Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer. Issue 5 (11th March 2021)

• Record Type: Journal Article
• Authors: Hoppe, Michal M; Jaynes, Patrick; Wardyn, Joanna D; Upadhyayula, Sai Srinivas; Tan, Tuan Zea; Lie, Stefanus; Lim, Diana G Z; Pang, Brendan N K; Lim, Sherlly; P S Yeong, Joe; Karnezis, Anthony; Chiu, Derek S; Leung, Samuel; Huntsman, David G; Sedukhina, Anna S; Sato, Ko; Topp, Monique D; Scott, Clare L; Choi, Hyungwon; Patel, Naina R; Brown, Robert; Kaye, Stan B; Pitt, Jason J; Tan, David S P; Jeyasekharan, Anand D
• Is Part Of: EMBO molecular medicine. Volume 13:Issue 5(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-03-11
• Subjects: HRD -- immune exclusion -- multiplexed IHC -- ovarian cancer -- RAD51; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202013366
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A‐priori identification of platinum resistance is therefore crucial to improve on standard first‐line carboplatin–paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum‐induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK‐compliant study of pre‐treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ . In a discovery cohort ( n = 284), RAD51‐High tumours had shorter progression‐free and overall survival compared to RAD51‐Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort ( n = 264) and was predominantly noted in HR‐proficient cancers (Myriad HRDscore < 42). Interestingly, overexpression of RAD51 modified expression of immune‐regulatory pathways in vitro, while RAD51‐High tumours showed exclusion of cytotoxic T cells in situ . Our findings highlight RAD51 expression as a determinant of platinum resistance and suggest possible roles for therapy to overcome immune exclusion in RAD51‐High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression. Synopsis: Quantitative immunohistochemistry (qIHC) reveals that high expression of the DNA repair protein RAD51 in epithelial ovarian cancer is associated with early relapse after platinum chemotherapy, and also with decreased cytotoxic T‐cell infiltration into tumors. High nuclear expression score for RAD51 (RAD51NES) was correlated with early relapse and shorter survival in two independent EOC patient cohorts ( n = 264 + 284). RAD51NES was prognostically relevant primarily for EOCs that did not have homologous recombination deficiency (HRD). RAD51 expression was correlated with a unique immune phenotype in cancer, with increased chemokines but reduced cytotoxic T‐cell infiltration. Abstract : Quantitative immunohistochemistry (qIHC) reveals that high expression of the DNA repair protein RAD51 in epithelial ovarian cancer (EOC) is associated with early relapse after platinum chemotherapy, and also with decreased cytotoxic T‐cell infiltration into tumors.