Abstract
The female carriers of BRCA1/2 pathogenic variants (mutations) face a high lifetime risk of developing breast and/or ovarian cancer. However, the risk may differ depending on various genetic and non-genetic elements, including metabolic and hormonal factors. We previously showed that a 6-month Mediterranean dietary intervention trial reduced body weight and the levels of insulin-like growth factor I and other metabolic factors in BRCA mutation carriers. We also found that higher baseline levels of glucose and insulin were significantly associated with BRCA loss-of-function (LOF) variants. In this study, we evaluated whether the BRCA mutation type influences in a different way the metabolic and hormonal response to the dietary intervention in 366 female carriers. The LOF variant carriers randomized in the intervention group (IG) showed significantly higher changes in most considered parameters compared to the control group (CG). The nonsynonymous variant carriers in the IG showed similar changes, but none of them were statistically significant. Performing the “delta” analysis of differences (intention-to-treat analysis), we observed that in LOF variant carriers, the reduction of insulin levels was significantly more pronounced that in nonsynonymous variant carriers. These findings suggest that the changes in insulin levels might be modulated by a different response to the dietary intervention mediated by BRCA LOF variants.
Highlights
The women carriers of pathogenic variants in the BRCA1 and BRCA2 genes (BRCA1/2) show a very high risk of breast cancer (BC) and/or ovarian cancer (OC) (Kuchenbaecker et al, 2017)
In a previous randomized controlled trial (NCT03066856), we showed that a 6-month dietary intervention based on the Mediterranean diet with moderate protein restriction, significantly modifies the potential metabolic-related modulators of BRCA mutation penetrance, such as body weight, insulin-like growth factor I (IGF-I), and metabolic syndrome (MS) parameters in the female carriers of the BRCA mutations of the intervention group (IG) compared to the control group (CG) (Pasanisi et al, 2014; Bruno et al, 2018; Pasanisi et al, 2018; Bruno et al, 2020; Daniele et al, 2020; Bruno et al, 2021)
We had previously shown that in the whole population of BRCA1/2 mutation carriers who joined our 6-month randomized controlled trial, the dietary intervention based on the Mediterranean diet with moderate protein restriction was effective in reducing IGF-I, body weight, and MS markers but not insulin (Bruno et al, 2020)
Summary
The women carriers of pathogenic variants (mutations) in the BRCA1 and BRCA2 genes (BRCA1/2) show a very high risk of breast cancer (BC) and/or ovarian cancer (OC) (Kuchenbaecker et al, 2017). In the trial on the participants with a complete genetic test, we analyzed the association of the baseline metabolic and hormonal factors (before starting the dietary intervention) with the BRCA1/ 2 variant type, which are categorized into loss-of- function (LOF) or nonsynonymous variants This explorative analysis suggested that higher levels of glucose and insulin were significantly associated with BRCA LOF variants (p = 0.03 and p < 0.001, respectively) (Oliverio et al, 2020). The aim of the present study was to evaluate whether the BRCA pathogenic variant type (LOF vs nonsynonymous) influences in a different way the metabolic and hormonal responses after a 6month dietary intervention, i.e., the different changes in factors including insulin and IGF-I levels, body weight, and MS parameters These changes were further analyzed on the basis of group randomization (IG-nonsynonymous vs CGnonsynonymous and IG-LOF vs CG-LOF). The study included 366 female BRCA mutation carriers who completed our dietary randomized controlled trial
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