Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome frequently associated with germ line TP53 mutations. Unpredictable and disparate age of cancer onset is a major challenge in the management of LFS. Genetic modifiers, including the MDM2-SNP309 polymorphism, and genetic anticipation have been suggested as plausible explanations for young age of tumor onset, but the molecular mechanisms for these observations are unknown. We speculated that telomere attrition will increase genomic instability and cause earlier tumor onset in successive generations. We analyzed mean telomere length and MDM2-SNP309 polymorphism status in individuals from multiple LFS families and controls. A total of 45 peripheral blood lymphocyte samples were analyzed from 9 LFS families and 15 controls. High rate of MDM2-SNP309 was found in TP53 carriers (P = 0.0003). In children, telomere length was shorter in carriers affected with cancer than in nonaffected carriers and wild-type controls (P < 0.0001). The same pattern was seen in adults (P = 0.002). Within each family, telomere length was shorter in children with cancer than in their nonaffected siblings and their noncarrier parents. Telomere attrition between children and adults was faster in carriers than in controls. Our results support the role of MDM2-SNP309 as a genetic modifier in LFS. The novel finding of accelerated telomere attrition in LFS suggests that telomere length could explain earlier age of onset in successive generations of the same family with identical

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TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1α, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading to enhanced vesicular trafficking and secretion. The mut-p53/HIF1α/miR-30d axis potentiates the release of soluble factors and the deposition and remodeling of the ECM, affecting mechano-signaling and stromal cells activation within the tumor microenvironment, thereby enhancing tumor growth and metastatic colonization.

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Although telomeres are maintained in most cancers by telomerase activation, a subset of tumors utilize alternative lengthening of telomeres (ALT) to sustain self-renewal capacity. In order to study the prevalence and significance of ALT in childhood brain tumors we screened 517 pediatric brain tumors using the novel C-circle assay. We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p = 0.001). ALT was highly enriched in primitive neuroectodermal tumors (12 %), choroid plexus carcinomas (23 %) and high-grade gliomas (22 %). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p = 1.01 × 10(-8)). Of the other alterations examined, only ATRX point mutations and reduced expression were associated with the ALT phenotype (p = 0.0005). Interestingly, ALT attenuated the poor outcome conferred by TP53 mutations in specific pediatric brain tumors. Due to very poor prognosis, one year overall survival was quantified in malignant gliomas, while in children with choroid plexus carcinoma, five year overall survival was investigated. For children with TP53 mutant malignant gliomas, one year overall survival was 63 ± 12 and 23 ± 10 % for ALT positive and negative tumors, respectively (p = 0.03), while for children with TP53 mutant choroid plexus carcinomas, 5 years overall survival was 67 ± 19 and 27 ± 13 % for ALT positive and negative tumors, respectively (p = 0.07). These observations suggest that the presence of ALT is limited to a specific group of childhood brain cancers which harbor somatic TP53 mutations and may influence the outcome of these patients. Analysis of ALT may contribute to risk stratification and targeted therapies to improve outcome for these children.