RET-mediated gene expression pattern is affected by isoform but not oncogenic mutation

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Multiple endocrine neoplasia type 2 (MEN 2) is an inherited cancer syndrome caused by RET receptor tyrosine kinase mutations.
• MEN 2 subtypes, including MEN 2A and the severe MEN 2B, present with distinct RET mutations and varying disease severity.
• The MEN 2B-associated RET M918T mutation is predicted to alter downstream signaling and gene expression.

Purpose of the Study:

• To identify target genes modulated by RET receptor tyrosine kinase.
• To compare gene expression patterns influenced by oncogenic RET mutants associated with MEN 2A (2ARET) and MEN 2B (2BRET) subtypes.
• To investigate the role of different RET COOH-terminal isoforms (RET9 and RET51) in gene expression.

Main Methods:

• Gene expression microarray analysis was employed to identify RET-modulated target genes.
• Quantitative real-time PCR was used to validate microarray findings.
• Comparison of gene expression profiles between wildtype RET, 2ARET, and 2BRET mutants, considering receptor activity levels.

Main Results:

• Both 2ARET and 2BRET mutants modulated genes with similar functional ontologies.
• No major differences in gene expression were detected between mutants when receptor activity levels were normalized.
• Significant differences in gene expression were observed between RET9 and RET51 isoforms, independent of the RET mutation status.

Conclusions:

• Transcriptional programs are largely conserved across different forms of MEN 2.
• Differences in target gene expression induced by RET9 and RET51 isoforms may explain developmental pattern variations observed in MEN 2.
• RET isoforms, rather than specific MEN 2-associated mutations, appear to be key drivers of differential gene expression patterns.