Unknown,Transcriptomics,Genomics,Proteomics

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A Genome-wide Study of Cytogenetic Changes in Colorectal Cancer Using SNP Microarrays: Possibilities for Future Personalized Treatment

ABSTRACT: In colorectal cancer (CRC), chromosomal instability (CIN) is typically studied using comparative-genomic hybridization (CGH) arrays. We studied paired (tumor and surrounding healthy) fresh-frozen tissue from 86 CRC patients using Illumina’s Infinium-based SNP array. This method allowed us to study CIN in CRC, with simultaneous analysis of copy number (CN) and B-allele frequency (BAF), which is a representation of allelic composition. This data helped us to detect mono-allelic and bi-allelic amplifications/deletion, copy neutral loss of heterozygosity, and levels of mosaicism for mixed cell populations, some of which can not be assessed with other methods that do not measure BAF. We identified associations between CN abnormalities and different CRC phenotypes (MSI, histological diagnosis, location, tumor grade, stage, MSI and presence of lymph node metastasis). We showed commonalities between regions of CN change observed in CRC and the regions reported in previous studies of other solid cancers (e.g., amplifications of 20q, 13q, 8q, 5p and deletions of 18q, 17p and 8p). From the Therapeutic Target Database we found relevant drugs, targeted to the genes located in these regions with CN changes, approved or in trials for other cancers and common diseases. These drugs may be considered for future therapeutic trials in CRC, based on personalized cytogenetic diagnosis. We also found many regions harboring genes which are not currently targeted by any relevant drugs that may be considered for future drug discovery studies. Our study shows the application of high-density SNP arrays for cytogenetic study in CRC and its importance for personalized treatment. DNA was extracted from colon tissue samples provided by 86 CRC patients. Each patient provided paired CRC tumor tissue and adjacent normal colon mucosa samples, which were fresh-frozen after resection. Samples were genotyped using Illumina's Infinium-based 610 Quad and CytoSNP 12 microarray chips. The genotype data from paired tumor and normal samples was used to detect tumor-specific chromosomal instabilities in copy number, including copy-neutral LOH, which cannot be assessed by many other cytogenetic methods. Supplementary file "GSE34678_raw_GPL8887.txt" includes the raw data for Samples using GPL8887 (GSM853162-GSM853239); supplementary file "GSE34678_raw_GPL13829.txt" includes the raw data for Samples using GPL13829 (GSM853240-GSM853363).

ORGANISM(S): Homo sapiens

SUBMITTER: Muhammad Kibriya

PROVIDER: E-GEOD-34678 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

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A Genome-wide Study of Cytogenetic Changes in Colorectal Cancer Using SNP Microarrays: Possibilities for Future Personalized Treatment

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