Low rate of TP53 germline mutations in breast cancer/sarcoma families not fulfilling classical criteria for Li-Fraumeni syndrome. (Letter to JMG).

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 inheri ted 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.

MATERIAL AND METHODS

Over the last 20 years our group has ascertained families with a history of early onset tumours in addition to sarcoma. (4-6,17) In the last 10 years we have also received samples from families ascertained at other genetics and oncology centres in the UK. We have retrospectively analysed the outcome of TP53 germline mutation testing in families with a single proven sarcoma where that person or a first degree relative developed early onset (<60 years) breast cancer, but the family as a whole did not fulfil criteria for classical LFS (table 1). Twenty-one such families were identified (table 2) in addition to 30 families which we had tested that fulfilled classical criteria. Twenty-five families which fulfilled criteria for Li-Fraumenilike (LFL, table 1) were tested including seven from the 21 identified in the current study. (17) The families in this study fulfilling LFL criteria were compared with the 18 LFL families not including a single sarcoma or breast cancer occurrence.

Mutation detection was carried out as described previously. (7) All exons (coding and non-coding), all splice junctions, the promoter, and the 3' untranslated region were analysed by direct sequencing. Any sequence variants were confirmed by sequencing the complementary strand. Wherever possible, multiple affected subjects from the families were analysed to verify that any putative mutation segregated with the disease. All these studies were carried out with approval of relevant local ethics committees.

RESULTS

Only one mutation was identified in the 21 breast/sarcoma families studied. This family (family 2252, table 2) only failed to meet LFS criteria as the sarcoma was diagnosed four years after the qualifying date (49 rather than <45 years). There is also a suggestion of a further sarcoma in the mother of the tested subject who …