genomic sequences across the genome, and using the PCAWG set of 2583 pan-cancer whole genomes, we associate 11-mers with mutational signatures, hotspots of single nucleotide variants, and specific genomic regions. We evaluate the mutation rates of individual and combined sets of 11-mers and derive mutational sequence motifs.We show that hotspots generally identify highly mutable sequence contexts. Using these, we show that some mutational signatures are enriched in hotspot sequence contexts, corresponding to well-defined sequence preferences for the underlying localized mutational processes. This includes signature 17b (of unknown etiology) and signatures 62 (POLE deficiency), 7a (UV), and 72 (linked to lymphomas). In some cases, the mutation rate and sequence preference increase further when focusing on certain genomic regions, such as signature 62 in transcribed regions, where the mutation rate is increased up to 9-folds over cancer type and mutational signature average.We summarize our findings in a catalog of localized mutational processes, their sequence preferences, and their estimated mutation rates.© 2023. BioMed Central Ltd., part of Springer Nature.