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Integrative Genomics Reveals Mechanisms of Copy Number Alterations Responsible for Transcriptional Deregulation in Colorectal Cancer

ABSTRACT: To evaluate the mechanisms and consequences of chromosomal aberrations in colorectal cancer (CRC), we used a combination of spectral karyotyping, array comparative genomic hybridization (aCGH), and array-based global gene expression profiling on 31 primary carcinomas and 15 established cell lines. Importantly, aCGH showed that the genomic profiles of primary tumors are recapitulated in the cell lines. We revealed a preponderance of chromosome breakpoints at sites of copy number variants (CNVs) in the CRC cell lines, a novel mechanism of DNA breakage in cancer. The integration of gene expression and aCGH led to the identification of 157 genes localized within high-level copy number changes whose transcriptional deregulation was significantly affected across all of the samples, thereby suggesting that these genes play a functional role in CRC. Genomic amplification at 8q24 was the most recurrent event and led to the overexpression of MYC and FAM84B. Copy number dependent gene expression resulted in deregulation of known cancer genes such as APC, FGFR2, and ERBB2. The identification of only 36 genes whose localization near a breakpoint could account for their observed deregulated expression demonstrates that the major mechanism for transcriptional deregulation in CRC is genomic copy number changes resulting from chromosomal aberrations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE126053 | GEO | 2019/02/05

REPOSITORIES: GEO

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Project description:Human colorectal cancer (CRC) cell lines are a used widely-used to model system for investigation investigate of tumour biology, experimental therapytherapeutic and biomarkers discovery. However, to what extent these established CRC cell lines represent and maintain the genetic diversity of primary cancers is uncertain. In this study, we analyzed 70 CRC cell lines were analysed for mutations using whole exome sequencing and DNA copy-number using by whole-exome sequencing and SNP microarray profilings, respectively. Presence of gGene expression was defined using RNA-Seq. Data from cellCell line datas were was compared to those that published from for primary CRCs published by in The the Cancer Genome Atlas Network. Notably, we found that The spectrum of exome mutations and DNA copy-number aberrations spectra in 70 CRC cell lines closely resembled those seen inat of primary colorectal tumours. Similarities included the presence of at least two hypermutation phenotypes, as defined by signatures of for defective DNA mismatch repair and DNA polymerase ? (POLE) proof-reading deficiency, and along with concordant mutation profiles in the broadly altered WNT, MAPK, PI3K, TGF? and p53 pathways. In additionFurther, we documented mutations were enriched in genes involved in chromatin remodelling (ARID1A, CHD6, SRCAP) and histone methylation or acetylation (ASH1L, EP300, EP400, MLL2, MLL3, PRDM2, TRRAP). Chromosomal instability was prevalent in non-hypermutated cases, with similar patterns of whole, partial and focal chromosomal aberrations and overlapping significant minimal regions ofchromosomal gains and losses. While paired cell lines derived from the same tumour were found to exhibited considerable mutation and DNA copy-number differences, in silico simulations suggest that these differenceslargely mainly reflected a pre-existing heterogeneity in the tumour cells heterogeneity. In conclusion, our results establish that human CRC lines are representative of the main subtypes of primary tumours at the genomic level, further validating underscoring their utility as tools for to investigating investigate CRC biology and drug responses. 69 colorectal cancer cell lines were analysed for DNA copy number profiles.

Project description:Chromosomal instable colorectal cancer is marked by specific large chromosomal copy number aberrations. Recently, focal aberrations of 3Mb or smaller have been identified as a common phenomenon in cancer. Inherent to their limited size, these aberrations harbour one or few genes. The aim of this study is to identify recurrent focal chromosomal aberrations and their candidate driver genes in a well defined series of stage II colon cancers and assess their potential clinical relevance. High resolution DNA copy number profiles were obtained from 38 formalin fixed paraffin embedded colon cancer samples with matched normal mucosa as a reference using array comparative genomic hybridization. In total, 81 focal chromosomal aberrations were identified that harboured 177 genes. Statistical validation of focal aberrations and identification of candidate driver genes was performed by enrichment analysis and mapping copy number and mutation data of colorectal-, breast-, pancreatic cancer and glioblastomas to loci of focal aberrations in stage II colon cancer. This analysis demonstrated a significant overlap with previously identified focal amplifications in colorectal cancer, but not with cancers from other sites. In contrast, focal deletions seem less tumour type specific since they also show significant overlap with focal deletions of other sites. Focal deletions detected are significantly enriched for cancer genes and genes frequently mutated in colorectal cancer. The mRNA expression of these genes is significantly correlated with DNA copy number status, supporting the relevance of focal aberrations. Loss of 5q34 and gain of 13q22.1 were identified as independent prognostic factors of survival in this series of patients. In conclusion, focal chromosomal copy number aberrations in stage II colon cancer are enriched in cancer genes which contribute to and drive the process of colorectal cancer development. DNA copy number status of these genes correlate with mRNA expression and some are associated with clinical outcome. 38 Stage II colorectal cancer (CRC) tissue samples (FFPE) of which 19 were done on expression arrays. One sample (Stage II colorectal cancer tissue samples (FFPE) 26) was also done on the 135K NimbleGen array. Fresh frozen and FFPE of the same CRC stage I sample was done on 105K agilent. The fresh frozen was across array in silico set out against a pool of blood of 18 healthy females.

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Integrative Genomics Reveals Mechanisms of Copy Number Alterations Responsible for Transcriptional Deregulation in Colorectal Cancer

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