Exon expression arrays as a tool to identify new cancer genes

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http://hdl.handle.net/1765/14910

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epidermal growth factor receptor phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase protein p53 retinoblastoma protein uvomorulin analytic method article cancer cell culture cancer genetics controlled study DNA microarray exon gene expression gene identification genetic algorithm genetic analysis genetic screening genetic transcription genetic variability human human cell human cell culture mutational analysis nucleotide sequence pattern based correlation sequence analysis single nucleotide polymorphism structure analysis wild type breast tumor cell transformation female gene expression profiling genetics population genetics tumor cell line tumor gene

Creators:

Nagel, J.H.A. Duijm, E. Vuerhard, M.J. Schutte, M. Wasielewski, M. Hollestelle, A. Elstrodt, F. Spek, P.J. van der Sillevis Smitt, P.A.E. French, P.J. Bralten, L.B.C. Peeters, J.K.

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Description

Background: Identification of genes that are causally implicated in oncogenesis is a major goal in cancer research. An estimated 10-20% of cancer-related gene mutations result in skipping of one or more exons in the encoded transcripts. Here we report on a strategy to screen in a global fashion for such exon-skipping events using PAttern based Correlation (PAC). The PAC algorithm has been used previously to identify differentially expressed splice variants between two predefined subgroups. As genetic changes in cancer are sample specific, we tested the ability of PAC to identify aberrantly expressed exons in single samples. Principal Findings: As a proof-of-principle, we tested the PAC strategy on human cancer samples of which the complete coding sequence of eight cancer genes had been screened for mutations. PAC detected all seven exon-skipping mutants among 12 cancer cell lines. PAC also identified exon-skipping mutants in clinical cancer specimens although detection was compromised due to heterogeneous (wild-type) transcript expression. PAC reduced the number candidate genes/exons for subsequent mutational analysis by two to three orders of magnitude and had a substantial true positive rate. Importantly, of 112 randomly selected outlier exons, sequence analysis identified two novel exon skipping events, two novel base changes and 21 previously reported base changes (SNPs). Conclusions: The ability of PAC to enrich for mutated transcripts and to identify known and novel genetic changes confirms its suitability as a strategy to identify candidate cancer genes.

Source

PLoS ONE, Volume 3, Issue 8, 20 August 2008, Article number e3007

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Article

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