美国哈佛医学院Eliezer M. Van Allen和Felix Dietlein研究组合作取得最新进展。他们对癌症中体细胞非编码突变模式进行了全基因组分析。2022年4月8日，国际知名学术期刊《科学》发表了这一成果。

他们在代表 19 种肿瘤类型的 3949 个全癌症基因组中建立了体细胞突变事件的全基因组概要。蛋白质编码事件捕获了成熟的驱动因素。组织特异性基因附近的非编码事件，例如肝脏中的 ALB 或前列腺中的 KLK3，表征了局部乘客突变模式，并可能反映肿瘤细胞起源印记。调节启动子和增强子区域中的非编码事件经常涉及癌症相关基因，例如 BCL6、FGFR2、RAD51B、SMC6、TERT 和 XBP1，并代表可能的驱动因素。与大多数非编码调控事件不同，XBP1 突变主要在基因启动子之外积累，他们使用 CRISPR 干扰筛选和荧光素酶报告基因分析验证了它们对基因表达的影响。

总的来说，他们的研究为捕获整个基因组的突变事件提供了蓝图，以指导生物发现、治疗和诊断的进展。

附：英文原文

Title: Genome-wide analysis of somatic noncoding mutation patterns in cancer

Author: Felix Dietlein, Alex B. Wang, Christian Fagre, Anran Tang, Nicolle J. M. Besselink, Edwin Cuppen, Chunliang Li, Shamil R. Sunyaev, James T. Neal, Eliezer M. Van Allen

Issue&Volume: 2022-04-08

Abstract: We established a genome-wide compendium of somatic mutation events in 3949 whole cancer genomes representing 19 tumor types. Protein-coding events captured well-established drivers. Noncoding events near tissue-specific genes, such as ALB in the liver or KLK3 in the prostate, characterized localized passenger mutation patterns and may reflect tumor-cell-of-origin imprinting. Noncoding events in regulatory promoter and enhancer regions frequently involved cancer-relevant genes such as BCL6, FGFR2, RAD51B, SMC6, TERT, and XBP1 and represent possible drivers. Unlike most noncoding regulatory events, XBP1 mutations primarily accumulated outside the gene’s promoter, and we validated their effect on gene expression using CRISPR-interference screening and luciferase reporter assays. Broadly, our study provides a blueprint for capturing mutation events across the entire genome to guide advances in biological discovery, therapies, and diagnostics.

DOI: abg5601

Source: https://www.science.org/doi/10.1126/science.abg5601