Pathogenic mutations in BRCA1 or BRCA2 are only detected in 25% of families with a strong history of breast cancer, though hereditary factors are expected to be involved in the remaining families with no recognized mutation. Molecular characterization is expected to provide new insight into the tumor biology to guide the search of new high-risk alleles and provide better classification of the growing number ofBRCA1/2 variants of unknown significance (VUS). In this review, we provide an overview of hereditary breast cancer, its genetic background, and clinical implications, before focusing on the pathologically and molecular features associated with the disease. Recent transcriptome and genome profiling studies of tumor series from BRCA1/2 mutation carriers as well as familial non-BRCA1/2 will be discussed. Special attention is paid to its association with molecular breast cancer subtypes as well as the latest advances in predicting BRCA1/2 involvement (BRCAness) using molecular signatures, for improved diagnostics and selection of patients sensitive to targeted therapeutics.

Keywords: hereditary breast cancer, molecular profiling, microarray, review, clinical genetics, BRCA1/2


Breast cancer is the most frequent malignant disease and the leading cause of cancer death among women in both economically developed and developing countries. Globally, 1.4 million new breast cancer cases are diagnosed each year, of whom approximately one-third die of the disease.1 The incidence rates are highest in the Western world, where the lifetime risk of developing breast cancer is estimated to be one in nine. Owing to increased awareness, early detection, and better treatment options available, breast cancer mortality rates have declined in recent years.2

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In the middle of the 19th century, the first reports emerged, describing familial aggregation of breast cancers.3 Today, positive family history is one of the most important risk factors for developing breast cancer. It is currently estimated that approximately 5–10% of all breast cancers have a hereditary background. These families show an apparently dominant inheritance pattern and are often characterized by an early age of onset, overrepresentation of ovarian cancers, bilateral breast cancers, and male breast cancers.4

BRCA1– and BRCA2-associated Breast Cancer

Early reports suggested that germline mutations in the genes BRCA1 and BRCA2 were responsible for the majority of hereditary breast cancers, although more recent studies have demonstrated that mutations in the two genes only account for 25–28% of the family risk.5,6 However, it is expected that additional BRCA1/2 mutations remain undetected by the screening methods used today. Women carrying a BRCA1 or BRCA2 germline mutation also have increased risk of developing ovarian cancer and fallopian tube cancer. In addition, BRCA2 mutation carriers also have increased risk of other cancer types such as male breast cancer, prostate cancer, pancreas cancer, gastrointestinal cancers (gall bladder, bile duct, and stomach), and melanoma.7–9 In a large study by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), the median age of diagnosis was found be to be 40 years among BRCA1 and 43 years among BRCA2 mutation carriers.10

Even though germline mutations in BRCA1 and BRCA2 confer high risk of breast and ovarian cancers, the penetrance of these genes is incomplete. The risk in BRCA1 and BRCA2 mutation carriers of developing breast cancer by the age of 70 is 45–87%. For ovarian cancer, the risk is 45–60% among BRCA1 mutation carriers and 11–35% among BRCA2 mutation carriers.11–14 However, the penetrance depends on several different factors, including the type of mutation and exogenous factors. Lifestyle factors such as physical exercise and lack of obesity in adolescence have been associated with significant delay in breast cancer onset.11 It has been shown that common breast cancer susceptibility alleles may act multiplicatively on the breast cancer-risk in BRCA1 and BRCA2 mutation carriers, which might explain why the risk seems to be highest in women from families with multiple breast cancer cases.15

Both BRCA1 and BRCA2 have considerable complex genomic structures, and the coding regions show no homology to previously described genes or to each other. The BRCA1 gene is composed of 24 exons encoding a very large protein of 1,863 amino acids, while BRCA2 consists of 27 exons encoding an even larger protein of 3,418 amino acids. In both genes, the first exon (exon 1) is non-coding and exon 11 is remarkably large.16,17

BRCA1 and BRCA2 function as tumor suppressor genes and are important in maintenance of genomic stability through their role in DNA damage signaling and DNA repair. Both BRCA1 and BRCA2 are implicated in mediating repair of double strand breaks by homologous recombination (HR) by interactions with RAD51. Upon DNA damage, BRCA1 will associate with RAD51 and localize to the damaged region by which BRCA1 becomes phosphorylated. BRCA2 functions downstream of BRCA1 by complex-formation with RAD51. The primary function of BRCA2 is to facilitate HR.18 Cells deficient for BRCA1 or BRCA2 are unable to repair double strand breaks by the error-free HR, resulting in repair by the error-prone non-homologous end-joining (NHEJ) pathway introducing chromosomal instability.19,20 During S-phase, the expression levels of BRCA1 and BRCA2 increase, indicating a function in maintaining genomic stability during the DNA replication process.21 Besides its role in HR, BRCA1 appears to have additional functions in DNA repair. BRCA1 is also part of the BRCA1-associated genome-surveillance complex (BASC), which includes ATM, RAD50, MRE11, and NBS1 and the mismatch repair proteins MLH1, PMS2, MSH2, and MSH6.22 BRCA1 has also been demonstrated to be involved in transcription-coupled excision repair, chromatin remodeling, and together with BARD1 in the ubiquitination process, by which proteins are tagged for degradation by the proteasome.18,23