Low rate of TP53 germline mutations in breast cancer/sarcoma families not fulfilling classical criteria for Li-Fraumeni syndrome

Breast cancer and sarcoma are key components of Li-Fraumeni syndrome (LFS).1–6 Sarcoma, particularly childhood osteosarcoma or rhabdomyosarcoma in addition to childhood adrenocortical carcinoma (ACC), is the strongest predictor of the presence of a TP53 mutation.7,8 However, while up to 80% of unselected series of ACC have TP53 germline mutations,8 only 3-10% of unselected sarcomas have been found to have such mutations.9–11 At least half of these would have been predicted on the basis of family history and many of the rest could have arisen de novo.12 While breast cancer is common in LFS and the penetrance of TP53 germline mutations in women for breast cancer may be as high as 56% by the age of 45 years (80% of female cancer incidence aged 16-45 years),13,14 it is also common in the general population with nearly 2% of women now developing breast cancer by the age of 50 in the general population in the western world.15,16 In contrast to sarcoma and ACC, there are other more common inherited syndromes to account for familial aggregation of breast cancer ( BRCA1 / 2 ). As a major referral centre for research testing for TP53 , we have become aware that the possibility of TP53 mutations is often raised fairly strongly in the context of even a single case of sarcoma in addition to breast cancer. In order to assess the likelihood of TP53 germline mutations in this population, we have assessed the outcome of such testing in families containing a single (but no more) sarcoma and at least one breast cancer where the family as a whole does not fulfil LFS criteria. Over the last 20 years our group has ascertained families with a history of early onset tumours in addition to sarcoma. …