Genomic-transcriptomic evolution in lung cancer and metastasis.
Genomic-transcriptomic evolution in lung cancer and metastasis.
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DOI：
10.1038/s41586-023-05706-4
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发表时间：
2023-04
期刊：
影响因子：
64.8
通讯作者：
McGranahan, Nicholas
中科院分区：
文献类型：
--
作者：
Martinez-Ruiz, Carlos;Black, James R. M.;Puttick, Clare;Hill, Mark;Demeulemeester, Jonas;Cadieux, Elizabeth Larose;Thol, Kerstin;Jones, Thomas;Veeriah, Selvaraju;Naceur-Lombardelli, Cristina;Toncheva, Antonia;Prymas, Paulina;Rowan, Andrew;Ward, Sophia;Cubitt, Laura;Athanasopoulou, Foteini;Pich, Oriol;Karasaki, Takahiro;Moore, David;Salgado, Roberto;Colliver, Emma;Castignani, Carla I.;Dietzen, Michelle;Huebner, Ariana;Al Bakir, Maise;Tanic, Miljana G.;Watkins, Thomas B. K.;Lim, Emilia;Al-Rashed, Ali;Lang, Danny;Clements, James;Cook, Daniel J.;Rosenthal, Rachel;Wilson, Gareth;Frankell, Alexander G.;Trecesson, Sophie de Carne;East, Philip;Kanu, Nnennaya;Litchfield, Kevin;Birkbak, Nicolai;Hackshaw, Allan;Beck, Stephan;Van Loo, Peter;Jamal-Hanjani, Mariam;Swanton, Charles;McGranahan, Nicholas
肿瘤内异质性 (ITH) 加速了肺癌的进化，从而导致免疫逃避和对治疗的抵抗。在这里，我们使用配对的全外显子组和 RNA 测序数据，研究了 354 个非小细胞肺癌肿瘤的肿瘤内转录组多样性，这些肿瘤来自 TRACERx 研究中前瞻性招募的首批 421 名患者中的 347 名。对代表原发性疾病和转移性疾病的 947 个肿瘤区域以及 96 个肿瘤邻近正常组织样本的分析表明转录组是表型变异的主要来源。基因表达水平和 ITH 与肿瘤进化过程中的正选择和负选择模式有关。我们观察到频繁的与表观基因组功能障碍相关的与拷贝数无关的等位基因特异性表达。等位基因特异性表达还可以导致基因组-转录组平行进化，最终导致癌症基因破坏。我们提取 RNA 单碱基替换的特征，并将其病因与 RNA 编辑酶 ADAR 和 APOBEC3A 的活性联系起来，从而揭示肿瘤中未被检测到的正在进行的 APOBEC 活性。为了表征原发性-转移性肿瘤对的转录组，我们结合了多种机器学习方法，利用基因组和转录组变量将转移播种潜力与原发性肿瘤区域内突变和增殖增加的进化背景联系起来。这些结果强调了基因组和转录组之间的相互作用对 ITH、肺癌进化和转移的影响。计算和机器学习方法整合了来自 TRACERx 队列的配对原发性和转移性非小细胞肺癌样本的基因组和转录组变异，揭示了转录事件在肿瘤进化中的作用。
Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis. Computational and machine-learning approaches that integrate genomic and transcriptomic variation from paired primary and metastatic non-small cell lung cancer samples from the TRACERx cohort reveal the role of transcriptional events in tumour evolution.
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影响因子：
64.8
作者：
Abbosh C;Frankell AM;Harrison T;Kisistok J;Garnett A;Johnson L;Veeriah S;Moreau M;Chesh A;Chaunzwa TL;Weiss J;Schroeder MR;Ward S;Grigoriadis K;Shahpurwalla A;Litchfield K;Puttick C;Biswas D;Karasaki T;Black JRM;Martínez-Ruiz C;Bakir MA;Pich O;Watkins TBK;Lim EL;Huebner A;Moore DA;Godin-Heymann N;L'Hernault A;Bye H;Odell A;Roberts P;Gomes F;Patel AJ;Manzano E;Hiley CT;Carey N;Riley J;Cook DE;Hodgson D;Stetson D;Barrett JC;Kortlever RM;Evan GI;Hackshaw A;Daber RD;Shaw JA;Aerts HJWL;Licon A;Stahl J;Jamal-Hanjani M;TRACERx Consortium;Birkbak NJ;McGranahan N;Swanton C
通讯作者：
Swanton C
影响因子：
7
作者：
Baran Y;Subramaniam M;Biton A;Tukiainen T;Tsang EK;Rivas MA;Pirinen M;Gutierrez-Arcelus M;Smith KS;Kukurba KR;Zhang R;Eng C;Torgerson DG;Urbanek C;GTEx Consortium;Li JB;Rodriguez-Santana JR;Burchard EG;Seibold MA;MacArthur DG;Montgomery SB;Zaitlen NA;Lappalainen T
通讯作者：
Lappalainen T
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
4.6
作者：
Amemiya, Haley M.;Kundaje, Anshul;Boyle, Alan P.
通讯作者：
Boyle, Alan P.
影响因子：
64.5
作者：
Chen, Kun;Liu, Juan;Cao, Xuetao
通讯作者：
Cao, Xuetao