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研究揭示结直肠癌中基因组和表观基因组的共同演化
2022-10-30 19:46

英国癌症研究所Andrea Sottoriva等研究人员合作揭示结直肠癌中基因组和表观基因组的共同演化。相关论文于2022年10月26日在线发表于国际学术期刊《自然》。

研究人员利用单个腺体的空间多组学分析,在单克隆分辨率下研究了结直肠肿瘤的基因组和表观基因组的共同演变。研究人员从30个原发性癌症和8个伴随性腺瘤中收集了1370个样本,生成了1207个染色质可及性图谱、527个全基因组和297个全转录组。研究人员发现染色质修饰基因DNA突变的正向选择和反复出现的体细胞染色质可及性改变,包括在原本没有基因突变的癌症驱动基因的调控区域。

转录因子结合可及性的全基因组改变涉及CTCF、干扰素的下调以及SOX和HOX转录因子家族的可及性增加,这表明在肿瘤发生过程中发育基因的参与。体细胞染色质可及性的改变是可遗传的,并将腺瘤与癌症区分开来。突变特征分析显示,表观基因组反过来影响了DNA突变的积累。这项研究提供了一个遗传和表观遗传的肿瘤异质性地图,对理解结直肠癌生物学具有根本性的意义。

据悉,结直肠恶性肿瘤是癌症相关死亡的一个主要原因,并且已经进行了广泛的基因组研究。然而,仅靠DNA突变并不能完全解释恶性肿瘤的转化。

附:英文原文

Title: The co-evolution of the genome and epigenome in colorectal cancer

Author: Heide, Timon, Househam, Jacob, Cresswell, George D., Spiteri, Inmaculada, Lynn, Claire, Mossner, Maximilian, Kimberley, Chris, Fernandez-Mateos, Javier, Chen, Bingjie, Zapata, Luis, James, Chela, Barozzi, Iros, Chkhaidze, Ketevan, Nichol, Daniel, Gunasri, Vinaya, Berner, Alison, Schmidt, Melissa, Lakatos, Eszter, Baker, Ann-Marie, Costa, Helena, Mitchinson, Miriam, Piazza, Rocco, Jansen, Marnix, Caravagna, Giulio, Ramazzotti, Daniele, Shibata, Darryl, Bridgewater, John, Rodriguez-Justo, Manuel, Magnani, Luca, Graham, Trevor A., Sottoriva, Andrea

Issue&Volume: 2022-10-26

Abstract: Colorectal malignancies are a leading cause of cancer-related death1 and have undergone extensive genomic study2,3. However, DNA mutations alone do not fully explain malignant transformation4,5,6,7. Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent somatic chromatin accessibility alterations, including in regulatory regions of cancer driver genes that were otherwise devoid of genetic mutations. Genome-wide alterations in accessibility for transcription factor binding involved CTCF, downregulation of interferon and increased accessibility for SOX and HOX transcription factor families, suggesting the involvement of developmental genes during tumourigenesis. Somatic chromatin accessibility alterations were heritable and distinguished adenomas from cancers. Mutational signature analysis showed that the epigenome in turn influences the accumulation of DNA mutations. This study provides a map of genetic and epigenetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology.

DOI: 10.1038/s41586-022-05202-1

Source: https://www.nature.com/articles/s41586-022-05202-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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