DNA Double Strand Break Repair Protein Expression Is Significantly Reduced in Tubal Secretory Cell Outgrowths
Richard Owings, Adam Cole, Charles Quick. University of Arkansas for Medical Sciences, Little Rock, AR
Background: Secretory cell outgrowths (SCOUTs) are suspected to be early precursors of tubal serous carcinoma. Previous studies have shown that some SCOUTs, as well as more advanced lesions such as serous tubal intraepithelial carcinoma (STIC), have increased levels of DNA double strand breaks (DNA DSB) as detected by increased staining of gamma-H2AX. DNA repair proteins in the MRN complex (MRE11, RAD50, NBS1) and 53BP1 are essential in the initial steps of DNA DSB repair. Our goal was to determine if expression of DNA DSB repair proteins is altered in SCOUTs.
Design: Archival fallopian tube blocks from patients with BRCA mutations, serous carcinoma with identified STIC, and benign hysterectomies (5 cases each) were used. Immunohistochemistry was performed using antibodies against MRE11, RAD50, NBS1, 53BP1, and PAX2. Absence of nuclear PAX2 staining in 30 or more secretory cells identified SCOUTs and allowed for localization of the other antibodies to the SCOUT. The nuclear intensity of antibody staining and percentage of epithelial cells (MRN proteins and 53BP1) was scored as nil (0), low (1+), medium (2+), and high (3+) and no staining (0), <25% (1), <50% (2), and >50 (3), respectively. The product of the two scores gave a single value from 0 to 9 and accounted for both the number of cells staining as well as the overall staining intensity. Results were analyzed by fisher exact test with p<0.05 considered significant.
Results: SCOUTs were identified in 3 of 5 cases from BRCA mutation carriers, 2 of 5 cases with serous carcinoma/STIC, and 1 of 5 from benign hysterectomies. SCOUTs showed markedly diminished staining of MRE11, RAD50, NBS1, and 53BP1. The combined staining score was significantly reduced in SCOUTS compared to the background tubal epithelium (2.8 +/-2.08 compared to 7.0 +/-1.0 for MRE11; 2.5 +/-1.9 compared to 8.5+/-0.4 for RAD50; 1.2+/-1.5 compared to 7.0+/-1.0 for NBS1; and 4.2+/-1.7 compared to 7.8+/-0.5 for 53BP1). The decreased staining in SCOUTs was statistically significant (p<0.05).
Conclusions: The markedly decreased to absent staining of MRE11, RAD50, NBS1, and 53BP1 in SCOUTs suggests a significant defect early in the DNA DSB repair sequence, which strengthens the postulate that SCOUTs are neoplastic precursors. These findings suggest that the increased DNA DSB indicated by increased gamma-H2AX expression in fallopian tube lesions may, in part, be due to aberrant DNA DSB repair. Further studies are needed to determine if there is single gene defect causing a breakdown in DNA DBS repair or a global defect in DNA repair mechanisms.
Category: Gynecologic & Obstetrics
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 181, Monday Morning