Cellular Oncology

, Volume 37, Issue 1, pp 1–8

Etiology of familial breast cancer with undetected BRCA1 and BRCA2 mutations: clinical implications


    • Department of Basic Medical Lessons Faculty of Health and Caring ProfessionsTechnological Educational Institute of Athens

DOI: 10.1007/s13402-013-0158-0

Cite this article as:
Yiannakopoulou, E. Cell Oncol. (2014) 37: 1. doi:10.1007/s13402-013-0158-0



Familial breast cancer accounts for 20–30 % of all breast cancer cases. Mutations in the BRCA1 and BRCA2 genes account for the majority of high risk families with both early onset breast cancer and ovarian cancer. Most of the families with less than six breast cancer cases and no ovarian cancer do not carry BRCA1 or BRCA2 mutations that can be detected using routine sequencing protocols. Here, we aimed to review the etiology of familial breast cancer in cases without BRCA1 and BRCA2 mutations.


After excluding BRCA1 and BRCA2 mutations, factors proposed to contribute to familial breast cancer include: chance clustering of apparently sporadic cases, shared lifestyle, monogenic inheritance, i.e., dominant gene mutations associated with a high risk (TP53, PTEN, STK11), dominant gene mutations associated with a relatively low risk (ATM, BRIP1, RLB2), recessive gene mutations associated with horizontal inheritance patterns (sister-sister), and polygenic inheritance where susceptibility to familial breast cancer is thought to be conferred by a large number of low risk alleles.


Current evidence suggests that in the majority of cases with BRCA1 and BRCA2 negative familial breast cancer the etiology is due to interactions of intermediate or low risk alleles with environmental and lifestyle factors. Thus, a careful selection of patients submitted to genetic testing is needed. Clearly, further research is required to fully elucidate the etiology of non-BRCA familial breast cancer.


Familial breast cancerHereditary breast cancerMendelian inheritancePolygenic inheritance

1 Introduction

Breast cancer is the most common malignancy in women in the western world. Familial breast cancer (i.e., positive family history of breast cancer) accounts for 20–30 % of all breast cancer cases [1, 2]. Up to 15 % of all healthy women have at least one first degree relative with breast cancer [3] and empirical data show that the risk to develop breast cancer doubles in these women [4]. It is estimated that an inherited predisposition accounts for 5 to 10 % of breast cancer cases [5]. Hereditary breast cancers are incompletely explained by BRCA1 or BRCA2 mutations, i.e., ~70 % of the cases are not associated with such mutations [6]. In familial breast cancer, BRCA1 and BRCA2 germline mutations explain ~25 % of the cases [7]. In fact, the proportion of families with breast cancer that carries mutations in either BRCA1 or BRCA2 strongly depends on the ethnic populations [8] and the characteristics of the families analyzed [9, 10]. According to those studies, BRCA1 accounts for ~15 % of the inherited breast cancers and ~45 % of the families with breast and ovarian cancer. BRCA1 and BRCA2 gene mutations account for the majority of high risk families with both early onset breast cancer and ovarian cancer. However, most of the families with less than six cases of familial breast cancer and no ovarian cancer or male breast cancer do not carry BRCA1 or BRCA2 mutations that can be detected using routine sequencing protocols [5]. Non-BRCA hereditary breast cancer accounts for 67 % of breast cancer cases in families with only female breast cancer and four or five affected members. In a Spanish study of 32 families with at least three cases of female breast cancer and at least one of them diagnosed before the age of 50 years, hereditary non-BRCA breast cancer accounted for 75 % of the cases [5].

Based on these observations, more recent research efforts have focused on the identification of additional susceptibility genes by applying multiple approaches. Families with three or more breast cancer cases have been subjected to traditional linkage studies aimed at capturing moderate or high penetrance susceptibility genes. Breast cancer case–control studies, an approach primarily appropriate for the identification of low penetrance susceptibility genes, have been used to identify genetic variants or polymorphisms that confer an increased risk of breast cancer through a wide variety of cellular pathways, including DNA damage repair and immune surveillance pathways [11]. In addition, non hereditary causes of familial breast cancer have been suggested. Here, we aimed to review the etiology of familial breast cancer that cannot be explained by BRCA1 or BRCA2 mutations detected by conventional methods.

