Cargando…

Linear and non-linear dependencies between copy number aberrations and mRNA expression reveal distinct molecular pathways in breast cancer

BACKGROUND: Elucidating the exact relationship between gene copy number and expression would enable identification of regulatory mechanisms of abnormal gene expression and biological pathways of regulation. Most current approaches either depend on linear correlation or on nonparametric tests of asso...

Descripción completa

Detalles Bibliográficos
Autores principales: Solvang, Hiroko K, Lingjærde, Ole Christian, Frigessi, Arnoldo, Børresen-Dale, Anne-Lise, Kristensen, Vessela N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128865/
https://www.ncbi.nlm.nih.gov/pubmed/21609452
http://dx.doi.org/10.1186/1471-2105-12-197
_version_ 1782207482821607424
author Solvang, Hiroko K
Lingjærde, Ole Christian
Frigessi, Arnoldo
Børresen-Dale, Anne-Lise
Kristensen, Vessela N
author_facet Solvang, Hiroko K
Lingjærde, Ole Christian
Frigessi, Arnoldo
Børresen-Dale, Anne-Lise
Kristensen, Vessela N
author_sort Solvang, Hiroko K
collection PubMed
description BACKGROUND: Elucidating the exact relationship between gene copy number and expression would enable identification of regulatory mechanisms of abnormal gene expression and biological pathways of regulation. Most current approaches either depend on linear correlation or on nonparametric tests of association that are insensitive to the exact shape of the relationship. Based on knowledge of enzyme kinetics and gene regulation, we would expect the functional shape of the relationship to be gene dependent and to be related to the gene regulatory mechanisms involved. Here, we propose a statistical approach to investigate and distinguish between linear and nonlinear dependences between DNA copy number alteration and mRNA expression. RESULTS: We applied the proposed method to DNA copy numbers derived from Illumina 109 K SNP-CGH arrays (using the log R values) and expression data from Agilent 44 K mRNA arrays, focusing on commonly aberrated genomic loci in a collection of 102 breast tumors. Regression analysis was used to identify the type of relationship (linear or nonlinear), and subsequent pathway analysis revealed that genes displaying a linear relationship were overall associated with substantially different biological processes than genes displaying a nonlinear relationship. In the group of genes with a linear relationship, we found significant association to canonical pathways, including purine and pyrimidine metabolism (for both deletions and amplifications) as well as estrogen metabolism (linear amplification) and BRCA-related response to damage (linear deletion). In the group of genes displaying a nonlinear relationship, the top canonical pathways were specific pathways like PTEN and PI13K/AKT (nonlinear amplification) and Wnt(B) and IL-2 signalling (nonlinear deletion). Both amplifications and deletions pointed to the same affected pathways and identified cancer as the top significant disease and cell cycle, cell signaling and cellular development as significant networks. CONCLUSIONS: This paper presents a novel approach to assessing the validity of the dependence of expression data on copy number data, and this approach may help in identifying the drivers of carcinogenesis.
format Online
Article
Text
id pubmed-3128865
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-31288652011-07-04 Linear and non-linear dependencies between copy number aberrations and mRNA expression reveal distinct molecular pathways in breast cancer Solvang, Hiroko K Lingjærde, Ole Christian Frigessi, Arnoldo Børresen-Dale, Anne-Lise Kristensen, Vessela N BMC Bioinformatics Research Article BACKGROUND: Elucidating the exact relationship between gene copy number and expression would enable identification of regulatory mechanisms of abnormal gene expression and biological pathways of regulation. Most current approaches either depend on linear correlation or on nonparametric tests of association that are insensitive to the exact shape of the relationship. Based on knowledge of enzyme kinetics and gene regulation, we would expect the functional shape of the relationship to be gene dependent and to be related to the gene regulatory mechanisms involved. Here, we propose a statistical approach to investigate and distinguish between linear and nonlinear dependences between DNA copy number alteration and mRNA expression. RESULTS: We applied the proposed method to DNA copy numbers derived from Illumina 109 K SNP-CGH arrays (using the log R values) and expression data from Agilent 44 K mRNA arrays, focusing on commonly aberrated genomic loci in a collection of 102 breast tumors. Regression analysis was used to identify the type of relationship (linear or nonlinear), and subsequent pathway analysis revealed that genes displaying a linear relationship were overall associated with substantially different biological processes than genes displaying a nonlinear relationship. In the group of genes with a linear relationship, we found significant association to canonical pathways, including purine and pyrimidine metabolism (for both deletions and amplifications) as well as estrogen metabolism (linear amplification) and BRCA-related response to damage (linear deletion). In the group of genes displaying a nonlinear relationship, the top canonical pathways were specific pathways like PTEN and PI13K/AKT (nonlinear amplification) and Wnt(B) and IL-2 signalling (nonlinear deletion). Both amplifications and deletions pointed to the same affected pathways and identified cancer as the top significant disease and cell cycle, cell signaling and cellular development as significant networks. CONCLUSIONS: This paper presents a novel approach to assessing the validity of the dependence of expression data on copy number data, and this approach may help in identifying the drivers of carcinogenesis. BioMed Central 2011-05-24 /pmc/articles/PMC3128865/ /pubmed/21609452 http://dx.doi.org/10.1186/1471-2105-12-197 Text en Copyright ©2011 Solvang et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Solvang, Hiroko K
Lingjærde, Ole Christian
Frigessi, Arnoldo
Børresen-Dale, Anne-Lise
Kristensen, Vessela N
Linear and non-linear dependencies between copy number aberrations and mRNA expression reveal distinct molecular pathways in breast cancer
title Linear and non-linear dependencies between copy number aberrations and mRNA expression reveal distinct molecular pathways in breast cancer
title_full Linear and non-linear dependencies between copy number aberrations and mRNA expression reveal distinct molecular pathways in breast cancer
title_fullStr Linear and non-linear dependencies between copy number aberrations and mRNA expression reveal distinct molecular pathways in breast cancer
title_full_unstemmed Linear and non-linear dependencies between copy number aberrations and mRNA expression reveal distinct molecular pathways in breast cancer
title_short Linear and non-linear dependencies between copy number aberrations and mRNA expression reveal distinct molecular pathways in breast cancer
title_sort linear and non-linear dependencies between copy number aberrations and mrna expression reveal distinct molecular pathways in breast cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128865/
https://www.ncbi.nlm.nih.gov/pubmed/21609452
http://dx.doi.org/10.1186/1471-2105-12-197
work_keys_str_mv AT solvanghirokok linearandnonlineardependenciesbetweencopynumberaberrationsandmrnaexpressionrevealdistinctmolecularpathwaysinbreastcancer
AT lingjærdeolechristian linearandnonlineardependenciesbetweencopynumberaberrationsandmrnaexpressionrevealdistinctmolecularpathwaysinbreastcancer
AT frigessiarnoldo linearandnonlineardependenciesbetweencopynumberaberrationsandmrnaexpressionrevealdistinctmolecularpathwaysinbreastcancer
AT børresendaleannelise linearandnonlineardependenciesbetweencopynumberaberrationsandmrnaexpressionrevealdistinctmolecularpathwaysinbreastcancer
AT kristensenvesselan linearandnonlineardependenciesbetweencopynumberaberrationsandmrnaexpressionrevealdistinctmolecularpathwaysinbreastcancer