XAF1 IN P53 SIGNALING, APOPTOSIS AND TUMOR SUPPRESSION

ABSTRACT We previously identified the TP53-R337H founder mutation in a group of Brazilian children who developed adrenocortical carcinoma. A general population screen of 175,000 newborns demonstrated that 1 in 375 individuals from southern Brazil (Rio de Janeiro, Sao Paulo and Parana, total population 80-100 million) are carriers of this mutation. Surprisingly many of these carriers are at low risk of cancer and remain tumor free. Subsequent genomic analyses identified a nonsense mutation in the putative tumor suppressor XAF1 (E134*) in linkage with the TP53- R337H mutation in a subset of carriers. XAF1 is also reported to function in apoptosis within a positive feedback loop with p53, and its expression is frequently selected against by epigenetic silencing in a broad range of human tumors. Based on these findings we propose that XAF1- E134* cooperates with p53-R337H in promoting tumorigenesis. Consistent with this hypothesis we found that the double mutant haplotype is significantly enriched in carriers who developed cancer in general, sarcomas and multiple tumors. Building upon these observations we will study the physiological role of XAF1 in apoptosis and tumor suppression and whether the nonsense mutation cooperates with the TP53-R337H mutation in promoting tumorigenesis using knockin and knockout mouse models. We will address these questions in the following two Specific Aims: 1) Does XAF1 function as a physiologic proapoptotic tumor suppressor? and 2) Do XAF1- E134* and TP53-R337H cooperate to enhance tumor susceptibility? Together, these studies will establish how these mutations interact, and explain the high tumor incidence in individuals carrying both mutations. In doing so, we will more generally address the disparities in outcome among individuals carrying the same p53 mutation.