BMC Cancer 2004, 4 http://www.biomedcentral.com/1471-2407/4/9 Conclusion: Some variants in genes within the base-excision repair pathway (XRCC1) and BRCA1 interacting proteins (BRIP1) may play a role as low penetrance breast cancer risk alleles. Previous association studies of breast cancer and BRCA2 N372H and functional observations for APEX D148E ran counter to our findings of decreased risks. Due to the many comparisons, cautious interpretation and replication of these relationships are warranted. Background Subtle functional deficiencies in highly conserved DNA repair or growth regulatory processes resulting from germ- line genetic variation have been proposed as possible mechanisms for increased genetic susceptibility to breast cancer [1-3], especially since it is estimated that the two known susceptibility genes BRCA1 and BRCA2 may account for less than 4% of all breast cancers [4,5]. Genetic epidemiologic studies suggest that BRCA1/2 account for no more than 20% of the familial risk of breast cancer, and the residual component is likely to be due polygenic inheritance of multiple low-penetrance sus- ceptibility alleles [4-12]. We are conducting genetic studies of breast cancer among a cohort of U. S. radiologic technologists (USRT), in which the primary carcinogen under study is occupational exposure to ionizing radiation. Because the direct and indirect damaging effects of external radiation include oxidized bases and DNA single and double strand breaks, we are investigating 19 candidate variants in eight genes that are either involved in base excision repair, interact with the BRCA1 gene, or regulate cell growth. These genes are also attractive candidates as general breast cancer sus- ceptibility factors because the repair process is not limited solely to exogenous radiation damage and includes carci- nogenic chemicals, dietary constituents, and estrogens. In addition, growth deregulation is common to many devel- oping tumors. In the USRT case-control study, blood samples were col- lected initially from breast cancer cases during 1999–2001 and are currently being collected from a comparable con- trol series. The available genotype data of the breast cancer cases provided an opportunity to perform kin-cohort analyses [13-15] using the case's family history data. In kin-cohort analyses, a cohort of relatives of index subjects is followed for disease occurrence. The genotypes of the relatives are unknown and are inferred based on the known genotype of the corresponding index subject (or proband) and Mendelian inheritance patterns. The kin- cohort method estimates risks in homozygous or hetero- zygous carriers and non-carriers of a variant and statisti- cally accounts for the uncertainty in the indirect genotype information. The kin-cohort analysis offers several unique aspects that distinguish it from the standard case-control analyses we plan to conduct in the future. First, in a kin-cohort analy- sis, risk estimates are obtained from the cancer history of the index cases' family members and thus provide data independent from the typical case-control analysis [16]. Second, kin-cohort analyses afford an opportunity to eval- uate potential survival bias when analyzing the breast can- cer case-control data that may be present given the prevalence sample in our study. The kin-cohort method is robust against such survival bias as cancer history among all family members is analyzed irrespective of the rela- tive's vital status. Third, the underlying population for the case-control study is the cohort of radiologic technolo- gists, who have been exposed to low levels of radiation from their occupation. The relatives of the radiologic tech- nologists, however, are unlikely to have experienced occu- pational radiation exposure. Thus, separate risk estimates from the kin-cohort analysis and the breast cancer case- control study will provide information on whether risk from the genetic variants differs within two populations that have different background risks from radiation exposure. Using the kin-cohort analytic method, we evaluated 19 single nucleotide polymorphism (SNP) variants in the fol- lowing eight genes: XRCC1, APEX, and POLD1 in the base excision repair pathway; BRCA2, BRIP1 (or BACH1), and ZNF350 (or ZBRK1) as BRCA1 interacting proteins; and the growth factor genes TGFß1 and IGFBP3, and their rela- tion to breast cancer risk. Methods Study population In 1982, the U. S. National Cancer Institute, in collabora- tion with the University of Minnesota and the American Registry of Radiologic Technologists, initiated a study of cancer incidence and mortality among 146,022 U.S. radi- ologic technologists who were certified for at least two years between 1926 and 1982. The primary objectives of the study are to describe the carcinogenic risks of long- term, low- to moderate-dose, fractionated occupational radiation exposures and to determine factors associated with radiation sensitivity or cancer susceptibility. The cur- rent median age for cohort members is 53.4 years, and 73% are female. During 1984–1989 and during 1993– 1998, two postal surveys were administered and included Page 2 of 12 (page number not for citation purposes)