Abstract
BackgroundIt has recently emerged that common epithelial cancers such as breast cancers have fusion genes like those in leukaemias. In a representative breast cancer cell line, ZR-75-30, we searched for fusion genes, by analysing genome rearrangements.ResultsWe first analysed rearrangements of the ZR-75-30 genome, to around 10kb resolution, by molecular cytogenetic approaches, combining array painting and array CGH. We then compared this map with genomic junctions determined by paired-end sequencing. Most of the breakpoints found by array painting and array CGH were identified in the paired end sequencing—55% of the unamplified breakpoints and 97% of the amplified breakpoints (as these are represented by more sequence reads). From this analysis we identified 9 expressed fusion genes: APPBP2-PHF20L1, BCAS3-HOXB9, COL14A1-SKAP1, TAOK1-PCGF2, TIAM1-NRIP1, TIMM23-ARHGAP32, TRPS1-LASP1, USP32-CCDC49 and ZMYM4-OPRD1. We also determined the genomic junctions of a further three expressed fusion genes that had been described by others, BCAS3-ERBB2, DDX5-DEPDC6/DEPTOR and PLEC1-ENPP2. Of this total of 12 expressed fusion genes, 9 were in the coamplification. Due to the sensitivity of the technologies used, we estimate these 12 fusion genes to be around two-thirds of the true total. Many of the fusions seem likely to be driver mutations. For example, PHF20L1, BCAS3, TAOK1, PCGF2, and TRPS1 are fused in other breast cancers. HOXB9 and PHF20L1 are members of gene families that are fused in other neoplasms. Several of the other genes are relevant to cancer—in addition to ERBB2, SKAP1 is an adaptor for Src, DEPTOR regulates the mTOR pathway and NRIP1 is an estrogen-receptor coregulator.ConclusionsThis is the first structural analysis of a breast cancer genome that combines classical molecular cytogenetic approaches with sequencing. Paired-end sequencing was able to detect almost all breakpoints, where there was adequate read depth. It supports the view that gene breakage and gene fusion are important classes of mutation in breast cancer, with a typical breast cancer expressing many fusion genes.
Highlights
It has recently emerged that common epithelial cancers such as breast cancers have fusion genes like those in leukaemias
In the last few years it has emerged that the common epithelial cancers, such as carcinoma of breast, prostate and lung, have fusion genes like those long associated with leukaemias, lymphomas and sarcomas [1,2]
The first to be discovered were in prostate cancer, where about half of all cases have the Transmembrane protease (TMPRSS2)-v-ets erythroblastosis virus E26 oncogene homolog (ERG) fusion gene [3,4], and lung cancer, where around 5% of lung cancers have a fusion that activates the Anaplastic lymphoma receptor tyrosine kinase (ALK) tyrosine kinase, the Echinoderm microtubule associated protein like 4 (EML4)-ALK fusion [5]
Summary
It has recently emerged that common epithelial cancers such as breast cancers have fusion genes like those in leukaemias. In the last few years it has emerged that the common epithelial cancers, such as carcinoma of breast, prostate and lung, have fusion genes like those long associated with leukaemias, lymphomas and sarcomas [1,2]. The first to be discovered were in prostate cancer, where about half of all cases have the TMPRSS2-ERG fusion gene [3,4], and lung cancer, where around 5% of lung cancers have a fusion that activates the ALK tyrosine kinase, the EML4-ALK fusion [5] These early examples were found by essentially ‘one-off’ methods, and did not answer the question of how many fusions a typical carcinoma expresses ([4,5] reviewed in [1]). Paired-end sequencing is being applied to cDNA to find fusion transcripts directly [13,14,15]
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