SFEBES2022 Oral Poster Presentations Endocrine Cancer and Late Effects (4 abstracts)
1Cambridge University, Cambridge, United Kingdom; 2Cambridge University Hospital, Cambridge, United Kingdom
Background: International consensus supports interval biochemical and imaging surveillance for all asymptomatic carriers of succinate dehydrogenase (SDHx) gene mutations and patients with a history of SDH deficient tumours. There is growing awareness that the life time penetrance of the SDHx genes is much lower than that originally estimated and that long term radiological surveillance carries a significant risk including ionizing radiation exposure and incidental findings. There is a need to consider alternative biomarkers for long-term clinical surveillance of SDHx mutation carriers and to identify new therapeutic targets. MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression at the post-transcriptional level and alterations can promote cancer specific molecular mechanisms. Fluctuations in specific miRNAs have been identified as sensitive biomarkers in a number of cancers.
Aims: To identify specific miRNA signatures in SDH deficient tumours compared to control tumours.
Results: Small RNA sequencing was performed on 44 tumour samples including; 13 SDH preserved (pSDH) PPGL, 11 SDH deficient (dSDH) PPGL, 15 pSDH and 15 dSDH GIST. Principle component analysis (PCA) demonstrated that differential miRNA signatures separated PPGL from GIST and within the tumour groups, unbiased PCA of miRNAs clustered tumours according to their underlying molecular drivers. Top miRNAs separating dSDH from pSDH PPGL included miR-183-5p, miR-182-5p and miR-96-5p, previously suggested as SDHx specific miRNAs, and associated with pro metastatic features in vitro. Novel findings include increased expression of miR-338-5p in dSDH vs pSDH GIST. Preferential miR-338-5p expression has been identified in colorectal cancel tissue and associated with an increased tendency towards migration and invasion through inhibition or repression of PI3KC mediated authophagy. MiR424-5p was also preferentially expressed in dSDH vs pSDH GIST. miR-424-5p targets genes responsible for cell division, and regulation of cell migration in a number of tumour types.