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

Andreina Oliverio,Siranoush Manoukian,Patrizia Pasanisi,Eleonora Bruno,Antonella Daniele,Angelo Paradiso,Donatella Guarino,Mara Colombo,Paolo Radice,Stefano Magno,Daniela Andreina Terribile,Bernard Peissel,Stefania Tommasi

doi:10.3390/cancers12123584

Abstract

Simple SummaryWomen who inherit a BRCAmutation face a high lifetime risk of developing cancer. However, several factors, genetic and/or “environmental”, may influence BRCA penetrance. We studied in 438 women carriers of BRCA1/2 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. The pathogenic variants were divided into loss of function (LOF) and nonsynonymous variants. Findings from this study suggest that higher insulin levels are significantly associated with BRCA LOF variants compared to nonsynonymous variant carriers. Therefore, our results support the hypothesis that the impairment of BRCA protein functions could result in a different association with “metabolic” factors, possibly due to a genetic effect on the etiology of altered response to metabolism.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.

Highlights

Women who have inherited pathogenic variants in the BRCA1 and BRCA2 genes (BRCA1/2) face a very high lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC).A recent prospective study, including approximately 10.000 BRCA1/2 pathogenic variant carriers, observed a chance of developing BC by age 80 of 72% for BRCA1 and of 69% for BRCA2 mutation carriers, respectively
N-terminal of the partner and localizers of BRCA2 (PALB2) protein, and a C-terminal BRCT domain that binds proteins phosphorylated by the Ataxia telangiectasia mutated (ATM) and Ataxia telangiectasia and Rad3-related (ATR) kinases [3]
Had small in-frame deletions, 5 (1.1%) had frameshift substitution and 5 (1.1%) had large deletion

Summary

Introduction

Women who have inherited pathogenic variants (mutations) in the BRCA1 and BRCA2 genes (BRCA1/2) face a very high lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC).A recent prospective study, including approximately 10.000 BRCA1/2 pathogenic variant carriers, observed a chance of developing BC by age 80 of 72% (95% CI, 65–79%) for BRCA1 and of 69% (95% CI, 61–77%) for BRCA2 mutation carriers, respectively. Women who have inherited pathogenic variants (mutations) in the BRCA1 and BRCA2 genes (BRCA1/2) face a very high lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC). BRCA1/2 proteins have several functional domains that bind to specific partners [2]. BRCA1 contains an N-terminal RING domain that has E3 ubiquitin ligase activity (which catalyzes protein ubiquitylation), a nuclear export sequence (NES), three nuclear localization signals (NLSs) in the central portion (which facilitates nuclear import of BRCA1), a coiled-coil domain that binds the. N-terminal of the partner and localizers of BRCA2 (PALB2) protein, and a C-terminal BRCT domain that binds proteins phosphorylated by the Ataxia telangiectasia mutated (ATM) and Ataxia telangiectasia and Rad3-related (ATR) kinases [3]. BRCA2 contains an N-terminal domain that interacts with the

Methods

Results

Conclusion