2 Monogenic inheritance: dominant gene mutations with a high penetrance

Hereditary breast cancer caused by mutations in BRCA1 or BRCA2 is the most common autosomal dominant disorder associated with a high breast cancer risk [12]. Besides, there are other rare cancer predisposing syndromes associated with an increased breast cancer risk, including Li Fraumeni Syndrome, Cowden syndrome, Hereditary Diffuse Gastric Cancer/Familial Lobular Breast Cancer syndrome and Peutz Jeghers syndrome.

Li Fraumeni syndrome is a clinically and genetically heterogeneous autosomal dominant disorder that is caused mainly by germline mutations in the TP53 gene (chromosome 17p13). The p53 protein plays a vital role in cell cycle regulation and apoptosis. Li Fraumeni syndrome is diagnosed based on the following criteria [13]: a proband with sarcoma diagnosed before 45 years of age, plus a first degree relative with any cancer before 45 years of age, plus one additional first or second degree relative with any cancer before the 45 years of age or a sarcoma at any age. According to Birch [14], Li Fraumeni-like syndrome is defined by the following criteria: a proband with any childhood cancer or sarcoma, a brain tumor or an adrenocortical tumor diagnosed before 45 years of age, plus a first or second degree relative with a classical Li Fraumeni syndrome tumor (i.e., sarcoma, premenopausal breast cancer, brain tumor, leukemia, adrenocortical tumor) at any age, plus a first or second degree relative with any cancer before 60 years of age. Alternatively, according to Eeles [15], Li Fraumeni-like syndrome is defined by the following criterion: two first or second degree relatives with Li Fraumeni syndrome-related malignancies at any age. Although no other gene has been found to be associated with Li-Fraumeni syndrome, recent data show that functional effects of particular genomic variants, such as polymorphisms in the TP53 gene or in some of its regulators such as MDM2 (murine double minute 2), DNA copy number variants (CNVs), and variations in telomere length may have a strong impact on an individual’s risk and on the tumor spectrum [16]. Recent studies in large cohorts have shown that TP53 mutations occur in 1:5,000 individuals [16]. Although TP53 mutations are detectable by sequencing, counseling and clinical follow up are problematic due to the wide variation in disease presentation [16].

Cowden syndrome is a rare genetic disorder related to increased cellular proliferation of ectodermal, mesodermal and endodermal tissues [17]. It is characterized by the occurrence of multiple hamartomas in the skin, breast, thyroid, gastrointestinal tract, endometrium and brain, as well as an increased risk for malignant tumors of the breast, thyroid, endometrium and skin [16, 17]. Affected individuals exhibit congenital abnormalities such as macrocephaly, facial trichelimmomas, acral keratosis, and papillomatous papules that present in the third decade [18]. Approximately 80 % of patients with Cowden syndrome have an identifiable germline mutation in the PTEN gene, a tumor suppressor gene that negatively regulates the pro-survival PI3K/Akt/mTOR pathway through its lipid phosphatase activity [19]. Loss of PTEN activity activates this pathway and leads to increased cellular growth, proliferation, migration and survival. Germline PTEN mutations have also been associated with syndromes that do not exhibit an increased risk of malignancy, including Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome and Proteus-like syndrome. Together, these syndromes are defined as PTEN hamartoma syndrome (PHTS) [20]. The diagnosis of PHTS is made only when a PTEN mutation is identified [18]. Although only Cowden syndrome is associated with an increased risk of malignancy, out of precaution all individuals with a PTEN mutation are currently recommended to follow the cancer surveillance protocol for Cowden Syndrome [20]. Surveillance for breast cancer in individuals with Cowden syndrome includes monthly self examination beginning at 18 years of age (females and males), annual clinical breast examinations beginning at 25 years of age, and annual mammography and breast MRI beginning at 30–35 years of age, or 5 to 10 years earlier than the youngest age at which breast cancer has been diagnosed in the family [18]. When a PTEN mutation has been found in a proband, molecular genetic testing of asymptomatic relatives will reveal those who have the family-specific mutation and, thus, need ongoing surveillance.

