Jiang Jiahong, Xu Yaping, Chang Lianpeng, Ru Guoqing, Xia Xuefeng, Yang Ling, Yi Xin, Chen Zheling, Huang Dong-Sheng, Yang Liu
Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
Department of Oncology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
Front Oncol. 2021 Oct 18;11:771247. doi: 10.3389/fonc.2021.771247. eCollection 2021.
As a main component of the tumor microenvironment, the stroma is critical in development, progression, and metastasis of pancreatic ductal adenocarcinoma (PDAC). The genomic status and its relationship of neoplastic and stromal components remain unclear in PDAC. We performed targeted sequencing for 1,021 cancer-suspected genes on parallel microdissected stromal and neoplastic components from 50 operable PDAC patients. Clonality analysis of mutations was conducted to reconstruct the evolutionary trajectory, and then molecular subtypes were established. Multi-lineage differentiation potential and mesenchymal transformation of -mutant cell line Panc1 were evaluated using RT-PCR and immunofluorescence staining. In this study, 39 (78.0%) were genomically altered in stroma, with (71.8%), (61.5%), and (23.1%) as the most commonly mutated genes. The majority of stromal mutations (89.8%) were detected in matched neoplastic components. Patients with -mut stroma demonstrated a higher tumor cell fraction (TCF) than did those with wild-type (WT) stroma ( = 0.0371, = 0.0014). In both components, mutants and often occurred as clonal events, and the allele frequencies presented linear correlation in the same specimen. All neoplasm-like stroma (characterized with all or initial neoplastic clones and driver events in stroma) harbored or mutations. Neoplasm-like and -mutant stroma was associated with shorter disease-free survival. It is a new finding for the existence of driver gene mutations in PDAC stroma. These data suggest that genomic features of stromal components may serve as prognostic biomarkers in resectable PDAC and might help to guide a more precise treatment paradigm in therapeutic options.
作为肿瘤微环境的主要组成部分，基质在胰腺导管腺癌（PDAC）的发生、发展和转移中起着关键作用。PDAC中肿瘤和基质成分的基因组状态及其关系仍不清楚。我们对50例可手术切除的PDAC患者的平行显微切割的基质和肿瘤成分中的1021个癌症疑似基因进行了靶向测序。对突变进行克隆性分析以重建进化轨迹，然后建立分子亚型。使用逆转录聚合酶链反应（RT-PCR）和免疫荧光染色评估突变细胞系Panc1的多谱系分化潜能和间充质转化。在本研究中，39例（78.0%）基质存在基因组改变，其中 （71.8%）、 （61.5%）和 （23.1%）为最常见的突变基因。大多数基质突变（89.8%）在匹配的肿瘤成分中被检测到。携带 -mut基质的患者比野生型（WT）基质患者表现出更高的肿瘤细胞分数（TCF）（ = 0.0371， = 0.0014）。在两种成分中，突变体 和 通常作为克隆事件发生，并且等位基因频率在同一样本中呈现线性相关。所有肿瘤样基质（以基质中所有或初始肿瘤克隆及驱动事件为特征）均携带 或 突变。肿瘤样和 -mutant基质与无病生存期缩短相关。PDAC基质中存在驱动基因突变是一项新发现。这些数据表明，基质成分的基因组特征可能作为可切除PDAC的预后生物标志物，并可能有助于在治疗选择中指导更精确的治疗模式。
