Abstract
BackgroundBreast cancer is the most common neoplasia among women in developed countries. The risk factors of breast cancer can be distinguished in modifiable and unmodifiable factors and, among the latter, genetic factors play a key role. Copy number variations (CNVs) are genetic variants that are classified as rare when present in less than 1% of the healthy population. Since rare CNVs are often cause of diseases, over the last years, their contribution in carcinogenesis has become a relevant matter of study. E2F1 is a transcriptional factor that plays an important role in regulating cell cycle and apoptosis. Its double and conflicting role is the reason why it acts both as oncogene and as tumour suppressor, depending on cell context. Since anomalies in expression or in number of copies of E2F1 have been related to several cancers, we aimed to study number of germline copies of E2F1 in women with breast cancer in order to better elucidate their contribution as predisposing factor to this tumour.MethodsWe performed, hence, a retrospective study on 222 Italian women with breast cancer recruited from October 2002 to December 2007. TaqMan CNV assay and Real-Time PCR were carried out to analyse, respectively, E2F1 CNV and E2F1 expression in the subjects of the study. Chi square test or Fisher’s exact test and Student's t‐test were used to calculate the frequency of CNVs and differences in continuous variables between groups, respectively.ResultsIntriguingly, we found that 10/222 (4.5%) women with breast cancer had more copies than controls (0/200, 0%), furthermore, the number of copies positively correlated with E2F1 gene expression in breast cancer tissue, suggesting that the constitutive gain of the gene could translate into an increased risk of genomic instability. Additionally, we found that altered E2F1 copies were present prevalently in the patients with contralateral breast cancer (20%) and all of them had a positive family history, both typically associated with hereditary cancer.ConclusionsOur findings suggest that copy number variations of E2F1 might be a susceptibility factor for breast cancer, however, further studies on large cohorts are to be performed in order to better delineate the phenotype linked to the gain of E2F1 copies.
Highlights
Breast cancer is the most common neoplasia among women in developed countries
We found that the frequency of germinal Copy number variations (CNVs) of E2F1 gene in patients with testicular cancer and melanoma was higher compared to healthy controls and, the increased number of copies of E2F1 correlated with an increased gene expression, especially under stress conditions, suggesting germline
E2F1 CNVs as risk factor of these two tumours (Rocca et al, 2017; Rocca et al 2018). Based on these recent evidence, the aim of this study was to investigate the frequency of CNV of E2F1 in 222 Italian women with breast cancer in order to better elucidate the contribution of this structural variant as a potential predisposing factor to breast carcinogenesis
Summary
Breast cancer is the most common neoplasia among women in developed countries. The risk factors of breast cancer can be distinguished in modifiable and unmodifiable factors and, among the latter, genetic factors play a key role. Breast cancer (BC) is the most diagnosed neoplastic disease and represents the second cause of cancerrelated death, after lung cancer, in women (DeSantis et al 2019) It is a complex and heterogeneous neoplasia whose aetiology involves several risk factors of genetic, Rocca et al Mol Med (2021) 27:26 environmental and behavioural origin (Orlandella et al 2020). Extrinsic risk factors include obesity, physical activity, alcohol consumption and ionizing radiation exposure, while intrinsic risk factors are unmodifiable parameters such as race, ethnicity, sex, age, early menarche, late menopause, late age at first birth, nulliparity, hormonal factor, family history and genetic mutations (Kaminska et al 2015) The latter include rare high-risk mutations (BRCA1 and BRCA2 genes), more moderate susceptibility variants (CHEK2 and ATM genes) and several still unidentified common susceptibility variants associated with low to moderate increased risk. These known risk factors, fail to fully elucidate the high incidence of BC
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