Hereditary Breast Cancer Syndromes: Molecular Pathogenesis and Diagnostics


Breast cancer is a major cause of morbidity and mortality worldwide. Approximately, 20% of breast cancer cases are due to a familial predisposition. Most of these familial breast cancers are due to mutations in well‐known genes linked to breast cancer, such as BRCA1, BRCA2, TP53, CHEK2, PTEN, CDH1, STK11/LKB1, RAD50, BRIP1 and PALB2. Some of these cancers are, however, due to (a combination of) mutations in lower penetrance genes or some cancers show no relationship with known susceptibility genes. In this article, we describe the function of recently known breast cancer susceptibility genes, the molecular pathogenesis and the histopathology of these hereditary breast cancer syndromes. This may provide a better understanding and classification of hereditary breast cancer and may offer tools for better diagnosis and selection of patients sensitive to specific targeted therapies.

Key Concepts

  • Breast cancer is the most frequent cancer diagnosed in women worldwide.
  • In 5–10% of total breast cancer cases, there is familial breast cancer susceptibility.
  • Hereditary breast cancer is familial breast cancer with a clear Mendelian inheritance pattern.
  • Breast cancer susceptibility genes can be divided into high‐, intermediate‐ and low‐risk genes, of which the high‐risk genes BRCA1 and BRCA2 are the best known.
  • Breast cancer susceptibility genes mostly involve DNA repair mechanisms.
  • The discovery of breast cancer susceptibility genes has improved our knowledge of breast carcinogenesis, including the morphological, immunohistochemical and molecular characterisation of familial breast cancer.
  • Moreover, knowledge of the biological processes underlying familial breast cancer offers tools for cancer screening, prevention and management.

Keywords: hereditary breast cancer; BRCA1 ; BRCA2 ; pathology; genetics

Figure 1. Distribution of breast cancer patients. (a) General breast cancer; (b) Familial breast cancer. Adapted from (Melchor and Benítez, ) with kind permission from Springer Science and Business Media.


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Further Reading

Aloraifi F , Alshehhi M , McDevitt T , et al. (2015) Phenotypic analysis of familial breast cancer: comparison of BRCAx tumors with BRCA1‐, BRCA2‐carriers and non‐familial breast cancer. European Journal of Surgical Oncology. DOI: 10.1016/j.ejso.2015.01.021.

Gudmundsdottir K and Ashworth A (2006) The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene 25: 5864–5874.

Jasin M (2002) Homologous repair of DNA damage and tumorigenesis: the BRCA connection. Oncogene 21: 8981–8993.

Tutt A and Ashworth A (2002) The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends in Molecular Medicine 8: 571–576.

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Vos, S, Van der Groep, P, Van der Wall, E, and Van Diest, Paul J(Sep 2015) Hereditary Breast Cancer Syndromes: Molecular Pathogenesis and Diagnostics. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005375]