纽约基因组中心Marcin Imieliski研究小组近日取得一项新成果。经过不懈努力，他们报道了乘客突变将人肺腺癌的细胞起源和转录同一性联系起来。这一研究成果于2025年11月27日发表在国际顶尖学术期刊《自然—遗传学》上。

因此，该课题组发现聚集性肺腺癌（LUAD）和鳞状癌（LUSC）的体细胞突变密度分别与远端（肺泡）和近端（基底）肺细胞类型特异性基因表达密切相关，这与假设的LUAD和LUSC细胞起源一致。分析个体基因组，21%的LUAD具有近端气道起源的突变足迹，38%的LUAD被归类为模棱两可。远端源LUAD主要发生在吸烟者中，富含KRAS和STK11驱动因子；近端起源LUAD富含EGFR驱动因子，在从不吸烟者中更为常见。歧义源LUAD显示APOBEC特征和SMARCA4改变。具有非远端细胞起源的TP53突变LUAD优先表现出非远端转录特性。他们的研究揭示了LUAD进化中谱系和身份之间复杂的相互作用，并提供了一种可扩展的策略来推断人类癌症的肿瘤起源。这项研究显示了肿瘤中的体细胞乘客突变和正常细胞转录组之间的联系如何能够以推断肺腺癌中的细胞起源为主题。

据了解，DNA损伤在表达基因中优先修复；因此，体细胞突变模式和正常细胞转录之间的全基因组相关性可能反映了肿瘤细胞的起源。

附：英文原文

Title: Passenger mutations link cellular origin and transcriptional identity in human lung adenocarcinomas

Author: Panja, Sukanya, Mantri, Padmaja, Johnson, Kofi Ennu, Andrade-Martinez, Juan Sebastian, Yang, Soo-Ryum, Deshpande, Aditya, Tian, Huasong, Beg, Shaham, Ohara, Kentaro, Leal, Alessandro, Rosiene, Joel, Stoeckius, Marlon, Smibert, Peter, Travis, William D., Mosquera, Juan Miguel, Polak, Paz, Imieliski, Marcin

Issue&Volume: 2025-11-27

Abstract: DNA damage is preferentially repaired in expressed genes; thus, genome-wide correlations between somatic mutation patterns and normal cell transcription may reflect tumor cell origins. Accordingly, we found that aggregate lung adenocarcinoma (LUAD) and squamous cancer (LUSC) somatic mutation density associated most strongly with distal (alveolar) and proximal (basal) lung cell-type-specific gene expression, respectively, consistent with presumed LUAD and LUSC cell origins. Analyzing individual genomes, 21% of LUADs bore mutational footprints of proximal airway origins, with 38% classified as ambiguous. Distal origin LUADs, enriched for KRAS and STK11 drivers, occurred mainly in smokers; proximal origin LUADs, enriched for EGFR drivers, were more common in never-smokers. Ambiguous origin LUADs showed APOBEC signatures and SMARCA4 alterations. TP53 mutant LUADs with non-distal cell origins preferentially exhibited non-distal transcriptional identity. Our study reveals a complex interplay between lineage and identity in LUAD evolution and offers a scalable strategy to infer tumor origins in human cancers. This study shows how the links between somatic passenger mutations in tumors and normal cell transcriptomes can be used to infer cell-of-origin in lung adenocarcinoma.

DOI: 10.1038/s41588-025-02418-5

Source: https://www.nature.com/articles/s41588-025-02418-5