Heterogeneity of Li-Fraumeni syndrome links to unequal gain-of-function effects of p53 mutations.

Mutations of p53 cause not only loss of wild-type function but also gain of novel oncogenic functions (GOF). Accumulating evidence suggest that p53 hotspot mutations may confer different types and magnitudes of GOF. Here we add support to the heterogeneity of mutant p53 GOF by showing their unequal association with early tumor onset and spectrum of tumor types. We stratified Li-Fraumeni syndrome (LFS) patients according to carried p53 mutations using data from the updated p53 germline mutation database. When compared to loss-of-function nonsense mutations, the R282 GOF mutation associated with significantly earlier onset, while the G245 mutation displayed later onset. The R175, Y220, R248, R282 and nonsense mutations showed preferential distribution in certain cancer types, which varied in the age of onset. Multivariate COX regression model adjusting for cancer types and patient sex suggested that nonsense and G245 mutations had lower risk than R248 for early onset, suggesting unequal strengths of mutant GOF effects. Our results suggest that Li-Fraumeni syndrome can be subdivided into subtypes linking to unequal GOF effects of p53 mutations. These findings have potential implications in the prevention, early detection and targeted treatment of LFS tumors.