BMC Cancer 2004, 4 http://www.biomedcentral.com/1471-2407/4/9 Table 2: Polymorphic variant frequencies among breast cancer cases (probands) from the US Radiologic Technologist Health Study Gene Polymorphism* Total** number Common homozygote frequency Heterozygote frequency Rare homozygote frequency Base Excision Repair Genes XRCC1 XRCC1 XRCC1 APEX APEX POLD1 BRCA1 interacting proteins BRCA2 BRCA2 BRCA2 BRIP1 BRIP1 ZBRK1 ZBRK1 ZBRK1 ZBRK1 Growth factor genes TGFß1 TGFß1 TGFß1 IGFΒP3 R194W(rs1799782) R280H(rs25489) R399Q(rs25478) Q51H(rs1048945) D148E(rs1130409) R119H(rs1726801) N289H(rs2421655) N372H(rs144848)*** T1915I(rs4987717) -64 G>A(rs2048718) P919S(rs4986764) L66P(rs2278420) S472P(rs4986771) R501S(rs2278415) 1845 C>T (rs4986770)*** L10P(rs1982073) P25R(rs1800471) T263I(rs1800472) -202A>C(rs2854744) 748 748 748 746 745 748 748 747 748 748 745 744 748 746 747 745 745 748 746 n 664 676 321 687 219 650 698 405 713 211 268 535 694 576 640 263 629 709 194 % 88.8 90.4 42.9 92.1 29.4 86.9 93.3 54.2 95.3 28.2 36.0 71.9 92.8 77.2 85.7 35.3 84.4 94.8 26.0 n 82 71 335 58 387 92 50 274 35 370 355 190 52 154 107 357 109 39 360 % 11.0 9.5 44.8 7.8 51.9 12.3 6.7 36.7 4.7 49.5 47.7 25.5 7.0 20.6 14.3 47.9 14.6 5.2 48.3 n 2 1 92 1 139 6 0 68 0 167 122 19 2 16 0 125 7 0 192 % 0.3 0.1 12.3 0.1 18.7 0.8 0.0 9.1 0.0 22.3 16.4 2.6 0.3 2.1 0.0 16.8 0.9 0 25.7 * 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. dbSNP reference sequence number in parentheses. ** Numbers vary because not all the cases could be genotyped due to technical issues with the sample. Also some genotyped cases were dropped from kin-cohort analyses because telephone interviews had not been completed at the time of blood collection. *** Test for significant deviation from Hardy Weinberg Equilibrium, p = 0.05 RR = 0.2; 0.1–0.5, respectively) and BRCA2 N372H heter- ozygotes (to age 70; HR = 0.2; 0.1–0.5) compared to com- mon homozygotes. When we adjusted the p-values for multiple comparisons, only the heterozygous associations of decreased risk up to age 70 in APEX D148E and BRCA2 N372H remained significant at p < 0.001. Estimates of the cumulative risk by age are graphically dis- played for each SNP (arranged in alphabetical order) in Figure 1. The SNPs in Figure 1 are either rare (prevalence of the homozygous variant was roughly less than 10%) or little curve separation was seen in the non-parametric approach, and so heterozygous and homozygous variant carriers were combined. For SNPs with a higher preva- lence, estimated cumulative risks are shown in Figure 2 for each genotype separately. The BRCA2 N372H and BRIP1 - 64 G>A plots show individuals homozygous for the com- mon allele with risks intermediate between heterozygotes (lowest breast cancer cumulative risk) and the homozygous carriers of the rare variant (highest breast cancer cumulative risk). For APEX D148E, the risk in homozygous common or variant carriers is nearly identi- cal. The XRCC1 R399Q plot shows nearly completely overlapping risk for the homozygous common allele and the heterozygotes, but the homozygous variant risk is ele- vated across the age range. The curves for the BRCA2 N372H and APEX D148E polymorphisms illustrate the extremely low estimated risk for heterozygous carriers. Discussion We found evidence of a differential breast cancer risk asso- ciated with the variants XRCC1 R194W, XRCC1 R399Q, BRIP1 P919S, APEX D148E, and BRCA2 N372H using the kin-cohort analytic method. Multiple forms of DNA repair are found in mammalian species, of which the base excision repair pathway is one type involving complex protein interactions with non-bulky lesions in DNA. Since XRCC1 is a scaffolding protein integral to base excision repair [reviewed in [20]], the polymorphic loci in XRCC1 (R194W, R280H and R399Q) have been evaluated for risk at various cancer sites because their location within the gene or their conserved status make them ideal candidates with functional significance more likely [21]. Although most studies of cancer have found a decreased risk for the Page 5 of 12 (page number not for citation purposes)