Phenotypic plasticity and genetic control in colorectal cancer evolution.
Phenotypic plasticity and genetic control in colorectal cancer evolution.
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DOI：
10.1038/s41586-022-05311-x
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发表时间：
2022-11
期刊：
影响因子：
64.8
通讯作者：
Graham, Trevor A.
中科院分区：
文献类型：
--
作者：
Househam, Jacob;Heide, Timon;Cresswell, George D.;Spiteri, Inmaculada;Kimberley, Chris;Zapata, Luis;Lynn, Claire;James, Chela;Mossner, Maximilian;Fernandez-Mateos, Javier;Vinceti, Alessandro;Baker, Ann-Marie;Gabbutt, Calum;Berner, Alison;Schmidt, Melissa;Chen, Bingjie;Lakatos, Eszter;Gunasri, Vinaya;Nichol, Daniel;Costa, Helena;Mitchinson, Miriam;Ramazzotti, Daniele;Werner, Benjamin;Iorio, Francesco;Jansen, Marnix;Caravagna, Giulio;Barnes, Chris P.;Shibata, Darryl;Bridgewater, John;Rodriguez-Justo, Manuel;Magnani, Luca;Sottoriva, Andrea;Graham, Trevor A.
遗传和表观遗传变异，以及转录可塑性，导致肿瘤内的异质性。这些生物学过程的相互作用及其对肿瘤进化的各自贡献尚不清楚。在这里，我们表明，肿瘤内的遗传祖先仅罕见地影响结直肠癌(CRC)的基因表达特征和亚克隆进化。利用空间分辨的成对全基因组和转录组测序，我们发现大多数肿瘤内基因表达的变异并不是强烈的遗传，而是“可塑性”。体细胞表达数量性状基因座分析通过顺式作用的编码基因和非编码基因突变发现了一些可能的基因表达控制，其中大多数是肿瘤内的克隆，并伴有频繁的结构变化。一贯地，对肿瘤系统发育的空间模式的计算推断发现，相当大比例的CRC没有显示出亚克隆选择的证据，只有推测的遗传驱动因素的子集与亚克隆扩张有关。克隆的空间混合很常见，一些肿瘤呈指数级增长，另一些只在外围生长。总而言之，我们的数据表明，大多数结直肠癌的遗传肿瘤内变异没有重大的表型后果，相反，转录可塑性在肿瘤中广泛存在。肿瘤内的遗传祖先很少影响结直肠癌的基因表达特征和亚克隆进化，大多数肿瘤内的遗传变异没有检测到表型后果，转录可塑性在肿瘤中普遍存在。
Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity. The interplay of these biological processes and their respective contributions to tumour evolution remain unknown. Here we show that intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer (CRC). Using spatially resolved paired whole-genome and transcriptome sequencing, we find that the majority of intratumour variation in gene expression is not strongly heritable but rather ‘plastic’. Somatic expression quantitative trait loci analysis identified a number of putative genetic controls of expression by cis-acting coding and non-coding mutations, the majority of which were clonal within a tumour, alongside frequent structural alterations. Consistently, computational inference on the spatial patterning of tumour phylogenies finds that a considerable proportion of CRCs did not show evidence of subclonal selection, with only a subset of putative genetic drivers associated with subclone expansions. Spatial intermixing of clones is common, with some tumours growing exponentially and others only at the periphery. Together, our data suggest that most genetic intratumour variation in CRC has no major phenotypic consequence and that transcriptional plasticity is, instead, widespread within a tumour. Intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer, with most genetic intratumour variation having no detected phenotypic consequence and transcriptional plasticity being widespread within a tumour.
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通过使用机器学习和种群遗传学对肿瘤的亚克隆重建。
影响因子：
30.8
作者：
Caravagna G;Heide T;Williams MJ;Zapata L;Nichol D;Chkhaidze K;Cross W;Cresswell GD;Werner B;Acar A;Chesler L;Barnes CP;Sanguinetti G;Graham TA;Sottoriva A
通讯作者：
Sottoriva A
影响因子：
11.2
作者：
Enderling, Heiko;Anderson, Alexander R. A.;Hahnfeldt, Philip
通讯作者：
Hahnfeldt, Philip
DOI：
10.1093/database/bax028
发表时间：
2017-01-01
期刊：
Database : the journal of biological databases and curation
影响因子：
--
作者：
Fishilevich S;Nudel R;Rappaport N;Hadar R;Plaschkes I;Iny Stein T;Rosen N;Kohn A;Twik M;Safran M;Lancet D;Cohen D
通讯作者：
Cohen D
影响因子：
16.8
作者：
Cross W;Kovac M;Mustonen V;Temko D;Davis H;Baker AM;Biswas S;Arnold R;Chegwidden L;Gatenbee C;Anderson AR;Koelzer VH;Martinez P;Jiang X;Domingo E;Woodcock DJ;Feng Y;Kovacova M;Maughan T;S:CORT Consortium;Jansen M;Rodriguez-Justo M;Ashraf S;Guy R;Cunningham C;East JE;Wedge DC;Wang LM;Palles C;Heinimann K;Sottoriva A;Leedham SJ;Graham TA;Tomlinson IPM
通讯作者：
Tomlinson IPM
DOI：
10.1093/bioinformatics/btv428
发表时间：
2015-11-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Galili T
通讯作者：
Galili T