载脂蛋白BmRNA编辑酶催化多肽样(APOBEC)酶突变特定的DNA序列和发夹环结构,挑战乘客和驾驶员热点突变之间的区别。这里,我们鉴定了115个转移性尿路上皮癌(mUC)的全基因组,以确定APOBEC诱变热点驱动因素.在92%的mUC中检测到APOBEC相关突变,并且在整个基因组中均匀分布,而APOBEC热点突变(ApoHMs)富集在开放染色质中。发夹环是didymi(希腊语中的双胞胎)的常见目标,以APOBECSBS2特征为特征的两个热点突变,结合未表征的突变上下文(Ap[C>T])。接下来,我们开发了一个统计框架,将ApoHMs确定为mUCs编码和非编码基因组区域的驱动因素.我们的结果和统计框架在23个非转移性UCs和17个转移性癌症的3,744个样本的独立队列中得到了验证。确定癌症类型特异性驱动因素。我们的研究强调了APOBEC在癌症发展中的作用,并可能有助于开发APOBEC驱动的癌症的新型靶向治疗方案。
Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (
APOBEC) enzymes mutate specific DNA sequences and hairpin-loop structures, challenging the distinction between passenger and driver hotspot mutations. Here, we characterized 115 whole genomes of metastatic urothelial carcinoma (mUC) to identify
APOBEC mutagenic hotspot drivers.
APOBEC-associated mutations were detected in 92% of mUCs and were equally distributed across the genome, while
APOBEC hotspot mutations (ApoHMs) were enriched in open chromatin. Hairpin loops were frequent targets of didymi (twins in Greek), two hotspot mutations characterized by the APOBEC SBS2 signature, in conjunction with an uncharacterized mutational context (Ap[C>T]). Next, we developed a statistical framework that identified ApoHMs as drivers in coding and non-coding genomic regions of mUCs. Our results and statistical framework were validated in independent cohorts of 23 non-metastatic UCs and 3,744 samples of 17 metastatic cancers, identifying cancer-type-specific drivers. Our study highlights the role of APOBEC in cancer development and may contribute to developing novel targeted therapy options for
APOBEC-driven cancers.