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BMC Medical Genomics

, 4:85

Functional and structural genomics


BackgroundIn a cancer cell the number of copies of a locus may vary due to amplification and deletion and these variations are denoted as copy number alterations CNAs. We focus on the disparity of CNAs in tumour samples, which were compared to those in blood in order to identify the directional loss of heterozygosity.

MethodsWe propose a numerical algorithm and apply it to data from the Illumina 109K-SNP array on 112 samples from breast cancer patients. B-allele frequency BAF and log R ratio LRR of Illumina were used to estimate Euclidian distances. For each locus, we compared genotypes in blood and tumour for subset of samples being heterozygous in blood. We identified loci showing preferential disparity from heterozygous toward either the A-B-allele homozygous allelic disparity. The chi-squared and Cochran-Armitage trend tests were used to examine whether there is an association between high levels of disparity in single nucleotide polymorphisms SNPs and molecular, clinical and tumour-related parameters. To identify pathways and network functions over-represented within the resulting gene sets, we used Ingenuity Pathway Analysis IPA.

ResultsTo identify loci with a high level of disparity, we selected SNPs 1 with a substantial degree of disparity and 2 with substantial frequency at least 50% of the samples heterozygous for the respective locus. We report the overall difference in disparity in high-grade tumours compared to low-grade tumours p-value < 0.001 and significant associations between disparity in multiple single loci and clinical parameters. The most significantly associated network functions within the genes represented in the loci of disparity were identified, including lipid metabolism, small-molecule biochemistry, and nervous system development and function. No evidence for over-representation of directional disparity in a list of stem cell genes was obtained, however genes appeared to be more often altered by deletion than by amplification.

ConclusionsOur data suggest that directional loss and amplification exist in breast cancer. These are highly associated with grade, which may indicate that they are enforced with increasing number of cell divisions. Whether there is selective pressure for some loci to be preferentially amplified or deleted remains to be confirmed.

Electronic supplementary materialThe online version of this article doi:10.1186-1755-8794-4-85 contains supplementary material, which is available to authorized users.

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Autor: Fatemeh Kaveh - Hege Edvardsen - Anne-Lise Børresen-Dale - Vessela N Kristensen - Hiroko K Solvang


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