Yeo Eugenia Li Ling, Hong Boon Hao, Tay Shi Hui, Neo Jialing, Ong Enya Hui Wen, Chow Wen Min, Tan Kah Min, Low Kar Perng, Sim Adelene Yen Ling, Lu Tianzhu, Zhang Xin, Huang Luo, Tan Janice Ser Huey, Wee Joseph Tien Seng, Soong Yoke Lim, Fong Kam Weng, Tan Terence Wee Kiat, Sin Sze Yarn, Sam Xin Xiu, Hwang Jacqueline Siok Gek, Lim Tony Kiat Hon, Lee Jia-Ying Joey, Loo Lit-Hsin, Soo Khee Chee, Iyer Narayanan Gopalakrishna, Loh Kwok Seng, Tay Joshua K, Liu Jianjun, Ang Mei Kim, Yeong Joe Poh Sheng, Bei Jin Xin, Tan Sze Huey, Lim Darren Wan Teck, Chua Melvin Lee Kiang
Division of Medical Sciences, National Cancer Centre Singapore, Singapore 168583, Singapore.
Department of Radiation Oncology, Jiangxi Cancer Hospital, Jiangxi 330029, China.
Cell Rep Med. 2025 Jun 17;6(6):102143. doi: 10.1016/j.xcrm.2025.102143. Epub 2025 May 23.
We investigate the molecular landscape of locally advanced nasopharyngeal carcinoma (LA-NPC) subtypes: limited (L), ascending (A), descending (D), and ascending-descending (AD). Using a cohort of 994 patients, we perform germline and somatic whole-exome sequencing (WES), transcriptomic profiling, multiplex immunohistochemistry (mIHC), and spatial histopathological analyses of tumor whole-slide images (WSIs). Germline WES reveals the most variants in AD subtypes, but somatic WES shows no subtype-specific mutations. Transcriptomics reveals higher extracellular matrix (ECM) gene expression in A and AD subtypes and higher immune gene expression in D and AD subtypes, agreeing with deconvolution and mIHC. Tumor immune microenvironment (TIME) of node-negative (N0) and node-positive (N+) L subtypes, considered early nasopharyngeal carcinoma (NPC), resembles A and D subtypes, respectively, suggesting distinct evolutionary trajectories. Spatial WSI analyses identify the most immune-dense tumors among D subtypes and association of TIME with disease-free survival in AD subtypes. These findings highlight the TIME's role in LA-NPC progression and its potential impact on treatment strategies.
我们研究了局部晚期鼻咽癌（LA-NPC）亚型的分子格局：局限型（L）、上行型（A）、下行型（D）和上下行型（AD）。我们对994例患者进行了队列研究，开展了种系和体细胞全外显子组测序（WES）、转录组分析、多重免疫组化（mIHC）以及肿瘤全切片图像（WSI）的空间组织病理学分析。种系WES显示AD亚型中的变异最多，但体细胞WES未显示出亚型特异性突变。转录组学显示A和AD亚型中细胞外基质（ECM）基因表达较高，D和AD亚型中免疫基因表达较高，这与反卷积和mIHC结果一致。被视为早期鼻咽癌（NPC）的淋巴结阴性（N0）和淋巴结阳性（N+）L亚型的肿瘤免疫微环境（TIME）分别类似于A和D亚型，提示不同的进化轨迹。空间WSI分析确定D亚型中免疫密度最高的肿瘤以及AD亚型中TIME与无病生存期的关联。这些发现突出了TIME在LA-NPC进展中的作用及其对治疗策略的潜在影响。
