转移性尿路上皮癌的 APOBEC 诱变全基因组图谱确定了驱动热点突变和新型突变特征。

IF 11.1 Q1 CELL BIOLOGY Cell genomics Pub Date : 2024-04-10 Epub Date: 2024-03-28 DOI:10.1016/j.xgen.2024.100528
J Alberto Nakauma-González, Maud Rijnders, Minouk T W Noordsij, John W M Martens, Astrid A M van der Veldt, Martijn P J Lolkema, Joost L Boormans, Harmen J G van de Werken
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引用次数: 0

摘要

载脂蛋白B mRNA编辑酶催化多肽样(APOBEC)酶会使特定的DNA序列和发夹环结构发生突变,这对区分乘客突变和驱动热点突变提出了挑战。在这里,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突变热点驱动因子。在92%的mUC中检测到了APOBEC相关突变,这些突变在整个基因组中平均分布,而APOBEC热点突变(ApoHMs)则富集在开放染色质中。发夹环是didymi(希腊语中的双胞胎)的常发目标,这两个热点突变具有APOBEC SBS2特征,同时还有一个未表征的突变背景(Ap[C>T])。接下来,我们建立了一个统计框架,以确定 ApoHMs 是 mUCs 编码和非编码基因组区域的驱动因素。我们的研究结果和统计框架在 23 个非转移性 UC 的独立队列和 17 个转移性癌症的 3,744 个样本中得到了验证,确定了癌症类型特异性驱动因子。我们的研究强调了 APOBEC 在癌症发展中的作用,并可能有助于为 APOBEC 驱动的癌症开发新的靶向治疗方案。
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Whole-genome mapping of APOBEC mutagenesis in metastatic urothelial carcinoma identifies driver hotspot mutations and a novel mutational signature.

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.

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