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High Frequency Strand Slippage Mutations in CTCF in MSI ‐Positive Endometrial Cancers
Author(s) -
Zighelboim Israel,
Mutch David G.,
Knapp Amy,
Ding Li,
Xie Mingchao,
Cohn David E.,
Goodfellow Paul J.
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22463
Subject(s) - ctcf , biology , haploinsufficiency , genetics , dna mismatch repair , gene , nonsense mediated decay , cancer research , coding region , endometrial cancer , dna repair , microbiology and biotechnology , cancer , enhancer , gene expression , rna splicing , phenotype , rna
Tumors with defective mismatch repair acquire large numbers of strand slippage mutations including frameshifts in coding sequence repeats. We identified a mutational hotspot, p.T204fs, in the insulator‐binding protein ( CTCF ) in MSI ‐positive endometrial cancers. Although CTCF was described as a significantly mutated gene by the endometrial cancer TCGA , the A 7 track variants leading to T204 frameshifts were not reported. Reanalysis of TCGA data using Pindel revealed frequent T204fs mutations, confirming CTCF is an MSI target gene and revealed the same frameshifts in tumors with intact mismatch repair. We show that T204fs transcripts are subject to nonsense‐mediated decay and as such, T204fs mutations are unlikely to act as dominant negatives. The spectrum and pattern of mutations observed is consistent with CTCF acting as a haploinsufficient tumor suppressor.