A Personal Breast Cancer Risk Stratification Model Using Common Variants and Environmental Risk Factors in Japanese Females

Abstract

Personalized approaches to prevention based on genetic risk models have been anticipated, and many models for the prediction of individual breast cancer risk have been developed. However, few studies have evaluated personalized risk using both genetic and environmental factors. We developed a risk model using genetic and environmental risk factors using 1319 breast cancer cases and 2094 controls from three case-control studies in Japan. Risk groups were defined based on the number of risk alleles for 14 breast cancer susceptibility loci, namely low (0-10 alleles), moderate (11-16) and high (17+). Environmental risk factors were collected using a self-administered questionnaire and implemented with harmonization. Odds ratio (OR) and C-statistics, calculated using a logistic regression model, were used to evaluate breast cancer susceptibility and model performance. Respective breast cancer ORs in the moderate- and high-risk groups were 1.69 (95% confidence interval, 1.39-2.04) and 3.27 (2.46-4.34) compared with the low-risk group. The C-statistic for the environmental model of 0.616 (0.596-0.636) was significantly improved by combination with the genetic model, to 0.659 (0.640-0.678). This combined genetic and environmental risk model may be suitable for the stratification of individuals by breast cancer risk. New approaches to breast cancer prevention using the model are warranted.

Keywords: breast cancer; environmental risk model; genetic risk model; personalized prevention; polygenic risk model.

Figure 1

Odds ratio of breast cancer risk in each risk group; OR; odds ratio, CI; confidence interval. (A) Age was included in the crude model. (B) Age, BMI, ethanol intake, smoking, physical activity, family history of breast cancer, age at menarche, parity, number of births, age at first birth, breastfeeding and hormone therapy were included in the adjusted model. Genetic risk group was defined by the number of risk alleles, with 0–10, 11–16 and 17–28 risk alleles defined as the low-, moderate- and high-risk groups, respectively.

Figure 2

ROC curves of genetic, environmental and inclusive risk models in (A) Nagano study, (B) Kagoshima study, (C) Aichi study, and (D) total population. Orange, yellow and navy lines are ROC curves of the Inclusive, Environmental and Genetic models, respectively. Age, body mass index, ethanol drinking, cigarette smoking, physical activity, family history of breast cancer, age at menarche, parity, number of children, age at first delivery, breastfeeding, hormone therapy and menopausal status were adjusted in the Environmental model.