HRAS1 rare minisatellite alleles and breast cancer in Australian women under age forty years

Background: A recent meta-analysis of 23 studies supported the empirically derived hypothesis that women who lack one of the four common minisatellite alleles at the HRAS1 locus are at increased risk of breast cancer. These s tudies relied on visual sizing of alleles on electrophoretic gels and may h ave underreported rare alleles, We determined whether this hypothesis appli ed to early-onset breast cancer by using a new method to size minisatellite alleles. Methods: We conducted a population-based, case-control-family stu dy of 249 Australian women under 40 years old at diagnosis of a first prima ry breast cancer and 234 randomly selected women, frequency matched for age . We sized HRAS1 minisatellite alleles with an Applied Biosystems model 373 automated DNA sequencer and GENESCAN(TM) software. All P values are two-si ded. Results: We found no association of rare alleles with breast cancer, b efore or after adjustment for risk factors and irrespective of how their ef fects were modeled (crude odds ratio = 1.04; 95% confidence interval [CI] = 0.071-1.53; P =.8), The rare allele frequency was 0.173 (95% CI = 0.149-0. 197), three times the pooled estimate of 0.058 (95% CI = 0.050-0.066) from previous studies (P<.001), and was similar for case subjects, 0.177 (95% CI = 0.143-0.221), and control subjects, 0.169 (95% CI = 0.135-0.203) (P =.7) , Conclusion: There was no support for an association between rare HRAS1 al leles and the risk of early-onset breast cancer, despite 80% power to detec t effects of the magnitude of those associations (1.7-fold) previously sugg ested. Implications: The question of whether cancer risk is associated with rare minisatellite HRAS1 alleles needs to be revisited with the use of new methods that have a greater ability to distinguish rare alleles from simil arly sized common alleles.