BMC Cancer 2004, 4 http://www.biomedcentral.com/1471-2407/4/9 KvFairngi-uacnrotehso1armt obnregafsetmcaalnecreerlactuivmeusloatfivperorbisaknedstimates up to age 80 by genotype for less frequent single nucleotide polymorphic Kin-cohort breast cancer cumulative risk estimates up to age 80 by genotype for less frequent single nucleotide polymorphic variants among female relatives of probands. (Amino acids and their symbols: R: Arginine, W: Tryptophan, H: Histidine, Q: Glutamine, D: Aspartic Acid, E: Glutamic Acid, N: Asparagine, P: Proline, S: Serine, L: Leucine, I: Isoleucine, T: Threonine.) XRCC1 194W allele [reviewed in [22]] including a large study of breast cancer [23], we found the opposite rela- tionship. Our results are in agreement with two recent breast cancer case-control studies that found non-signifi- cantly elevated 1.6- and 2-fold risks for at least one variant allele of XRCC1 194 [24,25]. Several studies of female breast cancer have reported elevated risk associated with the XRCC1 399Q allele among African Americans [23] and Koreans [26], but not among Caucasian [23-25,27] or Chinese women [28]. The mixed findings for the relation- ship of XRCC1 polymorphisms with breast cancer are dif- ficult to reconcile, but may simply represent variability around the for a non-susceptibility allele. Depending on the model system chosen, functional testing results indicate either a reduced DNA repair capacity associated with the XRCC1 399Gln allele [29], an increase in mitotic delay among healthy women with a family history of breast cancer after a γ-ray challenge [30], increased DNA adduct levels [31], or no difference related to the poly- morphism in single strand break repair ability or cell sur- vival in an isogenic background [32]. We evaluated two polymorphisms in the AP endonuclease APEX (also called APE1, HAP1, REF1) Q51H and D148E since this multi- functional endonuclease recognizes and begins the proc- ess of removing abasic sites in DNA [reviewed in [33]]. Further, the variant form of APEX 148 was functionally characterized as exhibiting post-irradiation challenge prolonged mitotic delay [30] and we expected the 148E allele would be associated with increased risk, but instead we found heterozygote carriers had significantly decreased Page 6 of 12 (page number not for citation purposes)