Genetic Susceptibility as a Possible Risk Factor for Breast Cancer.
Authors: Kulkarni S. , Zhou X. , Nesline M. , Murekeyisoni C. , Watroba N. , Berry M. , Davis W. , Ambrosone C. , Zheng Y. 
Published: December 2010

Background: Established risk factors for breast cancer (BC) only explain 25% to 47% of BC incidence. The Gail model is commonly used to assess BC risk and determine eligibility for prevention trials. Unfortunately, it has a discriminatory accuracy of 58% at the individual level. A greater understanding of BC risk factors is needed to offer improved risk stratification and prevention. It is plausible that BC risk may be related to deficiencies or abnormalities in DNA repair and cell cycle checkpoints because of their importance in maintaining genomic integrity. Recent epidemiologic studies support this hypothesis. In this pilot project, the bleomycin mutagen sensitivity assay (MSS), a measure of genetic susceptibility was performed on women of low, intermediate, and high risk based on commonly used risk models to determine if there was any correlation between MSS and established BC risk factors.Methods: Women in the Prevention Clinic at RPCI consented to donate blood for this study as part of the Data Bank and BioRepository (DBBR). Gail and Claus Models were calculated using CancerGene. Women were stratified into three groups low (&lt;20%), intermediate (20%-35%), and high (&gt; 35%) lifetime BC risk. For logistic regression analysis, women were grouped into low risk (&lt;20%) and high risk (≥20%). MSS in blood lymphocytes were performed at LCCC using fresh blood samples. The mean values of MSS were compared between low, intermediate, and high risk groups using Wilcoxon-Mann-Whitney tests. Multivariate logistic regression was used to analyze the relationship between BC risk groups and MSS.Results: A total of 78 women were enrolled in the study. MSS were performed on 70 blood samples and 67 had evaluable slides. There were 30, 26 and 11 women in the low, intermediate, and high risk groups respectively. The mean age was 49.1 years. There was no statistical difference between the three groups with respect to age, race, menopausal status, proportion of patients with a family history of BC or another cancer, and smoking status (never, former, or current). The mean MSS score was not significantly different among the three risk groups: mean ±SD = 0.86±0.37, 0.84±0.37 (p=0.565), and 0.76+0.44 (0.361) for low, intermediate and high risk groups respectively. Spearman correlation revealed that MSS score did not correlate with Gail lifetime BC risk score (r=-0.054, p=0.668) or Claus model-10 year risk score (r=-0.057, p=0.722). Using the median in low risk women as a cut point, when women who had higher MSS score were compared with women had lower MSS score, the adjusted OR was 1.16 (95% CI, 0.29 to 4.57), adjusted for age, race, smoking status, BMI and menopausal status. When the MSS score were categorized into quartiles, no significant dose-response relationship was observed.Conclusions: In this pilot study, there was no correlation between commonly used breast cancer risk assessment models based on hormonal, family and biopsy history and the MSS in our study population. Previous case-control studies have consistently shown that MSS is significantly associated with BC risk. The lack of correlation between mutagen sensitivity and Gail or Claus risk score suggests that mutagen sensitivity may measure the host susceptibility factors that are not considered by Gail or Claus risk models.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6067.