Activating IGF1R hotspot non-frameshift insertions define a novel, potentially targetable molecular subtype of...

Area of Science:

• Genomics and Molecular Oncology
• Cancer Driver Mutations
• Targeted Cancer Therapies

Background:

• The Insulin-like Growth Factor 1 Receptor (IGF1R) is a targetable tyrosine kinase receptor.
• Systematic characterization of IGF1R mutations, particularly activating alterations, is lacking.
• Understanding genetic alterations is crucial for developing effective cancer treatments.

Purpose of the Study:

• To systematically characterize mutations in the IGF1R gene across a large pan-cancer dataset.
• To identify specific mutation hotspots and their enrichment in different cancer types.
• To investigate the potential of IGF1R alterations as a targetable subtype in adenoid cystic carcinomas (ACCs).

Main Methods:

• Pan-cancer analysis of 326,911 tumor samples.
• Analysis of IGF1R alterations by variant effect prediction class, gene position, and cancer type.
• Statistical analysis to identify significantly enriched mutation hotspots, particularly non-frameshift insertions.

Main Results:

• 2.0% of analyzed samples (6502/326,911) harbored IGF1R alterations.
• Two distinct hotspots for activating non-frameshift insertions were identified in IGF1R: codons 663-666 and 1034-1049.
• These hotspot insertions were significantly enriched in ACCs (27.3-fold increase) and specific to ACCs among salivary gland tumors, often mutually exclusive with other ACC drivers.

Conclusions:

• Non-frameshift hotspot insertions in IGF1R define a novel, potentially targetable subtype of ACC.
• These findings highlight the importance of characterizing specific mutation patterns for precision oncology.
• Further research is warranted to evaluate patient response to existing IGF1R inhibitors for this ACC subtype.