Preliminary Results of the Mutational Analysis of the TP53 Gene in Women Diagnosed with Breast Cancer before the Age of 35 Years and Negative for BRCA1 and BRCA2 Mutations.

Background: Early onset breast cancer is part of the tumor spectrum in the Li-Fraumeni syndrome (MIM 151623), which is associated with germ-line mutations in the TP53 gene. The aim of the study is to determine the presence of inherited mutations in TP53 in women with early onset breast cancer regardless of their family history and after having obtained a negative result for the BRCA1 and BRCA2 mutations. Patients and methods: We analyzed 41 women with breast cancer (BC) diagnosed before the age of 35 years and a negative result for the BRCA1 and BRCA2 genes (analyzed by direct sequencing and MLPA). Patients were classified according their family history in three groups: A) no family history of cancer (n=11); B) family history of breast/ovarian cancer (BC/OC) (n=22); C) family history of other neoplasms (pancreas, kidney, brain, leukemia) without fulfilling the classical Li-Fraumeni criteria (n=8). The analysis of the TP53 gene was carried out by PCR amplification and direct sequencing of the exons 4 to 10. Analysis of the remaining exons, the 59 and 39 UTR regions of the gene, and the detection of large rearrangements are in progress. Results: Among the 41 women we identified two (4.8%) deleterious mutations, and both were observed in group C (2/8, 25%): c.375G>A in exon 4 (splicing mutation) and c.524G>A in exon 5 (p.R175H). Conclusions: These preliminary results suggest that, after a negative result in the analysis of the BRCA1 and BRCA2 genes, TP53 mutations may play a relevant etiological role in the genetic predisposition of early onset BC, especially in those families with presence of different neoplasms Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4072.