Rao Chinthalapally V, Xu Chao, Farooqui Mudassir, Zhang Yuting, Asch Adam S, Yamada Hiroshi Y
Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK 73104, USA.
Stephenson Cancer Center, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK 73104, USA.
Cancers (Basel). 2021 May 25;13(11):2586. doi: 10.3390/cancers13112586.
Chromosome Instability (CIN) in tumors affects carcinogenesis, drug resistance, and recurrence/prognosis. Thus, it has a high impact on outcomes in clinic. However, how CIN occurs in human tumors remains elusive. Although cells with CIN (i.e., pre/early cancer cells) are proposed to be removed by apoptosis and/or a surveillance mechanism, this surveillance mechanism is poorly understood. Here we employed a novel data-mining strategy (Gene Expression to Copy Number Alterations [CNA]; "GE-CNA") to comprehensively identify 1578 genes that associate with CIN, indicated by genomic CNA as its surrogate marker, in human lung adenocarcinoma. We found that (a) amplification/insertion CNA is facilitated by over-expressions of DNA replication stressor and suppressed by a broad range of immune cells (T-, B-, NK-cells, leukocytes), and (b) deletion CNA is facilitated by over-expressions of mitotic regulator genes and suppressed predominantly by leukocytes guided by leukocyte extravasation signaling. Among the 39 CNA- and survival-associated genes, the purine metabolism (PPAT, PAICS), immune-regulating CD4-LCK-MEC2C and CCL14-CCR1 axes, and ALOX5 emerged as survival-critical pathways. These findings revealed a broad role of the immune system in suppressing CIN/CNA and cancer development in lung, and identified components representing potential targets for future chemotherapy, chemoprevention, and immunomodulation approaches for lung adenocarcinoma.
肿瘤中的染色体不稳定（CIN）影响肿瘤发生、耐药性以及复发/预后。因此，它对临床结局有很大影响。然而，CIN在人类肿瘤中如何发生仍不清楚。尽管有人提出具有CIN的细胞（即癌前/早期癌细胞）会通过凋亡和/或监测机制被清除，但这种监测机制仍知之甚少。在这里，我们采用了一种新颖的数据挖掘策略（基因表达与拷贝数改变 [CNA]；“GE-CNA”），以全面鉴定1578个与CIN相关的基因，基因组CNA作为其替代标志物，这些基因存在于人类肺腺癌中。我们发现：（a）DNA复制应激因子的过表达促进扩增/插入CNA，而多种免疫细胞（T细胞、B细胞、NK细胞、白细胞）则抑制这种扩增/插入CNA；（b）有丝分裂调节基因的过表达促进缺失CNA，而主要由白细胞外渗信号引导的白细胞抑制这种缺失CNA。在39个与CNA和生存相关的基因中，嘌呤代谢（PPAT、PAICS）、免疫调节性CD4-LCK-MEC2C和CCL14-CCR1轴以及ALOX5成为生存关键途径。这些发现揭示了免疫系统在抑制肺中CIN/CNA和癌症发展方面的广泛作用，并确定了代表未来肺腺癌化疗、化学预防和免疫调节方法潜在靶点的成分。
