当前位置:科学网首页 > 小柯机器人 >详情
基因组学研究揭示乘客突变的影响
作者:小柯机器人 发布时间:2020/2/21 11:56:20

美国耶鲁大学Mark B. Gerstein小组探究了超过2500个癌症基因组的乘客突变。并揭示了其总体分子功能的影响和后果。该研究于2020年2月20日在线发表在国际学术期刊《细胞》杂志上。

研究人员利用了ICGC / TCGA全基因组泛癌分析(PCAWG)项目的综合变体数据集,证明除了二分法中高影响力和低影响力变数外,还有第三类中等影响变数:假定的乘客。

此外,研究人员还发现分子影响与亚克隆构架相关(即早期突变与晚期突变),并且不同的特征码编码具有不同影响的突变。

并且,研究人员根据对复杂性状的研究建立了附加效应模型,以此证明假定的乘客(包括未检测到的弱驱动基因)的综合效应提供了显著的额外功效(约12%的加性方差),超出了PCAWG识别的驱动突变。最后,该算法使科研人员能够估计PCAWG样本中潜在弱驱动突变的频率,这些突变缺乏任何典型驱动突变的特征。

研究人员表示,癌症中“驱动”和“乘客”的二分模型认为,只有少数突变会强烈影响肿瘤的进展,而其余突变则无关紧要。

附:英文原文

Title: Passenger Mutations in More Than 2,500 Cancer Genomes: Overall Molecular Functional Impact and Consequences

Author: Sushant Kumar, Jonathan Warrell, Shantao Li, Patrick D. McGillivray, William Meyerson, Leonidas Salichos, Arif Harmanci, Alexander Martinez-Fundichely, Calvin W.Y. Chan, Morten Muhlig Nielsen, Lucas Lochovsky, Yan Zhang, Xiaotong Li, Shaoke Lou, Jakob Skou Pedersen, Carl Herrmann, Gad Getz, Ekta Khurana, Mark B. Gerstein

Issue&Volume: 2020-02-20

Abstract: The dichotomous model of “drivers” and “passengers” in cancer posits that only a fewmutations in a tumor strongly affect its progression, with the remaining ones beinginconsequential. Here, we leveraged the comprehensive variant dataset from the ICGC/TCGAPan-Cancer Analysis of Whole Genomes (PCAWG) project to demonstrate that—in additionto the dichotomy of high- and low-impact variants—there is a third group of medium-impactputative passengers. Moreover, we also found that molecular impact correlates withsubclonal architecture (i.e., early versus late mutations), and different signaturesencode for mutations with divergent impact. Furthermore, we adapted an additive-effectsmodel from complex-trait studies to show that the aggregated effect of putative passengers,including undetected weak drivers, provides significant additional power (~12% additivevariance) for predicting cancerous phenotypes, beyond PCAWG-identified driver mutations.Finally, this framework allowed us to estimate the frequency of potential weak-drivermutations in PCAWG samples lacking any well-characterized driver alterations.

DOI: 10.1016/j.cell.2020.01.032

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30113-6

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/