Hereditary Diffuse Gastric Cancer syndrome is an inherited cancer susceptibility syndrome characterized by autosomal dominance and a high penetrance [21]. It is defined by > 2 cases of diffuse gastric carcinoma in first degree relatives, with at least one documented case of diffuse gastric carcinoma before the age of 50 years, or multiple cases of gastric cancer of which at least one is identified as diffuse gastric carcinoma before the age of 50 years. In 30–50 % of the cases a causative germline mutation in the CDH1 gene is identified. The CDH1 gene, located on chromosome 16q22.1, encodes E-cadherin, a calcium-dependent cell adhesion glycoprotein, which is important for cell-cell adhesion [22]. Females with familial diffuse gastric cancer have an increased risk of ~50 % of also getting lobular breast cancer [23]. At present, however, there are insufficient data on the efficacy of breast screening in females with pathogenic CDH1 mutations. But, for those who chose to undergo screening, monthly breast self examination starting at the age of 35 years, annual mammography and breast MRI, and a biannual clinical breast examination is recommended. Currently, there is still a lack of clinical information on the age at which breast cancer screening should be started [24].

Peutz-Jeghers syndrome is characterized by perioral pigmentation, hamartomatous polyposis and a predisposition to benign and malignant tumors of the gastrointestinal tract, breast, ovary, uterine cervix and testis [25]. This syndrome is caused by inactivating germline mutations in one allele of the STK11 gene. The STK11 (LKB1) gene, located on chromosome 19p13.3, encodes a serine/threonine kinase and functions mainly through inhibition of the mTOR pathway. STK11 mutations act in an autosomal dominant fashion. Patients with this syndrome have a 30–50 % risk of developing breast cancer [26].

3 Monogenic inheritance: dominant gene mutations with an intermediate risk

Understanding of the function of BRCA1 and BRCA2 in the DNA damage pathway has led to the assessment of functionally related genes and the concomitant identification of rare mutations in the CHEK2, ATM, BRIP1, PALB2, NBS1, MLH1, MSH2 and MSH6 genes. Subsequent family-based and population-based approaches have indicated that these genes confer an intermediate risk for breast cancer.

CHEK2 (checkpoint kinase 2) is the human homolog of Rad53 (Saccharomyces cerevisiae) and Cds1 (Schizosaccharomyces pombe). The CHEK2 gene is located on chromosome 22q12.1 and encodes a cell cycle checkpoint kinase which is a key mediator in DNA damage responses [27]. CHEK2 is activated by the kinases ATM and ATR in response to DNA double-strand breaks and replicative stress, respectively. Activated CHEK2 monomers phosphorylate numerous downstream substrates, including the p53 tumor suppressor, CDC25 family proteins and BRCA1 at serine 988, which activate cell-cycle checkpoints and enhance DNA repair efficiency. Thus, it has been suggested that CHEK2 plays a role in breast cancer susceptibility. The association between CHEK2 and breast cancer risk has been supported mainly by case–control studies of founder mutations. One recurrent truncating mutation in CHEK2, 1100delC, has been shown to confer an approximately three-fold increased risk for breast cancer in the general Danish population [28]. A larger CHEK2 deletion spanning exons 9 and 10 has been described as a Czech founder mutation and accounts for 0.9 % of breast cancer patients in Poland [29]. However, given the fact that recurrent founder mutations are rare in at least some populations, full gene sequencing has been suggested to determine whether other mutations may confer an increased risk for breast cancer [30]. In an interesting recent trial, Desrichard et al. [31] investigated the contribution of CHEK2 mutations to non-BRCA hereditary breast cancer by direct sequencing of its whole coding sequence in 507 hereditary breast cancer cases and 513 controls. Sixteen mutations were identified in cases and 4 in controls, including 9 missense variants with uncertain causality. The majority of the variants were found to be likely deleterious for protein function based both on in silico analyses and in vitro kinase activity assays. After removing one variant, present in both cases and controls that was proposed to be neutral, the mutation frequency was 1.48 % for cases and 0.29 % for controls (P = 0.0040). The odds ratio of breast cancer in the presence of a deleterious CHEK2 mutation was 5.18, implying that rare non-founder mutations in CHEK2 may confer a substantial risk in some populations. Available data suggest that women who carry a null mutation in CHEK2 have a two- to three-fold increased risk for breast cancer. Although genotyping for the 1100delC mutation of CHEK2 has been suggested for high risk women who are negative for BRCA1 and BRCA2, as of yet genetic testing for CHEK2 remains a matter of debate [31, 32].

