Song Myung Jin, Lee Sang Hoon, Kim Eun Young, Chang Yoon Soo
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
Transl Lung Cancer Res. 2020 Jun;9(3):659-669. doi: 10.21037/tlcr-19-589.
Intratumoral heterogeneity is a cause of drug resistance that leads to treatment failure. We investigated the clinical implication of intratumoral heterogeneity inferred from the number of subclones that constituted a tumor and reasoned the etiology of subclonal expansion using RNA sequencing data.
Simple nucleotide variation, clinical data, copy number variation, and RNA-sequencing data from 481 The Cancer Genome Atlas-Lung Squamous Cell Carcinoma (TCGA-LUSC) cases were obtained from the Genomic Data Commons data portal. Clonal status was estimated from the allele frequency of the mutated genes using the SciClone package.
The number of subclones that comprised a tumor had a positive correlation with the total mutations in a tumor (σ=0.477, P-value <0.001) and tumor stage (σ=0.111, P-value <0.015). Male LUSC tumors had a higher probability of having more subclones than female tumors (2.28 1.89, P-value =0.002, Welch Two Sample -test). On comparing the gene expression in the tumors that were comprised of five subclones with those of a single clone, 291 genes were found to be upregulated and 102 genes were found to be downregulated in the five subclone tumors. The upregulated genes included , , , , and , in order of magnitude of upregulation, and the biologic function of the upregulated genes was strongly enriched for the positive regulation of immune processes and inflammatory responses.
Male LUSC tumors were composed of a greater number of subclones than female tumors. The tumors with large numbers of subclones had overexpressed genes that positively regulated the immune processes and inflammatory responses more than tumors that consisted of a single clone.
肿瘤内异质性是导致耐药进而致使治疗失败的一个原因。我们利用RNA测序数据研究了从构成肿瘤的亚克隆数量推断出的肿瘤内异质性的临床意义，并对亚克隆扩增的病因进行了推理。
从基因组数据共享数据门户获取了481例癌症基因组图谱-肺鳞状细胞癌（TCGA-LUSC）病例的单核苷酸变异、临床数据、拷贝数变异和RNA测序数据。使用SciClone软件包根据突变基因的等位基因频率估计克隆状态。
构成肿瘤的亚克隆数量与肿瘤中的总突变数（σ=0.477，P值<0.001）和肿瘤分期（σ=0.111，P值<0.015）呈正相关。男性LUSC肿瘤比亚克隆数量较少的女性肿瘤具有更高的概率（2.28对1.89，P值=0.002，Welch双样本检验）。在比较由五个亚克隆组成的肿瘤与单个克隆组成的肿瘤中的基因表达时，发现五个亚克隆肿瘤中有291个基因上调，102个基因下调。上调的基因按上调幅度依次包括、、、、，上调基因的生物学功能在免疫过程和炎症反应的正调控方面显著富集。
男性LUSC肿瘤比女性肿瘤由更多数量的亚克隆组成。与由单个克隆组成的肿瘤相比，具有大量亚克隆的肿瘤具有更多正向调节免疫过程和炎症反应的过表达基因。
