美国纪念斯隆-凯特琳癌症中心Chaitanya Bandlamudi等研究人员合作发现，肿瘤抑制基因双等位基因失活的全癌症分析，揭示KEAP1合子基因型作为肺癌预测生物标志物的潜力。这一研究成果于2024年12月18日在线发表在国际学术期刊《细胞》上。

通过对48179例癌症患者的测序数据进行等位基因特异性分析，研究人员定义了肿瘤抑制基因（TSG）双等位基因失活的流行程度、选择压力和功能后果。TSG大致可分为两类：与全癌症（1类）或谱系特异性（2类）双等位基因丧失选择模式相关的基因，尽管也有一些TSG主要表现为单等位基因失活（3/4类）。

研究人员证明了双等位基因失活的选择，可以用于识别非经典背景中的驱动基因，包括一些肿瘤抑制基因（如KEAP1）的未确定意义变异（VUS）。基因组、功能和临床数据共同表明，KEAP1的VUS表现出与已知KEAP1致癌等位基因相似的表型，并且基因型，而非变异分类，是预测治疗反应的指标。因此，TSG的接合性是疾病病因和治疗敏感性的基本决定因素。

研究人员表示，TSG介导的致癌模型认为，双等位基因丧失是基因失活所必需的。

附：英文原文

Title: Pan-cancer analysis of biallelic inactivation in tumor suppressor genes identifies KEAP1 zygosity as a predictive biomarker in lung cancer

Author: Mark Zucker, Maria A. Perry, Samuel I. Gould, Arielle Elkrief, Anton Safonov, Rohit Thummalapalli, Miika Mehine, Debyani Chakravarty, A. Rose Brannon, Marc Ladanyi, Pedram Razavi, Mark T.A. Donoghue, Yonina R. Murciano-Goroff, Kristiana Grigoriadis, Nicholas McGranahan, Mariam Jamal-Hanjani, Charles Swanton, Yuan Chen, Ronglai Shen, Sarat Chandarlapaty, David B. Solit, Nikolaus Schultz, Michael F. Berger, Jason Chang, Adam J. Schoenfeld, Francisco J. Sánchez-Rivera, Ed Reznik, Chaitanya Bandlamudi

Issue&Volume: 2024-12-18

Abstract: The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4). We demonstrate that selection for biallelic inactivation can be utilized to identify driver genes in non-canonical contexts, including among variants of unknown significance (VUSs) of several TSGs such as KEAP1. Genomic, functional, and clinical data collectively indicate that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles and that zygosity, rather than variant classification, is predictive of therapeutic response. TSG zygosity is therefore a fundamental determinant of disease etiology and therapeutic sensitivity.

DOI: 10.1016/j.cell.2024.11.010

Source: https://www.cell.com/cell/abstract/S0092-8674(24)01327-8