The ataxia-telangiectasia mutated (ATM) gene encodes a protein kinase that plays a major role in activating cellular responses to DNA double-strand breaks through downstream phosphorylation of central players in DNA damage response pathways, including BRCA1, p53, and CHECK2 [33]. ATM is transmitted in an autosomal recessive manner. The carrier frequency is estimated to be approximately 1 % [34]. Assessment of the effect of ATM heterozygosity on breast cancer development was motivated through epidemiological studies of ataxia telangiectasia families indicating that heterozygous women may have an increased risk of breast cancer [35]. One of the clinical features of ataxia telangiectasia patients is an extreme cellular sensitivity to ionising radiation. This notion, together with the observation that a significant proportion of breast cancer patients shows an increased acute or late normal tissue reaction after radiotherapy, has led to the suggestion that ATM heterozygosity may play a role in radiosensitivity and breast cancer development [36]. Loss of heterozygosity (LOH) at the ATM locus has been reported in 30–40 % of breast tumors, and 50–70 % of breast tumors show altered ATM protein levels [37]. Current data indicate that women carrying a heterozygous ATM mutation exhibit a two- to five-fold increased risk of breast cancer [38]. Mutations that have been reported in ATM include truncating, splice site and missense mutations [39]. To what extent heterozygous ATM mutation carriers are at risk for breast cancer may depend on the type of mutation. Missense mutations may be responsible for the majority of breast cancers occurring among ATM heterozygotes [40].

Fanconi anaemia (FA) is a rare recessive DNA repair deficiency disorder which is linked to a number of genes (12 up till now) that, together with BRCA1, are involved in homologous recombination repair mechanisms. Mutations in FANCJ (BRIP1) and FANCN (PALB2) are associated with a two-fold increased risk of breast cancer [41, 42].

Nijmegen breakage syndrome is a chromosome instability syndrome that is caused by mutations in the NBS1 gene, located on chromosome 8q21. The NBS1 protein forms, together with proteins encoded by the RAD50 and MRE11 genes, the MRN complex that is involved in the recognition and repair of DNA double strand breaks [43]. DNA double strand breaks are extremely cytotoxic and elicit cell damage repair responses. ATM is the primary activator of these responses. The recruitment of ATM to double strand breaks requires proteins of the MRN complex [44]. Single gene disorders involving the MRN complex overlap with one another and with ataxia telangiectasia. The similarity between ATM and the MRN complex prompted investigators to assess the role of the MRN genes in breast cancer susceptibility [45]. By doing so, it was found that the NBS1 gene can be added to the growing list of genes involved in DNA double strand break repair which, if mutated, confers a 2- to 4-fold increased risk for breast cancer [46].

The mismatch repair genes MLH1, MSH2, MSH6 and PMS2 encode proteins that play significant roles in post-replication mismatch repair mechanisms that maintain microsatellite stability through the correction of base substitution mismatches and insertion/deletion events [47]. Mutations in these genes, and 3′ deletions of the MSH2 upstream gene EPCAM, have been associated with Lynch-syndrome (hereditary non-polyposis colorectal cancer) [48]. Women diagnosed with Lynch syndrome are at an increased risk of several cancers including breast cancer [49]. In fact, in some families breast cancer is part of the syndrome and appears to be related to the absence of either the MLH1 or the MSH2 protein [50]. In addition, a causative role of MSH6 in the occurrence of breast cancer has been suggested [51].

Neurofibromatosis type 1 is an autosomal dominant disorder characterized by multiple café-au-lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas and iris Lisch nodules. Less common, but potentially more serious manifestations include plexiform neurofibromas, optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia and vasculopathy. Three studies have indicated that women with NF1 gene mutations, especially those under 50 years of age, may be at an increased risk of breast cancer [5254].

Recently, genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in five novel genes associated with breast cancer susceptibility, i.e., TNRC9, FGFR2, MAP3K1, H19 and LSP1 [55]. The exact relevance of these genes in breast cancer risk still remains to be established.

4 Polygenic inheritance: multiple risk alleles and environmental factors

Next to the above mentioned monogenic models, also a polygenic mode of inheritance has been suggested for familial breast cancer [56]. A family history of late-onset breast cancer (FHLBC) suggests a multi-factorial scenario, including interactions between multiple genes, environmental factors and lifestyle factors that are often shared within families [57]. SNPs, the most common type of genetic variants, can occur in both coding and non-coding regions, with the majority of them being located in non-coding regions. SNPs located near a particular gene can be used as markers for that gene, whereas SNPs located in coding regions may actually affect the corresponding protein, primarily its expression level [58]. Yet, these SNPs are considered as low risk factors, since they are often present in both patients and healthy controls. The presence of one of these SNPs may only marginally affect the risk to develop breast cancer. Population-based candidate gene and GWAS studies have identified 18 SNPs that confer susceptibility to breast cancer [58]. These SNPs account for 8 % of the familial breast cancer cases [58] implying that many more relevant SNPs still await discovery. Currently, genotyping for low risk SNPs is not indicated, since it is expected that incorporation of this genetic information would only marginally improve the performance of routine approaches that are based on traditional (monogenic) risk factors [58].

