Genomic instability genes in lung and colon adenocarcinoma indicate organ specificity of transcriptomic impact on Copy Number Alterations

Chinthalapally V Rao; Chao Xu; Yuting Zhang; Adam S Asch; Hiroshi Y Yamada

doi:10.1038/s41598-022-15692-8

Genomic instability genes in lung and colon adenocarcinoma indicate organ specificity of transcriptomic impact on Copy Number Alterations

Sci Rep. 2022 Jul 11;12(1):11739. doi: 10.1038/s41598-022-15692-8.

Authors

Chinthalapally V Rao^{1

2

3}, Chao Xu^{4

5}, Yuting Zhang^{6

7}, Adam S Asch^{8

9}, Hiroshi Y Yamada^{10

11

12}

Affiliations

¹ Department of Medicine, Hematology/Oncology Section, Center for Cancer Prevention and Drug Development, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA. cv-rao@ouhsc.edu.
² Stephenson Cancer Center, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA. cv-rao@ouhsc.edu.
³ , 975 NE 10th St., BRC1203, Oklahoma City, OK, 73104, USA. cv-rao@ouhsc.edu.
⁴ Hudson College of Public Health, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA.
⁵ , 801 Northeast 13th Street, Room 321, P.O. Box 26901, Oklahoma City, OK, 73190, USA.
⁶ Department of Medicine, Hematology/Oncology Section, Center for Cancer Prevention and Drug Development, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA.
⁷ , 975 NE 10th St. BRC1209, Oklahoma City, OK, 73104, USA.
⁸ Stephenson Cancer Center, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA.
⁹ , 800 NE 10th St., 6th Floor, Oklahoma City, OK, 73104, USA.
¹⁰ Department of Medicine, Hematology/Oncology Section, Center for Cancer Prevention and Drug Development, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA. hiroshi-yamada@ouhsc.edu.
¹¹ Stephenson Cancer Center, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA. hiroshi-yamada@ouhsc.edu.
¹² , 975 NE 10th St., BRC1207, Oklahoma City, OK, 73104, USA. hiroshi-yamada@ouhsc.edu.

Abstract

Genomic instability (GI) in cancer facilitates cancer evolution and is an exploitable target for therapy purposes. However, specific genes involved in cancer GI remain elusive. Causal genes for GI via expressions have not been comprehensively identified in colorectal cancers (CRCs). To fill the gap in knowledge, we developed a data mining strategy (Gene Expression to Copy Number Alterations; "GE-CNA"). Here we applied the GE-CNA approach to 592 TCGA CRC datasets, and identified 500 genes whose expression levels associate with CNA. Among these, 18 were survival-critical (i.e., expression levels correlate with significant differences in patients' survival). Comparison with previous results indicated striking differences between lung adenocarcinoma and CRC: (a) less involvement of overexpression of mitotic genes in generating genomic instability in the colon and (b) the presence of CNA-suppressing pathways, including immune-surveillance, was only partly similar to those in the lung. Following 13 genes (TIGD6, TMED6, APOBEC3D, EP400NL, B3GNT4, ZNF683, FOXD4, FOXD4L1, PKIB, DDB2, MT1G, CLCN3, CAPS) were evaluated as potential drug development targets (hazard ratio [> 1.3 or < 0.5]). Identification of specific CRC genomic instability genes enables researchers to develop GI targeting approach. The new results suggest that the "targeting genomic instability and/or aneuploidy" approach must be tailored for specific organs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma* / genetics
Adenocarcinoma* / pathology
Colonic Neoplasms* / genetics
Colorectal Neoplasms* / genetics
DNA Copy Number Variations
Genomic Instability
Humans
Lung / pathology
Organ Specificity
Transcriptome

Grants and funding

P30 CA225520/CA/NCI NIH HHS/United States