Data integration from two microarray platforms identifies bi-allelic genetic inactivation of RIC8A in a breast cancer cell line

Aslaug Aamodt Muggerud, Henrik Edgren, Maija Wolf, Kristine Kleivi, Emelyne Dejeux, Jörg Tost, Therese Sørlie (Corresponding Author), Olli Kallioniemi (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

8 Citations (Scopus)

Abstract

Background

Using array comparative genomic hybridization (aCGH), a large number of deleted genomic regions have been identified in human cancers. However, subsequent efforts to identify target genes selected for inactivation in these regions have often been challenging.

Methods

We integrated here genome-wide copy number data with gene expression data and non-sense mediated mRNA decay rates in breast cancer cell lines to prioritize gene candidates that are likely to be tumour suppressor genes inactivated by bi-allelic genetic events. The candidates were sequenced to identify potential mutations.

Results

This integrated genomic approach led to the identification of RIC8A at 11p15 as a putative candidate target gene for the genomic deletion in the ZR-75-1 breast cancer cell line. We identified a truncating mutation in this cell line, leading to loss of expression and rapid decay of the transcript. We screened 127 breast cancers for RIC8A mutations, but did not find any pathogenic mutations. No promoter hypermethylation in these tumours was detected either. However, analysis of gene expression data from breast tumours identified a small group of aggressive tumours that displayed low levels of RIC8A transcripts. qRT-PCR analysis of 38 breast tumours showed a strong association between low RIC8A expression and the presence of TP53 mutations (P = 0.006).

Conclusion

We demonstrate a data integration strategy leading to the identification of RIC8A as a gene undergoing a classical double-hit genetic inactivation in a breast cancer cell line, as well as in vivo evidence of loss of RIC8A expression in a subgroup of aggressive TP53 mutant breast cancers.

Original languageEnglish
Article number26
Number of pages8
JournalBMC Medical Genomics
Volume2
DOIs
Publication statusPublished - 2009
MoE publication typeA1 Journal article-refereed

Fingerprint

Breast Neoplasms
Cell Line
Mutation
Gene Expression
Neoplasms
Comparative Genomic Hybridization
RNA Stability
Gene Deletion
Gene Silencing
Tumor Suppressor Genes
Genes
Genome
Polymerase Chain Reaction

Keywords

  • breast cancer
  • gene array
  • gene expression
  • tumor suppressor gene

Cite this

Muggerud, Aslaug Aamodt ; Edgren, Henrik ; Wolf, Maija ; Kleivi, Kristine ; Dejeux, Emelyne ; Tost, Jörg ; Sørlie, Therese ; Kallioniemi, Olli. / Data integration from two microarray platforms identifies bi-allelic genetic inactivation of RIC8A in a breast cancer cell line. In: BMC Medical Genomics. 2009 ; Vol. 2.
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Data integration from two microarray platforms identifies bi-allelic genetic inactivation of RIC8A in a breast cancer cell line. / Muggerud, Aslaug Aamodt; Edgren, Henrik; Wolf, Maija; Kleivi, Kristine; Dejeux, Emelyne; Tost, Jörg; Sørlie, Therese (Corresponding Author); Kallioniemi, Olli (Corresponding Author).

In: BMC Medical Genomics, Vol. 2, 26, 2009.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Data integration from two microarray platforms identifies bi-allelic genetic inactivation of RIC8A in a breast cancer cell line

AU - Muggerud, Aslaug Aamodt

AU - Edgren, Henrik

AU - Wolf, Maija

AU - Kleivi, Kristine

AU - Dejeux, Emelyne

AU - Tost, Jörg

AU - Sørlie, Therese

AU - Kallioniemi, Olli

PY - 2009

Y1 - 2009

N2 - Background Using array comparative genomic hybridization (aCGH), a large number of deleted genomic regions have been identified in human cancers. However, subsequent efforts to identify target genes selected for inactivation in these regions have often been challenging. Methods We integrated here genome-wide copy number data with gene expression data and non-sense mediated mRNA decay rates in breast cancer cell lines to prioritize gene candidates that are likely to be tumour suppressor genes inactivated by bi-allelic genetic events. The candidates were sequenced to identify potential mutations. Results This integrated genomic approach led to the identification of RIC8A at 11p15 as a putative candidate target gene for the genomic deletion in the ZR-75-1 breast cancer cell line. We identified a truncating mutation in this cell line, leading to loss of expression and rapid decay of the transcript. We screened 127 breast cancers for RIC8A mutations, but did not find any pathogenic mutations. No promoter hypermethylation in these tumours was detected either. However, analysis of gene expression data from breast tumours identified a small group of aggressive tumours that displayed low levels of RIC8A transcripts. qRT-PCR analysis of 38 breast tumours showed a strong association between low RIC8A expression and the presence of TP53 mutations (P = 0.006). Conclusion We demonstrate a data integration strategy leading to the identification of RIC8A as a gene undergoing a classical double-hit genetic inactivation in a breast cancer cell line, as well as in vivo evidence of loss of RIC8A expression in a subgroup of aggressive TP53 mutant breast cancers.

AB - Background Using array comparative genomic hybridization (aCGH), a large number of deleted genomic regions have been identified in human cancers. However, subsequent efforts to identify target genes selected for inactivation in these regions have often been challenging. Methods We integrated here genome-wide copy number data with gene expression data and non-sense mediated mRNA decay rates in breast cancer cell lines to prioritize gene candidates that are likely to be tumour suppressor genes inactivated by bi-allelic genetic events. The candidates were sequenced to identify potential mutations. Results This integrated genomic approach led to the identification of RIC8A at 11p15 as a putative candidate target gene for the genomic deletion in the ZR-75-1 breast cancer cell line. We identified a truncating mutation in this cell line, leading to loss of expression and rapid decay of the transcript. We screened 127 breast cancers for RIC8A mutations, but did not find any pathogenic mutations. No promoter hypermethylation in these tumours was detected either. However, analysis of gene expression data from breast tumours identified a small group of aggressive tumours that displayed low levels of RIC8A transcripts. qRT-PCR analysis of 38 breast tumours showed a strong association between low RIC8A expression and the presence of TP53 mutations (P = 0.006). Conclusion We demonstrate a data integration strategy leading to the identification of RIC8A as a gene undergoing a classical double-hit genetic inactivation in a breast cancer cell line, as well as in vivo evidence of loss of RIC8A expression in a subgroup of aggressive TP53 mutant breast cancers.

KW - breast cancer

KW - gene array

KW - gene expression

KW - tumor suppressor gene

U2 - 10.1186/1755-8794-2-26

DO - 10.1186/1755-8794-2-26

M3 - Article

VL - 2

JO - BMC Medical Genomics

JF - BMC Medical Genomics

SN - 1755-8794

M1 - 26

ER -