title: Frequent occurrence of uniparental disomy in colorectal cancer.
abstract: We used SNP arrays to identify and characterize genomic alterations associated with colorectal cancer (CRC). Laser microdissected cancer cells from 15 adenocarinomas were investigated by Affymetrix Mapping 10K SNP arrays. Analysis of the data extracted from the SNP arrays revealed multiple regions with copy number alterations and loss of heterozygosity (LOH). Novel LOH areas were identified at chromosomes 13, 14 and 15. Combined analysis of the LOH and copy number data revealed genomic structures that could not have been identified analyzing either data type alone. Half of the identified LOH regions showed no evidence of a reduced copy number, indicating the presence of uniparental structures. The distribution of these structures was non-random, primarily involving 8q, 13q and 20q. This finding was supported by analysis of an independent set of array-based transcriptional profiles, consisting of 17 normal mucosa and 66 adenocarcinoma samples. The transcriptional analysis revealed an unchanged expression level in areas with intact copy number, including regions with uniparental disomy, and a reduced expression level in the LOH regions representing factual losses (including 5q, 8p and 17p). The analysis also showed that genes in regions with increased copy number (including 7p and 20q) were predominantly upregulated. Further analyses of the SNP data revealed a subset of the identified alterations to be specifically associated with TP53 inactivation (including 8q gain and 17p loss) and lymph node metastasis status (gain of 7q and 13q). Another subset of the identified alterations was shown to represent intratumor heterogeneity. In conclusion, we demonstrate that uniparental disomy is frequent in CRC, and identify genomic alterations associated with TP53 inactivation and lymph node status.
authors.affiliation: Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Skejby DK-8200, Aarhus N, Denmark.
authors.forename: Claus Lindbjerg
authors.initials: CL
authors.lastname: Andersen
authors.forename: Carsten
authors.initials: C
authors.lastname: Wiuf
authors.forename: Mogens
authors.initials: M
authors.lastname: Kruhøffer
authors.forename: Marianne
authors.initials: M
authors.lastname: Korsgaard
authors.forename: Søren
authors.initials: S
authors.lastname: Laurberg
authors.forename: Torben Falck
authors.initials: TF
authors.lastname: Ørntoft
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000235:genetics*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018628:Gene Dosage; D023281:Genomics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D019656:Loss of Heterozygosity; D008207:Lymphatic Metastasis / Q000473:pathology; D018895:Microsatellite Repeats; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D024182:Uniparental Disomy / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016159:Tumor Suppressor Protein p53