ReviewWomen at high risk of breast cancer: Molecular characteristics, clinical presentation and management
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.
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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.
References (82)
- et al.
CHEK2 is a multiorgan cancer susceptibility gene
Am J Hum Genet
(2004) - et al.
Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012
Eur J Cancer
(2013) - et al.
Links between genome integrity and BRCA1 tumor suppression
Trends Biochem Sci
(2012) - et al.
Polymorphic variations in the FANCA gene in high-risk non-BRCA1/2 breast cancer individuals from the French Canadian population
Mol Oncol
(2013) - et al.
Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer
Genet Med
(2015) Molecular portraits of breast cancer: tumour subtypes as distinct disease entities
Eur J Cancer
(2004)Cancer susceptibility and the functions of BRCA1 and BRCA2
Cell
(2002)- et al.
Breast-cancer risk in families with mutations in PALB2
N Engl J Med
(2014) - et al.
Recent trends in incidence of five common cancers in 26 European countries since 1988: analysis of the European Cancer Observatory
Eur J Cancer
(2013) - et al.
DNA damage signalling guards against activated oncogenes and tumour progression
Oncogene
(2007)
Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome
Science
Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes
Eur J Hum Genet
Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease
Lancet
Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses' Health Study
Am J Epidemiol
Two decades after BRCA: setting paradigms in personalized cancer care and prevention
Science
Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer
J Clin Oncol
The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups
Nature
Germline RECQL mutations are associated with breast cancer susceptibility
Nat Genet
Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study
Breast Cancer Res
A new genome-driven integrated classification of breast cancer and its implications
EMBO J
Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality
JAMA
Gene-panel sequencing and the prediction of breast-cancer risk
N Engl J Med
Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation
J Clin Oncol
Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis
J Natl Cancer Inst
Rare variants in the ATM gene and risk of breast cancer
Breast Cancer Res
Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations
J Clin Oncol
Frequency and spectrum of cancers in the Peutz-Jeghers syndrome
Clin Cancer Res
Quantitative analysis of chromosomal CGH in human breast tumors associates copy number abnormalities with p53 status and patient survival
Proc Natl Acad Sci U. S. A
The PALB2 gene is a strong candidate for clinical testing in BRCA1- and BRCA2-negative hereditary breast cancer
Cancer Epidemiol Biomarkers Prev
Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups
JAMA
A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer
Biomed Res Int
Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer
JAMA
Breast cancer. The ‘other’ breast cancer genes
Science
Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer
Proc Natl Acad Sci U. S. A
The CHEK2 c.1100delC germline mutation rarely contributes to breast cancer development in the Czech Republic
Breast Cancer Res Treat
Survival and contralateral breast cancer in CHEK2 1100delC breast cancer patients: impact of adjuvant chemotherapy
Br J Cancer
Integrated molecular profiles of invasive breast tumors and ductal carcinoma in situ (DCIS) reveal differential vascular and interleukin signaling
Proc Natl Acad Sci U. S. A
Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland
N Engl J Med
The CHEK2 I157T variant and colorectal cancer susceptibility: a systematic review and meta-analysis
Asian Pac J Cancer Prev
The CHEK2 I157T variant and breast cancer susceptibility: a systematic review and meta-analysis
Asian Pac J Cancer Prev
Opportunities and strategies for breast cancer prevention through risk reduction
CA Cancer J Clin
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