RNA-Sequencing Reveals Distinct Mutation Specific Transcriptome Signatures in Aldosterone Producing Adenomas

Presentation Number: MON 387
Date of Presentation: April 3rd, 2017

Samuel Backman*, Tobias Akerstrom, Rajani Maharjan, Per Hellman and Peyman Bjorklund
Uppsala University, Sweden

Abstract

Introduction
Aldosterone producing adenomas (APAs) represent a common and potentially curable form of secondary hypertension, affecting several percent of the hypertensive population. The recent years have shed light on the genetic causes of APA tumourigenesis, with recurrent somatic mutations identified in KCNJ5, CACNA1D, ATP1A1, ATP2B3 and CTNNB1. In the present study we have used RNA-Sequencing to characterize the transcriptomes of APAs with different genetic backgrounds.


Methods

RNA was extracted from serial sections of fresh-frozen tumour tissues. The samples were subjected to rRNA depletion and conversion, followed by paired-end sequencing. Isoform quantification was performed on the generated raw data using kallisto and subsequent expression analyses were performed using sleuth. Special attention was given to genes in the Aldosterone Synthesis and Secretion and Apoptosis KEGG pathways.

 

Results

The dominant isoforms of genes involved in aldosterone synthesis and secretion, as well as in apoptosis in aldosterone producing adenomas were determined. Differential expression analysis revealed that 1152 transcripts were differentially expressed between tumours with CTNNB1 mutation and those without CTNNB1 mutations, while only 40 transcripts were differentially expressed between tumours with and without KCNJ5 mutation and 126 transcripts were differentially expressed between tumours with and without ATP1A1/ATP2B3 mutation. Hierarchical clustering based on the 3000 most variably expressed transcripts in the cohort generated two clusters characterized by the presence and absence of CTNNB1 mutations, respectively. Several genes in the Apoptosis pathway (including TP53 and ATM) and in the Aldosterone synthesis pathway (including PRKACA and STAR) had transcripts that were differentially expressed between tumours with and without CTNNB1 mutation.

 

Conclusion

We have characterized the expression of genes related to apoptosis and aldosterone production in APAs. Additionally, our isoform-level differential expression and clustering analyses suggest that the transcriptome of APAS with CTNNB1 mutation APA may differ substantially from APAs without CTNNB1 mutation.

 

Nothing to Disclose: SB, TA, RM, PH, PB