REDUCED DNA-REPAIR CAPACITY IN BREAST-CANCER PATIENTS AND UNAFFECTED INDIVIDUALS FROM BREAST-CANCER FAMILIES

If has been suggested that increased fragile site expression in lympho cyte cultures can be used as a marker for genetic predisposition to ca ncer. We wished to determine whether aphidicolin (APC), an inhibitor o f the DNA repair enzyme DNA polymerase alpha, could be used as a relia ble biomarker in identification of DNA repair capacity in unaffected i ndividuals at high risk from breast cancer families. PHA-stimulated ly mphocyte cultures, with and without APC, were set up in 65 individuals , of whom 14 were breast cancer patients, 26 were unaffected individua ls from breast cancer families, and 25 were controls. A significant pr oportion of breast cancer patients and unaffected individuals from fam ilial breast cancer (FBC) families exhibited premature separation of c entromeres (PSC) and aneuploidy in the untreated cultures. In the APC treated cultures, almost all such individuals exhibited a marked depre ssion of mitotic index and increased aneuploidy, as compared to contro ls. Our results indicate that these individuals have defective DNA rep air capacity. Such individuals could thus have a much higher risk of c ancer as compared to persons exhibiting PSC and aneuploidy or DNA repa ir defects alone. We propose that APC may be a valuable biomarker in i dentifying individuals with genetic predisposition to cancer from FBC families. (C) Elsevier Science Inc., 1998.