Background: The relative risks of breast cancer for women exposed to external radiation in childhood, adolescence and early reproductive years are among the highest known radiation related risks for any cancer type. A number of genes increase breast cancer susceptibility and are known to be involved in detection and repair of radiation-induced DNA damage. DNA repair mechanisms play an important role in the cellular response to radiation exposure and hence on the risk of radiation induced cancer. Mutations or polymorphisms in these genes may therefore render cells more sensitive to radiation-induced cancer.

Objective: The objective of the current project is to examine the joint roles of low dose radiation exposure and genetic susceptibility in the aetiology of breast cancer in young women.

Approach: Because of the low prevalence of mutation carriers and because of the generally low levels of ionising radiation exposure in the general population, population-based studies of breast cancer risk are unlikely to be informative for this purpose. The current project therefore focuses on the conduct of complementary multi-national nested case-control studies of breast cancer in different populations chosen - on the basis of high prevalence of radiation exposure and/or high prevalence of known mutations in susceptibility genes - to maximize the power to study the effects of radiation exposure on the risk of breast cancer and its interaction with relatively rare genetic mutations. These are

• Survivors of a first cancer in childhood, adolescence or early reproductive years; and
  
• Known carriers of a mutation in the BRCA1 or BRCA2 gene.
  

Overall, it is planned to collect information on radiation exposures and genes on about 1500 cases of breast cancer and their matched controls from France, Italy, the Netherlands, and the UK. The populations chosen have received, either environmentally or for medical reasons, a wide range of radiation doses to the breast. Genes of particular interest are BRCA1, BRCA2, ATM, CHEK2, NBS1, XRCC1, and XRCC3: these are amongst the most important genes known to be involved in detection and repair of radiation-induced DNA damage and mutations in these genes increase breast cancer susceptibility.

This project is partially supported by the European Union EURATOM Programme, under contract No: 012926 (FI6R). Participating institutions in the EU contract include:

• IARC (coordinator)
  
• Institut Gustave Roussy (France)
  
• Istituto G. Gaslini (Italy)
  
• Het Nederlands Kanker Institute (the Netherlands)
  
• Imperial College of Science, Technology and Medicine (the United Kingdom
  
• Institute for Cancer Research (the United Kingdom)
  
• The Chancellor, Master and Scholars of the University of Cambridge (the United Kingdom)
• University of Birmingham (the United Kingdom)
  
• Centre René Huguenin (France)