The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Thorac Cancer. 2022 May;13(9):1333-1341. doi: 10.1111/1759-7714.14393. Epub 2022 Apr 8.
Starting with low metastatic capability, T4N0M0 (diameter ≥ 7 cm) non-small cell lung cancers (NSCLCs) constitute a unique tumor subset, as with a large tumor size but no regional or distant metastases. We systematically investigated intratumoral heterogeneity, clonal structure, chromosomal instability (CIN), and immune microenvironment in T4N0M0 (≥7 cm) NSCLCs.
Whole-exome sequencing, RNA sequencing, and multiplex immunohistochemistry (mIHC) staining were conducted to analyze 24 spatially segregated tumor samples from eight patients who were pathologically diagnosed with T4N0M0 (diameter ≥ 7 cm) NSCLCs. The adjacent normal tissues and peripheral blood served as controls.
In total, 35.2% of mutations and 91.1% of somatic copy number alterations were classified as subclonal events, which exhibited widespread genetic intratumoral heterogeneity. In contrast, a low degree of CIN was observed. None of the patients had genome doubling. The burden of loss of heterozygosity, aneuploidy, and the genome instability index of these tumors were significantly lower than those in the TRACERx cohort. Expression profiles revealed significantly upregulated expression of cell division-related signals and the G2/M checkpoint pathway. In addition, a similar expression pattern of the immune microenvironment was observed in different regions of the tumor, which was confirmed by mIHC profiles.
Our study indicates the presence of intratumoral genetic heterogeneity and immune microenvironmental heterogeneity features in T4N0M0 NSCLCs, and the low degree of CIN may be related to the low metastatic capability.
从低转移性能力开始，T4N0M0（直径≥7cm）非小细胞肺癌（NSCLC）构成了一个独特的肿瘤亚群，因为肿瘤体积大，但没有局部或远处转移。我们系统地研究了 T4N0M0（≥7cm）NSCLC 中的肿瘤内异质性、克隆结构、染色体不稳定性（CIN）和免疫微环境。
对 8 名病理诊断为 T4N0M0（直径≥7cm）NSCLC 的患者的 24 个空间分离的肿瘤样本进行了全外显子组测序、RNA 测序和多重免疫组化（mIHC）染色。相邻的正常组织和外周血作为对照。
共有 35.2%的突变和 91.1%的体细胞拷贝数改变被归类为亚克隆事件，表现出广泛的肿瘤内遗传异质性。相反，观察到低度 CIN。没有患者发生基因组倍增。这些肿瘤的杂合性缺失负担、非整倍体和基因组不稳定性指数明显低于 TRACERx 队列。表达谱显示细胞分裂相关信号和 G2/M 检查点途径的表达显著上调。此外，不同肿瘤区域的免疫微环境表达模式相似，这通过 mIHC 谱得到了证实。
我们的研究表明，T4N0M0 NSCLC 存在肿瘤内遗传异质性和免疫微环境异质性特征，低度 CIN 可能与低转移性能力有关。
