title: High frequency strand slippage mutations in CTCF in MSI-positive endometrial cancers.
abstract: 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 A₇ 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.
authors.forename: Israel
authors.initials: I
authors.lastname: Zighelboim
authors.forename: David G
authors.initials: DG
authors.lastname: Mutch
authors.forename: Amy
authors.initials: A
authors.lastname: Knapp
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Mingchao
authors.initials: M
authors.lastname: Xie
authors.forename: David E
authors.initials: DE
authors.lastname: Cohn
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Goodfellow
mesh_terms: D001483:Base Sequence; D000076246:CCCTC-Binding Factor; D053843:DNA Mismatch Repair; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005260:Female; D016368:Frameshift Mutation; D014644:Genetic Variation; D057895:Haploinsufficiency; D006801:Humans; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D059645:Mutation Rate; D059365:Nonsense Mediated mRNA Decay; D012097:Repressor Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins