Details

Autor(en) / Beteiligte

• Sullivan, Meghan R.
• Prakash, Rohit
• Mihalevic, Michael J.
• Baird, Jared M.
• Jasin, Maria
• Bernstein, Kara A.

Titel

Abstract A08: A novel system determines the functional significance of ovarian tumor mutations in the homologous recombination gene RAD51C

Ist Teil von

• Clinical cancer research, 2018-08, Vol.24 (15_Supplement), p.A08-A08

Erscheinungsjahr

2018

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Abstract Homologous recombination (HR) deficiency is associated with hereditary ovarian carcinomas. HR deficiency can occur through somatic and germline mutations in BRCA1, BRCA2, and other associated genes such as RAD51C. Understanding the impact of HR gene mutations on DNA double-strand break (DSB) repair is critical for developing targeted therapeutic strategies for these patients. Although BRCA1 and BRCA2 deficiency has been well characterized, limited functional analysis has occurred in patients harboring mutations in RAD51C. RAD51C mutations are found in familial breast and ovarian cancers and in Fanconi anemia-like syndrome, FANCO. To determine which RAD51C-tumor associated mutations disrupt HR, we utilized a novel RAD51C conditional knockout breast epithelial cell line (MCF10A) generated by Dr. Maria Jasin. In collaboration with the Jasin laboratory, we complemented these cells with RAD51C and RAD51C cancer-associated mutants. Using yeast-two-hybrid and co-immunoprecipitation strategies, we identified RAD51C mutations that disrupt RAD51C protein-protein interactions. For example, we identified RAD51C mutations that impair RAD51C interaction with either its binding partner RAD51B, RAD51D, or XRCC3. We next measured RAD51C mutant cells for viability and HR proficiency at an I-SceI-induced DSB using a DR-GFP reporter assay. We identified RAD51C mutations that impact HR repair, suggesting that patients harboring these mutations would be good candidates for PARPi. Our goal is to identify specific RAD51C mutations that disrupt HR to predict which RAD51C-deficient tumors will respond to therapy. Citation Format: Meghan R. Sullivan, Rohit Prakash, Michael J. Mihalevic, Jared M. Baird, Maria Jasin, Kara A. Bernstein. A novel system determines the functional significance of ovarian tumor mutations in the homologous recombination gene RAD51C. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A08.