Genetics of Breast Cancer

BRCA1 & BRCA2

BRCA1:

• BRCA1 mutations also predispose to carcinoma of the ovary and possibly carcinoma of the Fallopian tube
  
• Mutations of this gene are particularly common in Ashkenazy Jews (2%)
  
• The risk of developing breast cancer among carriers is around 55% by age 70
  
• The product of BRCA1 is a cell cycle regulated phosphoprotein that can be detected immunohistochemically. Its known functions are:
  
  
  • Transcriptional regulation
  • DNA damage repair
    
  • Cell cycle checkpoint control
    
  • Ubiquitination
    
  • Chromatin remodelling
    
  
  
• Morphologically, BRCA1-associated breast cancers frequently show medullary-like features:
  
  
  • ER-poor or ER-negative
    
  • PGR-negative
    
  • Her-2 negative
    
  • P53-positive (77% v 35% for sporadic cancers)
    
  • CK 5/6 (and other markers of basal phenotype)-positive
    
  
  
• In so called triple negative breast cancers (ER, PGR & Her-2 negative) BRCA1 mutations may be seen in up to 20% of cases
• They express cell cycle proteins cyclins A, B1 and E and SKP2

BRCA2:

• The product of BRCA2 is involved in controlling gene function and DNA repair:



• Gene function:
• Involved in transcriptional activation and may well act in concert with the product of BRCA1


• Involved in the completion of cell division by cytokinesis


• DNA repair:


• BRCA2 gene promotes homologous recombination, a major pathway of DNA double-strand break repair

• The majority of BRCA2-associated tumors are invasive ductal, no special-type tumours


• There is an assosciation with families who develop male breast cancers


• Morphologicaly they are more likely to have pushing tumour margins


• Usually high grade


• More commonly show a luminal phenotype


• More commonly ER-positive - similar to sporadic breast cancers


• P53-positive (45% v 35% for sporadic cancers)


• Express cell cycle proteins cyclin D1 and p27

Testing for BRCA1 & 2

• There is a wide range of molecular-genetic tests for BRCA1 and BRCA2 cancer-predisposing mutations
• These techniques are expensive, complex and time consuming due to the large size of both genes
• For this and other reasons, such as the absence of hotspots for mutations, it is necessary to select liklely candidate families for testing
• Selection based on clinical criteria alone is being superseded using our additional knowledge of gene function and indicative pathological phenotyping

Ataxia telangiectasia mutation (ATM)

This is a very uncommon cancer-associated hereditory condition which is associated with familial breast cancer. There are no specific morphological or immunophenotypic features in the pathology of these breast cancers to suggest the diagnosis which is usually made clinically.

Prognosis