Comprehensive characterization of somatic variants associated with intronic polyadenylation in human cancers.
Comprehensive characterization of somatic variants associated with intronic polyadenylation in human cancers.
复制标题
人类癌症中与内含子多腺苷酸化相关的体细胞变异的综合表征
DOI：
10.1093/nar/gkab772
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发表时间：
2021-10-11
影响因子：
14.9
通讯作者：
Ni T
中科院分区：
文献类型：
--
作者：
Zhao Z;Xu Q;Wei R;Huang L;Wang W;Wei G;Ni T
摘要：癌症基因组中的体细胞单核苷酸变异 (SNV) 根据其基因组位置通过各种机制影响基因表达。虽然据报道，规范剪接位点附近的体细胞 SNV 会导致癌症相关基因的异常剪接，但这些 SNV 是否可以通过其他机制影响基因表达仍然是一个悬而未决的问题。在这里，我们分析了 4,998 名癌症患者（涵盖 10 种癌症类型）的 RNA 测序和外显子组数据，并鉴定了剪接位点附近与异常内含子多腺苷酸化 (IPA) 相关的 152 个体细胞 SNV。与受体剪接位点相比，IPA 相关的体细胞变异有利于供体剪接位点附近的定位。一部分 SNV 相关 IPA 事件与 U1 小核核糖核蛋白 (snRNP) 抑制引发的过早裂解和多聚腺苷酸化事件重叠。 GC含量、内含子长度和多腺苷酸化信号是区分SNV相关IPA和内含子保留的三个基因组特征。值得注意的是，IPA 相关的 SNV 富含肿瘤抑制基因 (TSG)，包括众所周知的 TSG，例如具有复发性 SNV 相关 IPA 事件的 PTEN 和 CDH1。小基因检测证实来自 PTEN、CDH1、VEGFA、GRHL2、CUL3 和 WWC2 的 SNV 可以导致 IPA。这项工作揭示了 IPA 作为一种新机制解释了体细胞 SNV 在人类癌症中的功能后果。
Abstract Somatic single nucleotide variants (SNVs) in cancer genome affect gene expression through various mechanisms depending on their genomic location. While somatic SNVs near canonical splice sites have been reported to cause abnormal splicing of cancer-related genes, whether these SNVs can affect gene expression through other mechanisms remains an open question. Here, we analyzed RNA sequencing and exome data from 4,998 cancer patients covering ten cancer types and identified 152 somatic SNVs near splice sites that were associated with abnormal intronic polyadenylation (IPA). IPA-associated somatic variants favored the localization near the donor splice sites compared to the acceptor splice sites. A proportion of SNV-associated IPA events overlapped with premature cleavage and polyadenylation events triggered by U1 small nuclear ribonucleoproteins (snRNP) inhibition. GC content, intron length and polyadenylation signal were three genomic features that differentiated between SNV-associated IPA and intron retention. Notably, IPA-associated SNVs were enriched in tumor suppressor genes (TSGs), including the well-known TSGs such as PTEN and CDH1 with recurrent SNV-associated IPA events. Minigene assay confirmed that SNVs from PTEN, CDH1, VEGFA, GRHL2, CUL3 and WWC2 could lead to IPA. This work reveals that IPA acts as a novel mechanism explaining the functional consequence of somatic SNVs in human cancer.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Davoli T;Xu AW;Mengwasser KE;Sack LM;Yoon JC;Park PJ;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
64.8
作者：
Lee SH;Singh I;Tisdale S;Abdel-Wahab O;Leslie CS;Mayr C
通讯作者：
Mayr C
影响因子：
7
作者：
Braunschweig U;Barbosa-Morais NL;Pan Q;Nachman EN;Alipanahi B;Gonatopoulos-Pournatzis T;Frey B;Irimia M;Blencowe BJ
通讯作者：
Blencowe BJ