Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma
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 ap...
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MDPI AG
2021-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/11/2586 |
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| author | Chinthalapally V. Rao Chao Xu Mudassir Farooqui Yuting Zhang Adam S. Asch Hiroshi Y. Yamada |
| author_facet | Chinthalapally V. Rao Chao Xu Mudassir Farooqui Yuting Zhang Adam S. Asch Hiroshi Y. Yamada |
| author_sort | Chinthalapally V. Rao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T11:04:09Z |
| format | Article |
| id | doaj.art-28ee9a265f084bedb5ba8b04830c15cd |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T11:04:09Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-28ee9a265f084bedb5ba8b04830c15cd2023-11-21T21:17:32ZengMDPI AGCancers2072-66942021-05-011311258610.3390/cancers13112586Survival-Critical Genes Associated with Copy Number Alterations in Lung AdenocarcinomaChinthalapally V. Rao0Chao Xu1Mudassir Farooqui2Yuting Zhang3Adam S. Asch4Hiroshi Y. Yamada5Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK 73104, USAHudson College of Public Health, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK 73104, USADepartment of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USACenter for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK 73104, USAStephenson Cancer Center, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK 73104, USACenter for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK 73104, USAChromosome 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.https://www.mdpi.com/2072-6694/13/11/2586genomic instabilitylung tumortumor heterogeneitytumor genomics |
| spellingShingle | Chinthalapally V. Rao Chao Xu Mudassir Farooqui Yuting Zhang Adam S. Asch Hiroshi Y. Yamada Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma Cancers genomic instability lung tumor tumor heterogeneity tumor genomics |
| title | Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma |
| title_full | Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma |
| title_fullStr | Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma |
| title_full_unstemmed | Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma |
| title_short | Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma |
| title_sort | survival critical genes associated with copy number alterations in lung adenocarcinoma |
| topic | genomic instability lung tumor tumor heterogeneity tumor genomics |
| url | https://www.mdpi.com/2072-6694/13/11/2586 |
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