英国弗朗西斯·克里研究所Peter Van Loo研究组取得一项新突破。他们探明表征2658个人类癌症基因组的肿瘤内遗传异质性（ITH）。这一研究成果于2021年4月7日发表在国际顶尖学术期刊《细胞》杂志上。
他们在38种跨癌症的2658个样品的全基因组测序中广泛地描述了ITH。几乎所有信息量样本（95.1％）都包含明显的亚克隆扩展证据，且亚克隆之间频繁分支。他们观察到跨大多数癌症类型的亚克隆驱动子突变的阳性选择，并确定了驱动基因突变、融合、结构变异和拷贝数变化以及亚克隆扩增之间突变过程的动态变化的癌症类型特异性亚克隆模式。
他们的结果强调了ITH及其驱动程序在肿瘤进化中的重要性，并提供了从全基因组测序数据中全面注释的亚克隆事件的泛癌资源。
据了解，ITH是治疗耐药性的机制，因此是一项重要的临床挑战。但是，人们对跨癌症类型的ITH的程度、起源和驱动因素知之甚少。
附：英文原文
Title: Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes
Author: Stefan C. Dentro, Ignaty Leshchiner, Kerstin Haase, Maxime Tarabichi, Jeff Wintersinger, Amit G. Deshwar, Kaixian Yu, Yulia Rubanova, Geoff Macintyre, Jonas Demeulemeester, Ignacio Vázquez-García, Kortine Kleinheinz, Dimitri G. Livitz, Salem Malikic, Nilgun Donmez, Subhajit Sengupta, Pavana Anur, Clemency Jolly, Marek Cmero, Daniel Rosebrock, Steven E. Schumacher, Yu Fan, Matthew Fittall, Ruben M. Drews, Xiaotong Yao, Thomas B.K. Watkins, Juhee Lee, Matthias Schlesner, Hongtu Zhu, David J. Adams, Nicholas McGranahan, Charles Swanton, Gad Getz, Paul C. Boutros, Marcin Imielinski, Rameen Beroukhim, S. Cenk Sahinalp, Yuan Ji, Martin Peifer, Inigo Martincorena, Florian Markowetz, Ville Mustonen, Ke Yuan, Moritz Gerstung, Paul T. Spellman, Wenyi Wang, Quaid D. Morris, David C. Wedge, Peter Van Loo, Stefan C. Dentro, Ignaty Leshchiner, Moritz Gerstung, Clemency Jolly, Kerstin Haase, Maxime Tarabichi, Jeff Wintersinger, Amit G. Deshwar, Kaixian Yu, Santiago Gonzalez, Yulia Rubanova, Geoff Macintyre, Jonas Demeulemeester, David J. Adams, Pavana Anur, Rameen Beroukhim, Paul C. Boutros, David D. Bowtell
Issue&Volume: 2021-04-07
Abstract: Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
DOI: 10.1016/j.cell.2021.03.009
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00294-4