BERKELEY, CA (UroToday.com) - In a recent article in the online version of Genome Research, Dr. Mark Rubin and collaborators examined whole transcriptomes of 25 prostate cancer (CaP) specimens looking for no-ETS fusions.
Gene fusions between TMPRSS2 and ETS transcription family members occur in up to 45% of patients with prostate cancer. Prostate cancer may be prone to recurrent gene fusions involving androgen-regulated genes and ETS transcriptional factors. In this study the investigators sought to determine the extent to which novel gene fusions or chimeric read-through transcripts are involved in CaP.
They used whole transcriptomes sequencing of 25 CaP samples enriched for ETS fusion negative samples and 3 prostate samples without cancer. Their methodology used next-generation RNA sequencing (RNA-seq) to interrogate the genome and identify chimeric transcripts and alternative splicing of genes and point mutations. Whether identified fusions would be functionally driving cellular events or a bystander event was not known. They validated selected read-through chimeras by RT-PCR and their data suggests that read-through events are not cancer-restrictive, as several validated chimeric read-through transcripts were nominated in both malignant and benign prostate tissues. A total of 7 high-scoring inter/intrachromosomal cancer specific chimeric candidates were nominated for experimental validation. Two novel gene fusions were found in TMPRSS2-ERG fusion negative tumor samples. They involved ETS family members KLK2-ETVa and FKBP5-ERG and both are androgen regulated. The KLK2-ETVa fusion was validated at the transcript level by RT-PCR, and at the DNA level by FISH. FKBP5 fusion was found to be a triple fusion event involving TMPRSS2 and ERG. Two novel gene fusions - CDNK1A-CD9 and TNPO1-IKBKB were found in a TRPRSS2-ERG positive tumor sample. Both occurred only in malignant tissue, not benign. CDNK1A-CD9 fusion influences the expression of CDKN1A, which was found to be low. They were able to sort out the mechanistic implications of the CDNK1A-CD9 fusion. TNPO1-IKBKB correlated with an IKK-beta gene expression level 9X higher than the median expression by other CaP samples. A fusion between MIER2 and RSRC2 was detected in a third TMPRSS2 fusion positive sample. The fusion likely impairs the proper functioning of these two genes. This work demonstrates that other gene fusions are occurring in CaP and impact expression levels of genes and thereby can alter cellular function.
Pflueger D, Terry S, Sboner A, Habegger L, Esgueva R, Lin PC, Svensson MA, Kitabayashi N, Moss BJ, Macdonald TY, Cao X, Barrette T, Tewari AK, Chee MS, Chinnaiyan AM, Rickman DS, Demichelis F, Gerstein MB, Rubin MA
Genome Res. 2011 Jan;21(1):56-67
10.1101/gr.110684.110
PubMed Abstract
PMID: