Poster Presentation 29th Lorne Cancer Conference 2017

CTCF Genetic Alterations in Endometrial Carcinoma are Functionally Pro-tumorigenic   (#222)

Amy D Marshall 1 2 , Chuck Bailey 1 2 , Kat Champ 1 2 , Melissa Vellozzi 1 2 , Patrick O'Young 1 2 , Cynthia Metierre 1 2 , Yue Feng 1 2 , Annora Thoeng 1 2 , Tony Richards 3 , Mate Biro 4 , Reyka Jayasinghe 5 , Li Ding 5 , Lyndal Anderson 2 6 , Elaine Mardis 5 , John EJ Rasko 1 2 7
  1. Centenary Institute, Camperdown, NSW, Australia
  2. Sydney Medical School, University of Sydney, Camperdown, NSW, Australia
  3. Gynaecological Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
  4. School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
  5. McDonnell Genome Institute, Washington University in St Louis, St Louis, MO, USA
  6. Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
  7. Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, NSW, Australia

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 within these patients. 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.