Elsevier

The Breast

Volume 28, August 2016, Pages 136-144
The Breast

Review
Women at high risk of breast cancer: Molecular characteristics, clinical presentation and management

https://doi.org/10.1016/j.breast.2016.05.006Get rights and content

Highlights

  • Mechanisms of breast cancer development are discussed.

  • Family history of breast cancer and breast cancer risk factors are highlighted.

  • Use of biomarkers for definition of high-risk women is proposed.

  • Clinical utility of the identification of breast cancer-susceptibility genes.

  • Women at high risk may be more sensitive to radiotherapy.

Abstract

The presence of breast cancer in any first-degree female relative in general nearly doubles the risk for a proband and the risk gradually increases with the number of affected relatives. Current advances in molecular oncology and oncogenetics may enable the identification of high-risk individuals with breast-cancer predisposition. The best-known forms of hereditary breast cancer (HBC) are caused by mutations in the high-penetrance genes BRCA1 and BRCA2. Other genes, including PTEN, TP53, STK11/LKB1, CDH1, PALB2, CHEK2, ATM, MRE11, RAD50, NBS1, BRIP1, FANCA, FANCC, FANCM, RAD51, RAD51B, RAD51C, RAD51D, and XRCC2 have been described as high- or moderate-penetrance breast cancer-susceptibility genes. The majority of breast cancer-susceptibility genes code for tumor suppressor proteins that are involved in critical processes of DNA repair pathways. This is of particular importance for those women who, due to their increased risk of breast cancer, may be subjected to more frequent screening but due to their repair deficiency might be at the risk of developing radiation-induced malignancies. It has been proven that cancers arising from the most frequent BRCA1 gene mutation carriers differ significantly from the sporadic disease of age-matched controls in their histopathological appearances and molecular characteristics. The increased depth of mutation detection brought by next-generation sequencing and a better understanding of the mechanisms through which these mutations cause the disease will bring novel insights in terms of oncological prevention, diagnostics, and therapeutic options for HBC patients.

Introduction

Cancer has emerged as the leading cause of morbidity and mortality in European populations [2]. The most common diagnose among women worldwide is breast cancer (excluding non-melanoma skin cancers), occurring with the highest incidence in developed countries including the EU, Australia, and the US. Overall, 464,000 women developed breast cancer and 131,000 women died of this diagnosis in Europe in 2012 [18]. It has been estimated that 10–12% of women will develop breast cancer over the course of their life. In contrast to incidence, which has been rising constantly during the last two decades in most countries, the mortality rate has remained stable (data from www.dep.iarc.fr; and seer.cancer.gov), indicating an improvement in breast cancer diagnostics and care.

Numerous genetic, lifestyle and environmental factors affect the risk of breast cancer development ([43]; Table 1). Among these, genetic factors are of particular importance. The presence of breast cancer in any first-degree female relative in general nearly doubles the risk for a proband and the risk gradually increases with the number of affected relatives [7]. Current advances in molecular oncology and oncogenetics enable the identification of high-risk individuals who may benefit from the knowledge about their breast cancer-predisposition in terms of oncological prevention, diagnostics, and therapeutic options.

Section snippets

Breast cancer development

The development of cancer is caused by a gradual and lifelong accumulation of acquired (somatic) mutations and epigenetic changes that, in the case of breast cancer, affect mammary tissue cells and their progenitors [58]. Recent genome-wide analyses of tumor samples have enabled a comprehensive identification of mutations, including those that direct the process of tumorigenesis and are referred to as driver mutations [71]. Multiple driver mutations that have been identified in breast cancer

Family history of breast cancer and breast cancer risk factors

The probability of breast cancer development is higher in high-risk individuals carrying causative germline (constitutive) mutations in the breast cancer-susceptibility genes [60] responsible for hereditary breast cancer (HBC). Patients with HBC form a small but important fraction of breast cancer patients. It has been estimated that heritable factors contribute to 27% of breast cancer cases [39], and the presence of breast cancer in at least one first-degree relative has been documented in 13%

Use of biomarkers for definition of high-risk women. Breast cancer susceptibility genes

The main breast cancer-susceptibility genes (BRCA1 and BRCA2) were discovered in the last decade of the 20th century [49], [81]. Since this pioneering discovery, many other breast cancer-susceptibility genes have been characterized; however, none of the others shows a mutation frequency and clinical importance comparable to BRCA1 and BRCA2.

All breast cancer-susceptibility genes have variable penetrance, which is determined by the proportion of carriers who develop breast cancer over the course

Major breast cancer susceptibility genes BRCA1 and BRCA2

The BRCA1 and BRCA2 genes are the most important breast cancer-susceptibility genes responsible for the development of familial breast and ovarian cancer syndromes 1 and 2 (OMIM #604370, #612555). They account for the development of 3–6% of all breast cancers (Fig. 2). Although both proteins are structurally unrelated, they are a key component of large multiprotein complexes contributing to DDSB repair [38]. The frequency of pathogenic mutations in both genes varies among populations worldwide,

Clinical interpretation of sequence variants in breast cancer-susceptibility genes

The relative rarity of mutations in breast cancer-susceptibility genes restricts mutation analyses only to high-risk individuals. National guidelines largely assume the guidelines of the National Comprehensive Cancer Network (NCCN; www.nccn.org) tailored to the particular population characteristics. Recently introduced NGS-based analyses targeting a collection of numerous cancer susceptibility genes (gene panels) have been adopted to replace the single gene-by-gene analyses (reviewed in [17]).

Radiosensitivity of women at high risk

Due to the involvement of BRCA1 and BRCA2 in the DDSB repair described above (Fig. 1), which eliminates alterations caused by radiation, BRCA1/2 mutation carriers are suspected to have increased sensitivity to radiation [84], [86], [88], [89], [90]. In addition to the mechanisms of involvement in DNA repairs described above, a DNA damage-induced BRCA1 protein complex has very recently been described as a part of the mRNA-splicing machinery. In response to DNA damage, this complex regulates the

Histopathological and molecular characteristics of tumors in this population

The molecular and histopathological characteristics of breast cancers bearing BRCA1 mutations significantly differ from those in non-carriers or in BRCA2 mutation carriers because of the increased prevalence of basal-like and TNBCs, and the increased frequency of medullary and atypical medullary cancers [45]. A BRCA1 mutation analysis is frequently performed in premenopausal patients with medullary and TNBC histology regardless of the familial breast cancer and/or ovarian cancer history. A

Conclusion and further perspectives

Besides lifestyle risk factors, numerous genetic factors have been associated with breast cancer development. The improvement of high-throughput technologies and their availability for clinical cancer research dramatically change our understanding of breast cancer biology and genetics. A recent implementation of NGS into clinical settings improves the identification of genetic breast cancer risks as well as the determination of predictive and prognostic biomarkers in breast tumors. Despite the

Conflict of interest statement

The authors disclose any conflict of interest.

Acknowledgments

We thank our colleagues for their critical comments in the writing of the manuscript. ZK is supported by the grant NT14054 of the Ministry of Health of the Czech Republic. VNK is supported by the K.G. Jebsen Centre for Breast Cancer Research.

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