BRCA1/2 Variants and Metabolic Factors: Results From a Cohort of Italian Female Carriers

Abstract

Women carriers of pathogenic variants (mutations) in the BRCA1/2 genes face a high lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC). However, metabolic factors may influence BRCA penetrance. We studied the association of metabolic factors with BRCA1/2 variants and the risk effect of metabolic exposures in relation to the position of the mutations within the BRCA1/2. Overall, 438 women carriers of BRCA1/2 mutations, aged 18–70, with or without a previous diagnosis of BC/OC and without metastases, who joined our randomized dietary trial, were included in the study. The pathogenic variants were divided, according to their predicted effect, into loss of function (LOF) and nonsynonymous variants. The association between metabolic exposures and variants were analyzed by a logistic regression model. LOF variant carriers showed higher levels of metabolic parameters compared to carriers of nonsynonymous variants. LOF variant carriers had significantly higher levels of plasma glucose and serum insulin than nonsynonymous variant carriers (p = 0.03 and p < 0.001, respectively). This study suggests that higher insulin levels are significantly associated with LOF variants. Further investigations are required to explore the association of metabolic factors with LOF variants and the mechanisms by which these factors may affect BRCA-related cancer risk.

The Impact of Mediterranean Dietary Intervention on Metabolic and Hormonal Parameters According to BRCA1/2 Variant Type

“…This hypothesis is further supported by the lack of significant differences in the changes of dietary habits when comparing the IG of LOF vs. nonsynonymous variant carriers. It has to be remarked that since we had previously observed that higher levels of insulin at baseline were significantly associated with BRCA LOF variants (Oliverio et al, 2020), the intention-to-treat analysis was carried out controlling for the baseline insulin levels, to rule out a possible bias due to this factor. Insulin, stimulating mitosis and inhibiting apoptosis, promotes cancer growth (Draznin, 2010).…”

“…Detailed information regarding the Italian multicenter, prospective, dietary randomized controlled trial (NCT03066856) and its main results have already been reported ( Pasanisi et al, 2014 ; Bruno et al, 2018 ; Pasanisi et al, 2018 ; Bruno et al, 2020 ; Daniele et al, 2020 ; Oliverio et al, 2020 ; Bruno et al, 2021 ). Following the inclusion criteria of the above trial, study subjects were recruited through family clinics and patient associations among women (18–70 years) carriers of BRCA1/2 mutations, with or without a previous diagnosis of BC/OC and without a clinical evidence of metastases.…”

“…Detailed information regarding the variant nomenclature and classification has been previously described (Oliverio et al, 2020). The pathogenic or likely pathogenic variants were divided into two groups, according to their predicted effect:…”

“…In the trial on the participants with a complete genetic test, we also 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 ). This association seemed stronger in the BRCA2 LOF variant carriers who, in addition, showed at the baseline a worse metabolic condition compared to nonsynonymous variant carriers ( Oliverio et al, 2020 ).…”

“…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 ). This association seemed stronger in the BRCA2 LOF variant carriers who, in addition, showed at the baseline a worse metabolic condition compared to nonsynonymous variant carriers ( 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 6-month dietary intervention, i.e., the different changes in factors including insulin and IGF-I levels, body weight, and MS parameters.…”