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Abstract
Introduction/Background We previously showed that low homologous recombination (HR) scores correlate with platinum sensitivity and better outcome in high-grade serous ovarian cancer (HGSOC) (Tumiati et al. 2018). Previous studies have reported loss of the tumor suppressor gene Fragile Histidine Triad (FHIT) in many cancers including HGSOC. FHIT contains FRA3B, a common fragile site, which is prone to aberrations under replication stress. Fhit protein protects cells from DNA damage accumulation through modulation of DNA damage checkpoint proteins, and some previous publications have reported a link between FHIT and HR. We analyzed Fhit protein expression in HGSOC and tested for correlation between Fhit expression and HR status.
Methodology 25 FFPE samples from 13 HGSOC patients were studied by immunofluorescence against Fhit. Only vital tumor cells were analyzed and scored. Percentage of positive tumor cells and staining intensity were analyzed by a pathologist and a FHIT score was calculated (intensity multiplied by percentage of positive cells). FHIT score was plotted against HR score and their association was calculated by linear regression.
Results Fhit staining intensity varied from negative to strong (figure 1). 16% of the samples were negative (n=4) and 25% were weakly positive (n=6) for Fhit, while 60% were moderately or strongly positive (n=15). Both cytoplasmic and nuclear staining was seen (figure 1). Most of the samples were HR proficient (n=15; 65,2%), two were HR deficient (8,7%), and the rest were HR low (n=6; 26%). FHIT score values ranged from 0 to 285. There was a positive correlation between Fhit expression and HR score: both HR deficient samples were negative for Fhit and the higher the HR score, the higher the Fhit expression (figure 2, Pearson´s correlation coefficient 0,27).
Conclusion Loss of Fhit is associated with HR deficiency in HGSOC. Fhit expression positively correlates with HR score suggesting low FHIT expression indicates platinum sensitivity.
Disclosure Sources of funding: the Finnish Medical Foundation (N.S.), the Maud Kuistila Memorial Foundation (N.S.), University of Helsinki (A.V. and M.T.), Helsinki University Hospital (A.V.), the Academy of Finland (M.T. and L.K.), the Sigrid Juselius Foundation (L.K.), and the Finnish Cancer Foundation (M.T. and L.K). The authors have no conflicts of interest to disclose.
Examples of Fhit protien immunofluorescence stainings. Fhit protient is shown red, CK-7 green and nulei are blue. A) Normal Fallopian tube epithelium (postive control). B) Negative adnex Fhit staining in patient EOC148. C) Moderate omentum staining in patient EOC809. D) Strong staining in ovary of patient EOC939. Magnification 20X, scal bar 50µm
Fhit Expression vs. HR Score