CTCF genetic alterations in endometrial carcinoma are pro-tumorigenic.
CTCF is a haploinsufficient tumour suppressor gene with diverse normal functions in genome structure and gene regulation. However the mechanism by which CTCF haploinsufficiency contributes to cancer development is not well understood. CTCF is frequently mutated in endometrial cancer. Here we show that most CTCF mutations effectively result in CTCF haploinsufficiency through nonsense-mediated decay of mutant transcripts, or loss-of-function missense mutation. Conversely, we identified a recurrent CTCF mutation K365T, which alters a DNA binding residue, and acts as a gain-of-function mutation enhancing cell survival. CTCF genetic deletion occurs predominantly in poor prognosis serous subtype tumours, and this genetic deletion is associated with poor overall survival. In addition, we have shown that CTCF haploinsufficiency also occurs in poor prognosis endometrial clear cell carcinomas and has some association with endometrial cancer relapse and metastasis. Using shRNA targeting CTCF to recapitulate CTCF haploinsufficiency, we have identified a novel role for CTCF in the regulation of cellular polarity of endometrial glandular epithelium. Overall, we have identified two novel pro-tumorigenic roles (promoting cell survival and altering cell polarity) for genetic alterations of CTCF in endometrial cancer.
Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
A D
AD
Marshall
Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
C G
CG
Bailey
Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
K
K
Champ
Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
M
M
Vellozzi
Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
P
P
O'Young
Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
C
C
Metierre
Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
Y
Y
Feng
Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
A
A
Thoeng
Gynaecological Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
A M
AM
Richards
Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
U
U
Schmitz
Cell Motility and Mechanobiology, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
M
M
Biro
Cancer Genomics, McDonnell Genome Institute, Washington University in St Louis, St Louis, MO, USA.|Division of Oncology, Department of Medicine, Washington University in St Louis, St Louis, MO, USA.
R
R
Jayasinghe
Cancer Genomics, McDonnell Genome Institute, Washington University in St Louis, St Louis, MO, USA.|Division of Oncology, Department of Medicine, Washington University in St Louis, St Louis, MO, USA.
L
L
Ding
Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
L
L
Anderson
Cancer Genomics, McDonnell Genome Institute, Washington University in St Louis, St Louis, MO, USA.|Division of Oncology, Department of Medicine, Washington University in St Louis, St Louis, MO, USA.
E R
ER
Mardis
Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
J E J
JEJ
Rasko
D000076246:CCCTC-Binding Factor; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D020125:Mutation, Missense; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics*
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D012097:Repressor Proteins