体细胞拷贝数增加在各种癌症类型中普遍存在，但它们在肿瘤发生中的作用尚未得到充分评估。这种不足部分是由于跨越大染色体区域的复制增益，掩盖了因果位点。在这里，我们采用类器官模型来评估通过对癌症基因组图谱中与极端表达失调重叠的极端复制增益进行综合计算分析而确定的候选致癌位点。 “异常”候选者的子集被根据背景筛选为具有初始致癌突变的同源食管、口腔、结肠、胃、胰腺和肺类器官内的组织特异性 cDNA 慢病毒文库。迭代分析将 12q15 处的激酶 DYRK2 命名为 p53-/- 口腔粘膜类器官中扩增的头颈鳞癌癌基因。同样，FGF3 在 41% 的食管鳞状癌中在 11q13 处扩增，通过 FGFR 的小分子和可溶性受体拮抗作用促进 p53-/- 食管类器官生长。我们的研究建立了基于类器官的候选基因组驱动因素背景筛选，从而能够在早期肿瘤发生过程中进行功能评估。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

Somatic copy number gains are pervasive across cancer types, yet their roles in oncogenesis are insufficiently evaluated. This inadequacy is partly due to copy gains spanning large chromosomal regions, obscuring causal loci. Here, we employed organoid modeling to evaluate candidate oncogenic loci identified via integrative computational analysis of extreme copy gains overlapping with extreme expression dysregulation in The Cancer Genome Atlas. Subsets of "outlier" candidates were contextually screened as tissue-specific cDNA lentiviral libraries within cognate esophagus, oral cavity, colon, stomach, pancreas, and lung organoids bearing initial oncogenic mutations. Iterative analysis nominated the kinase DYRK2 at 12q15 as an amplified head and neck squamous carcinoma oncogene in p53-/- oral mucosal organoids. Similarly, FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, promoted p53-/- esophageal organoid growth reversible by small molecule and soluble receptor antagonism of FGFRs. Our studies establish organoid-based contextual screening of candidate genomic drivers, enabling functional evaluation during early tumorigenesis.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.