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癌症中端粒激活维持机制的基因组足迹。

Genomic footprints of activated telomere maintenance mechanisms in cancer.

机构信息

Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.

Faculty of Biosciences, Heidelberg University, 69120, Heidelberg, Germany.

出版信息

Nat Commun. 2020 Feb 5;11(1):733. doi: 10.1038/s41467-019-13824-9.

DOI:10.1038/s41467-019-13824-9
PMID:32024817
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7002710/
Abstract

Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXX) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXX tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.

摘要

癌症需要端粒维持机制来实现无限的复制潜力。它们通过 TERT 的激活或与 ATRX 或 DAXX 缺失相关的替代性端粒延长来实现这一点。在这里，作为 ICGC/TCGA 全基因组泛癌症分析 (PCAWG) 联盟的一部分，我们对来自 36 种不同肿瘤类型的超过 2500 对匹配的肿瘤-对照样本的全基因组测序数据进行了剖析，这些样本聚集在 ICGC/TCGA 全基因组泛癌症分析 (PCAWG) 联盟中，以描述这些机制的基因组足迹。虽然 ATRX 或 DAXX 突变 (ATRX/DAXX) 的肿瘤中端粒含量增加，但 TERT 修饰的肿瘤中端粒含量则适度下降。四分之一的肿瘤样本包含端粒序列的体细胞整合到非端粒 DNA 中。这一分支在 ATRX/DAXX 肿瘤中增加到 80%的流行率，这些肿瘤携带异常的端粒变体重复 (TVR) 分布，作为另一个基因组标记。后者的特征包括以前未描述的单一体 TVRs TTCGGG 和 TTTGGG 的富集或耗尽，分别。我们的系统分析为与癌症中端粒维持机制相关的复发性基因组改变提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e80/7002710/d97e16e4af10/41467_2019_13824_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e80/7002710/fbc3aa72e158/41467_2019_13824_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e80/7002710/5202d95b10a4/41467_2019_13824_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e80/7002710/1fa7c96a9239/41467_2019_13824_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e80/7002710/afd1c7969cd4/41467_2019_13824_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e80/7002710/d97e16e4af10/41467_2019_13824_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e80/7002710/fbc3aa72e158/41467_2019_13824_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e80/7002710/5202d95b10a4/41467_2019_13824_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e80/7002710/1fa7c96a9239/41467_2019_13824_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e80/7002710/afd1c7969cd4/41467_2019_13824_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e80/7002710/d97e16e4af10/41467_2019_13824_Fig5_HTML.jpg

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