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Study Used Iso-Seq Method to Unravel Activity of Receptors in Prostate Cancer

Thursday, June 29, 2017

A new publication in Clinical Cancer Research from scientists at the Mayo Clinic, University of Minnesota, and other institutions presents results from a study to evaluate androgen receptor (AR) isoforms as biomarkers for chemotherapy resistance in prostate cancer patients. The team used the Iso-Seq method with SMRT Sequencing to better characterize the structures of AR variants, discovering that the exon structure of this prostate cancer driver had previously been misreported due to the limitations of short-read sequencing.

Androgen receptor variant AR-V9 is co-expressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance” comes from lead authors Manish Kohli and Yeung Ho, senior author Scott Dehm, and collaborators. The team aimed to expand on previous discoveries about androgen receptor transcription factors that confer resistance to targeted therapies in cases of prostate cancer. Androgen receptor variant AR-V7 was already known to promote resistance, but scientists wanted to see if other elements contributed to this effect.

For the project, researchers combined data from short-read sequencing and SMRT Sequencing, using long reads to capture full-length transcripts. They discovered a significant error in previous studies that highlighted AR-V7. Specifically, AR-V9 includes a cryptic exon that had been thought to be unique to AR-V7. “This work re-annotates AR-V9 mRNA structure, and finds that the role of AR-V9 in therapeutic resistance has been obscured by extensive overlap in mRNA sequence with AR-V7,” the scientists write. “The finding that high AR-V9 mRNA expression in metastases was predictive of primary resistance to the androgen synthesis inhibitor abiraterone indicates that monitoring and inhibition of AR-V9 may be needed to overcome therapeutic resistance.”

The problem with short-range information of any type is that it precludes direct observation of the full transcript, the scientists note. Generating information about small pieces of a transcript necessitates inferring expression levels and relationships, “as is the case for short-read RNA-seq data, quantitative RT-PCR with primers flanking splice junctions, or hybridization of probes to single exons,” they add.

The team analyzed expression in circulating tumor cells collected from 12 patients with castration-resistant prostate cancer (CRPC) who had been treated with androgen receptor-targeted therapies or an androgen receptor antagonist. PacBio sequencing revealed that the 3’ terminal exon for AR-V9 is 2.4 kb, much longer than previous annotations had found. This exon was shared with AR-V7. “Since AR-V7 and AR-V9 proteins are both constitutively active, the overall levels and functional impact of AR-Vs in prostate cancer may be greater than would be anticipated from analyses of either AR-V alone,” the scientists report.

They concluded that “high AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate.”

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