High frequency strand slippage mutations in CTCF in MSI-positive endometrial cancers

Area of Science:

• Genomics
• Cancer Biology
• Molecular Genetics

Background:

• Tumors with defective mismatch repair accumulate strand slippage mutations, including frameshifts in coding repeats.
• The insulator-binding protein (CTCF) is a significantly mutated gene in endometrial cancer.

Purpose of the Study:

• To investigate the role of CTCF mutations in endometrial cancer.
• To identify specific CTCF mutational hotspots and their functional consequences.

Main Methods:

• Reanalysis of The Cancer Genome Atlas (TCGA) endometrial cancer data using Pindel.
• Analysis of mutation spectrum and pattern.
• Assessment of nonsense-mediated decay for T204fs transcripts.

Main Results:

• A mutational hotspot, p.T204fs, was identified in CTCF in MSI-positive endometrial cancers.
• Frequent T204fs mutations were confirmed in TCGA data, indicating CTCF is an MSI target gene.
• Identical frameshifts were found in tumors with intact mismatch repair, and T204fs transcripts undergo nonsense-mediated decay.

Conclusions:

• CTCF frameshift mutations are frequent in endometrial cancer and are not exclusively associated with mismatch repair deficiency.
• The observed mutation spectrum suggests CTCF acts as a haploinsufficient tumor suppressor, as T204fs mutations are unlikely to exert dominant-negative effects.