RET Alterations in Cancer: Fusions and Activating Mutations

RET Fusions

A fusion joins the RET kinase domain to a partner gene, commonly KIF5B or CCDC6 in lung cancer and CCDC6 or NCOA4 in papillary thyroid cancer. The partner drives expression and dimerisation, activating the kinase.

RET fusions occur in roughly 1 to 2 percent of non-small-cell lung cancers and about 10 to 20 percent of papillary thyroid cancers, and are generally mutually exclusive with other drivers.

Activating RET Mutations

Medullary thyroid cancer is characterised by point mutations in RET, most often at codon 634 (in the cysteine-rich domain) or M918T (in the kinase domain). These are different molecular events from fusions.

Germline RET mutations cause multiple endocrine neoplasia type 2 (MEN2), an inherited syndrome, so a RET mutation in medullary thyroid cancer raises a specific question about whether it is germline.

Detection

RET fusions are best detected by RNA-based next-generation sequencing, since DNA panels can miss breakpoints in large introns, or by break-apart fluorescence in-situ hybridisation. RET point mutations are detected by DNA sequencing.

A test aimed at point mutations will not reliably detect fusions and vice versa, so the assay design should match the clinical question.

Selective RET Inhibitors

Selpercatinib and pralsetinib are potent, selective RET inhibitors approved for RET fusion-positive lung and thyroid cancers and for RET-mutant medullary thyroid cancer. Response rates are high in both fusion- and mutation-driven disease.

Older multikinase inhibitors (cabozantinib, vandetanib) also have RET activity but with more off-target toxicity. Acquired resistance to selective inhibitors can occur through solvent-front RET mutations or bypass signalling.

Interpretation Notes

A RET report should distinguish a fusion from a point mutation, and for medullary thyroid cancer a somatic RET mutation should prompt consideration of germline testing and family implications.

RET fusion partner identity is worth recording, though selective inhibitors are active across partners.

Key Takeaways

• ·RET fusions drive a subset of lung and thyroid cancers; RET point mutations drive medullary thyroid cancer.
• ·Germline RET mutations cause MEN2, so somatic findings can raise an inherited-risk question.
• ·Fusions need RNA sequencing or FISH; point mutations need DNA sequencing.
• ·Selpercatinib and pralsetinib are effective against both fusion- and mutation-driven RET cancers.