5 DNA copy number variations and familial breast cancer

DNA copy number variations (CNVs) encompass large (> 100 kb) insertions, deletions and duplications. CNVs have recently been reported to represent the most common structural variations present within the human genome, affecting approximately 12 % of the human genome [59]. The impact of CNVs on gene expression and protein structure has amply been reported [60]. CNVs involving deletions have been reported in a large number of highly penetrant cancer predisposing genes, including BRCA1 and BRCA2. However, the overall role of CNVs in the etiology of familial breast cancer has, as yet, not been adequately assessed. Data from a very recent trial concerning whole genome CNV profiling of 64 familial and early onset breast cancer patients that were negative for BRCA1/BRCA2 mutations have, however, suggested that rare CNVs can contribute to the etiology of BRCA-negative familial breast cancer [61].

6 Epigenetics and familial breast cancer

Epigenetic modifications include DNA methylation, covalent histone methylation and acetylation, chromatin remodelling, and non-coding RNA-mediated regulation of gene expression [62]. DNA methylation studies in cancer have revealed both hypermethylation of promoter CpG islands and global hypomethylation of primarily repetitive DNA sequences [63]. CpG islands located in promoter regions of protein coding genes are normally unmethylated. Anomalous hypermethylation of these promoter regions is associated with transcriptional silencing. Thus, hypermethylation serves as an alternative mechanism for inactivation of tumor suppressor genes [64]. The role of epigenetic changes in the development and progression of sporadic cancers has been well documented. These somatic epigenetic changes are observed in both tumor tissues and precursor lesions. Recently, however, it has been recognized that epigenetic aberrations can also occur as ‘constitutional or germline epimutations’ involving soma-wide hypermethylation of tumor suppressor genes or DNA mismatch repair genes in normal body cells that confer a similar, but not necessary identical, cancer phenotype as a genetic mutation within the same gene [6567]. These so called epimutations are associated with distinct patterns of inheritance, depending on the nature of the mechanisms underlying them [68]. The role of epigenetic alterations in the etiology of familial breast cancer has not been adequately addressed yet. In addition, it is not really known whether such epigenetic changes act as early driving epimutations or as late event epimutations [69]. In familial tumors, the importance of epigenetic inactivation largely depends on the gene involved. Tumors resulting from germline mutations in, for example, the APC or BRCA1 gene frequently exhibit second-hits such as somatic mutations or LOH, thus leaving little ‘room’ for hypermethylation [70]. On the other hand, in Lynch syndrome- and Peutz-Jeghers syndrome-associated tumors, epigenetic second-hit modifications may be found [70]. In addition, it has been shown that hereditary breast cancer tumors may show promoter hypermethylation of other tumor suppressor genes and global hypomethylation similar to that observed in sporadic tumors [70]. A recent genome wide DNA methylation profiling study performed on familial breast cancer cases to identify patterns of methylation specific to BRCA1-, BRCA2-, and non-BRCA familial breast cancers revealed that non-BRCA familial breast cancers share a distinct DNA methylation profile.

BRCA1 is considered to be a tumor suppressor gene, implying that loss of expression of both alleles is necessary for function failure. The most prominent feature of BRCA1 deficient cells is the inability to repair DNA cross-links and DNA double strand breaks induced by error-free homologous recombination [71]. BRCA-dependent hereditary breast cancers are most commonly attributed to germline ‘first hit’ mutations, followed by loss of the second allele, commonly through genomic deletion (‘second hit’). However, BRCA1 may also participate in hereditary carcinogenesis through other mechanisms, including promoter hypermethylation and somatic mutation [72, 73]. The impact and significance of epigenetic silencing of BRCA1 is functionally equivalent to carrying a germline BRCA1 mutation, with both events leading to the same disturbance of gene expression in a cancer cell [74]. It has been shown that aberrant CpG island methylation never occurs when only one mutant allele is present in the tumor. In case two alleles are present, and the tumor carries a germline mutation on one allele, promoter methylation on the other wild-type allele may occur to accomplish biallelic inactivation of that particular gene. However, it has been proposed that in breast tumors with germline BRCA1 or BRCA2 mutations promoter hypermethylation does not constitute a frequent second-hit event. On the contrary, LOH and somatic mutations are the most commonly observed second-hits in these tumors [75].

