Abstract 5003: Gene expression to copy number alterations analysis in colorectal cancers: Organ specificity of transcriptomic impact on copy number alterations
Authors: Rao Chinthalapally V. , Xu Chao , Zhang Yuting , Asch Adam S. , Yamada Hiroshi Y. 
Published: June 2022

Background: Colorectal cancers (CRCs) is the third most commonly diagnosed cancer and the second most lethal cancer worldwide. CRCs carry high degrees of genomic instability (GI), which enables cancer evolution and makes prognosis poorer. Thus, GI is an exploitable target for therapy purposes. GI can be caused by gene mutation, alteration in gene expression, epigenetic modification, and other infectious or environmental factors. Several mutated genes involved in Chromosome instability and/or microsatellite instability have been identified. Yet it has not been technically feasible to modify functions of mutated genes (e.g., APC, TP53). From the drug development’ standpoint, inhibition of over-expressed target gene is preferred. However, specific genes involved in GI via expression alterations in CRCs have not been comprehensively identified. The gap in knowledge hinders development of CRC therapies targeting GI in CRC. In a previous study, we developed a data mining strategy (Gene Expression to Copy Number Alterations; “GE-CNA”) and comprehensively identified 1,578 genes that associate with CNA in lung adenocarcinoma, among which 39 were survival-critical (i.e., expression levels correlate with significant differences in patients’ survival).

Rationale: Causal genes for GI via expressions have not been comprehensively identified in CRCs. Thus, the mechanistic understanding of GI generation in CRC remains incomplete. Few attempts have been made to understand the organ-specificity of genomic instability in cancer.

Main Results: We applied the GE-CNA approach to 592 TCGA CRC datasets, and identified 513 genes whose expression levels associate with CNA. Among these, 27 were survival-critical. Comparison with previous results from lung adenocarcinoma indicated striking differences between lung adenocarcinoma and CRC: (a) overall CNA numbers are higher in lung adenocarcinoma than CRC in all stages, (b) 262 CRC-CNA facilitator genes did not show significant concentration in a specific pathway, and (c) 251 CRC-CNA suppressor genes are concentrated in the following pathways: Interferon Signaling, Antigen Presentation Pathway, Heme Biosynthesis II, Natural Killer Cell Signaling, Retinoic acid Mediated Apoptosis Signaling, JAK/Stat Signaling, Glucocorticoid Receptor Signaling, Heme Biosynthesis from Uroporphyrinogen-III I, and Glutathione Redox Reactions II.

Implications: The 27 survival-critical genomic instability genes are potential targets to suppress CRC genomic instability and therefore are targets for CRC drug development. Causal genes for genomic instability via expressions differ among organs. Hence, the “targeting genomic instability and/or aneuploidy” approach will need to be tailored for the specific target organ.

Citation Format: Chinthalapally V. Rao, Chao Xu, Yuting Zhang, Adam S. Asch, Hiroshi Y. Yamada. Gene expression to copy number alterations analysis in colorectal cancers: Organ specificity of transcriptomic impact on copy number alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5003.