Clinical Omics Analysis of Colorectal Cancer Incorporating Copy Number Aberrations and Gene Expression Data

Abstract

Background:Colorectal cancer (CRC) is one of the most frequently occurring cancers in Japan, and thus a wide range of methods have been deployed to study the molecular mechanisms of CRC. In this study, we performed a comprehensive analysis of CRC, incorporating copy number aberration (CRC) and gene expression data. For the last four years, we have been collecting data from CRC cases and organizing the information as an “omics” study by integrating many kinds of analysis into a single comprehensive investigation.In our previous studies, we had experienced difficulty in finding genes related to CRC, as we observed higher noise levels in the expression data than in the data for other cancers.Because chromosomal aberrations are often observed in CRC, here, we have performed a combination of CNA analysis and expression analysis in order to identify some new genes responsible for CRC.This study was performed as part of the Clinical Omics Database Project at Tokyo Medical and Dental University. The purpose of this study was to investigate the mechanism of genetic instability in CRC by this combination of expression analysis and CNA, and to establish a new method for the diagnosis and treatment of CRC.Materials and methods:Comprehensive gene expression analysis was performed on 79 CRC cases using an Affymetrix Gene Chip, and comprehensive CNA analysis was performed using an Affymetrix DNA Sty array. To avoid the contamination of cancer tissue with normal cells, laser micro-dissection was performed before DNA/RNA extraction. Data analysis was performed using original software written in the R language.Result:We observed a high percentage of CNA in colorectal cancer, including copy number gains at 7, 8q, 13 and 20q, and copy number losses at 8p, 17p and 18. Gene expression analysis provided many candidates for CRC-related genes, but their association with CRC did not reach the level of statistical significance. The combination of CNA and gene expression analysis, together with the clinical information, suggested UGT2B28, LOC440995, CXCL6, SULT1B1, RALBP1, TYMS, RAB12, RNMT, ARHGDIB, S1000A2, ABHD2, OIT3 and ABHD12 as genes that are possibly associated with CRC. Some of these genes have already been reported as being related to CRC. TYMS has been reported as being associated with resistance to the anti-cancer drug 5-fluorouracil, and we observed a copy number increase for this gene. RALBP1, ARHGDIB and S100A2 have been reported as oncogenes, and we observed copy number increases in each. ARHGDIB has been reported as a metastasis-related gene, and our data also showed copy number increases of this gene in cases with metastasis.Conclusion:The combination of CNA analysis and gene expression analysis was a more effective method for finding genes associated with the clinicopathological classification of CRC than either analysis alone. Using this combination of methods, we were able to detect genes that have already been associated with CRC. We also identified additional candidate genes that may be new markers or targets for this ...

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“…High expression of RAB12 on chromosome 18p11.22 is associated with poor DFS. RAB12 is a Ras oncogene family member and is overexpressed in colorectal cancers (44). Furthermore, the COLEC12 gene is known prognostic marker in anaplastic thyroid cancer and brain tumors (45,46).…”

Somatic gene copy number alterations in colorectal cancer: new quest for cancer drivers and biomarkers

“…Deletion and downregulation of UGT2B28 (located on 4q13.2) may facilitate CRC progression, and inhibition of both SULT1B1 (located on 4q13.3) and UGT2B28 may contribute to the dedifferentiation processes during colorectal carcinogenesis. 72 Moreover, PPAT (located on 4q21), RG9MTD2 (4q23) and the low expression of PLA2G12A (4q25) may also be involved in CRC. 69…”

“…67,68 Other chromosome loci with gene gains in 20q related to CRC contain confirmed oncogenes such as 20q11.23 (SRC and CTNNBL1), 20q11.21-20q11.22 (DNMT3B) and 20q11.22 (DYNLRB1), 26 20q13 (SERPINB5), 69 20q11-13 (SRC, MAFB, TOP1 and GNAS), 70 22q12.3 (APOL6) 71 and 20p11.21 (ABHD12). 72 Efforts have also been made to exclude genes from the set of potential cancer drivers in the 20q amplicon. As an example, BCL2L1 seems to be functionally involved in several CRC-related processes, and its protein expression is associated with 20q gain.…”

“…129 ARHGDIB located at the same region shows copy number loss and low expression in the study. 72 It regulates the tumor-related gene cyclooxygenase (COX2) that is correlated with cancer development by activating the NFAT1 (nuclear factor of activated T cells 1). As an inhibitor of Rho GTPase, ARHGDIB has been found to affect the distant metastasis of CRC.…”