Epigenetic and genetic field changes in BRCA 1/2 mutation carrier’s organs at risk

Principal Supervisor: Martin Widschwendter

Subsidiary Supervisor: Dan Reisel

Project Summary:

BRCA1/2 mutations impair a cell’s capacity to repair DNA, ultimately resulting in cancer development. If this were the only mechanism of cancer predisposition in BRCA1/2 mutation carriers, a large number of tissues, especially tissues with high mitotic rates would be expected to show elevated cancer risk. Strikingly, this is not the case. In the past few years our team at the UCL Department of Women’s Cancer has established the several lines of evidence (Reference 1-6) supporting the view that cancer development in BRCA1/2 mutation-carriers involves interplay between cell-autonomous factors, directly driven by BRCA1/2 mutations within the cells that have elevated cancer risk, and cell non-autonomous factors, which include epigenetic alterations and are driven by the downstream and/or systemic consequences of the BRCA1/2 mutation. This PhD project is picking up on these lines of evidence to define the detailed Outcome Parameters at the level of the genome and epigenome in the tissue at risk.

References:

  1. Bartlett TE, Chindera K, McDermott J, Breeze C, Cooke WR, Jones A, Reisel D, Karegodar ST, Arora R, Beck S, Menon U, Dubeau L, Widschwendter M. Epigenetic reprogramming of Fallopian tube fimbriae in BRCA mutation carriers defines ovarian cancer evolution. Nature Communications. (2016). In Print.
  2. Teschendorff AE Gao Y, Jones A, Ruebner M, Beckmann MW, Wachter DL, Fasching PA, Widschwendter M. DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer. Nature Communications. (2016 Jan 29); 7:10478
  3. Widschwendter M, Burnell M, Fraser S, Rosenthal AN, Philpott S, Reisel D, Dubeau L, Cline M, Pan Y, Ping-Cheng Y, Evans DG, Jacobs IJ, Menon U, Wood CE, Dougall WC. Osteoprotegerin (OPG), the Endogenous Inhibitor of Receptor Activator of NF-κB Ligand (RANKL), is Dysregulated in BRCA Mutation Carriers. EBioMedicine. (2015 Sep 09); 2(10): 1331–1339
  4. Teschendorff AE, Yang Z, Wong A, Pipinikas CP, Jiao Y, Jones A, Anjum S, Hardy R, Salvesen HB, Thirlwell C, Janes SM, Kuh D, Widschwendter M. Correlation of Smoking-Associated DNA Methylation Changes in Buccal Cells With DNA Methylation Changes in Epithelial Cancer. JAMA Oncol. (2015 Jul 1); 1(4):476-85
  5. Jones A, Teschendorff AE, Li Q, Hayward JD, Kannan A, Mould T, West J, Zikan M, Cibula D, Fiegl H, Lee S-H, Wik E, Hadwin R, Arora R, Lemech C, Turunen H, Pakarinen P, Jacobs IJ, Salvesen HB, Bagchi MK, Bagchi IC, Widschwendter M. Role of DNA Methylation and Epigenetic Silencing of HAND2 in Endometrial Cancer Development. PLoS MED. (2013 Nov 12); 10(11): e1001551
  6. Widschwendter M, Rosenthal AN, Philpott S, Rizzuto I, Fraser L, Hayward J, Intermaggio MP, Edlund CK, Ramus SJ, Gayther SA, Dubeau L, Fourkala EO, Zaikin A, Menon U, and Jacobs IJ. The sex hormone system in carriers of BRCA1/2 mutations: a case-control study. The Lancet Oncology (2013 Nov); 14(12): 1226–32