7 Other breast cancer inheritance patterns

Non-BRCA high risk families have been associated with a history of prostate cancer [7679]. A very recent trial has proposed an association between lobular breast cancer and a paternal history of cancer, most commonly prostate cancer. Based on these observations, a number of possible etiologies have been suggested by the investigators: (i) imprinting, i.e., the gene or polymorphism involved undergoes maternal imprinting and, therefore, only the father’s allele would be expressed and thus predispose to (prostate) cancer in men and breast cancer in their daughters. This paternal model of inheritance involving men with prostate cancer and women with breast cancer is further supported by other studies [79] that revealed an (imprinted) region on chromosome 11p15 with a paternal inheritance associated with breast cancer; (ii) copy number variation of a gene beneficial for cancer development, that would predispose men for prostate cancer and women for breast cancer; (iii) the presence of common recessive haplotypes, that in a heterozygous state predispose to cancer in men and in a homozygous state to breast cancer in women; in case of uniparental disomy both alleles would be inherited from the father [80].

As yet, little is known about the occurrence of recessive inheritance (horizontal inheritance) in breast cancer. In a recent trial, investigators attempted to define the phenotype of horizontal inheritance in breast cancer [81]. In a clinical series of 1,676 breast cancer patients, a family history was scored as vertical (grandmother-aunt-mother-sister-daughter) or horizontal (sister-sister) and, subsequently, related to histopathological characteristics or other clinical parameters. By doing so, tubular breast cancer was found to be associated with a horizontal family history. X-linked recessive inheritance has been suggested in a case of familial male breast cancer [82].

Finally, familial breast cancer may not be due to an hereditary component, but rather to a shared lifestyle, i.e., smoking, (absence of) physical activity, (adverse) food consumption and/or alcohol (ab)use [83] or, alternatively, a mere chance clustering of apparently sporadic cases.

8 Conclusion and future perspectives

It has been estimated that familial breast cancers may account for approximately one third of all breast cancers. We reviewed the etiology of non-BRCA familial breast cancers, including its multi-factorial etiology, taking into account multiple genetic, epigenetic and lifestyle/environmental factors. Since epigenetic modifications constitute links between environmental and genomic factors, it is suggested that genetic, epigenetic and environmental factors may underlie the pathogenesis of familial breast cancer. In fact, multiple interactions are expected among multiple genetic, epigenetic and environmental factors, leading to multiple causative mechanisms. Clearly, there are also cases of familial breast cancer without any overt genetic component.

Although research efforts in the past have mainly focused on BRCA gene mutations, these mutations may only represent the top of the proverbial iceberg. Data presented in this review suggest that in the majority of cases with non-BRCA familial breast cancer its etiology may be due to interactions of large numbers of intermediate or low risk alleles with environmental and lifestyle factors. Thus, a careful selection of patients submitted to genetic testing is recommended, i.e., a negative genetic test does not imply the absence of an inherited component. On the other hand, women with a history of familial breast cancer should be counseled to adopt a healthy lifestyle.

Clearly, further research is needed to fully elucidate the etiology of non-BRCA familial breast cancer. Future research efforts should encompass various genetic variants, i.e., mutations, single nucleotide polymorphisms, copy number variants, micro- and mini-satellites, in conjunction with various epigenetic variations, i.e., DNA methylation, histone modification and non-coding (micro)RNAs. Although such a perspective would be technologically demanding, modern technological achievements, such as third generation sequencing, are expected to render such an approach feasible. Elucidation of the etiology of familial breast cancer is expected to significantly contribute to the estimation of breast cancer risk in women with a familial history of breast cancer, as well as to the primary and secondary prevention of breast cancer using personalized chemoprophylaxis strategies, lifestyle changes and personalized breast cancer screening policies. In addition, elucidation of the etiology of familial breast cancer is expected to unravel novel cellular and molecular mechanisms underlying breast cancer development, leading to the identification of new putative drug targets enabling the rational design of novel treatment strategies for breast cancer and chemoprophylaxis.

Conflict of interest

The authors have nothing to disclose.

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© International Society for Cellular Oncology 2013