+3157343224 info@lifraumeni.eu

Timeline-LiFraumeni

Timeline for Li Fraumeni

Increasingly, more is being discovered about the precise location of the mutation in the p53 gene, how frequently it occurs, and the types of malignant tumors that result from it (Fig. 2). As shown in the image below, having a congenital p53 gene mutation leads to a different spectrum of tumors compared to acquiring a p53 mutation later in life.

p53 20 Frequency (%) 10 TP53 germ-line mutations Frequency (%) 5 TP53 somatic mutations Breast 10 Ovary Hematopoietic 1.3% system Co Stomach 1.5% 2.1% Lung 3.1% Skin 3.3% Adrenal gland 6.7% Kidney 1.3% Other 11.5% 24.9% Othe 19% T125 R158 R213 G245 R273 Colorectum 22% in Breast Brain 16.4. Bone Soft 12.8% R175 G245 R273 Lung Ovary Soft tissues 1% pancreas Skin 2% em atop oietic system Bladde r 4% Stomach 4% Esophagus tissues .3 Tumor site distribution Of five hotspot TP53 germ-line mutations R337 Tumor site distribution of five hotspot TP53 somatic mutations Tratds Figure 2. Mutational Landscape of TP53 Germline and Somatic Mutations in Human Cancer. TP53 missense mutation data are obtained from the Intemational Agency for Research on Cancer (IARC) TP53 database (http://p53.iarc.fr/). The distribution of p53 mutations is plotted over the function of amino acid position; the left side indicates germline mutations and the right side indicates somatic mutations. The horizontal axis shows the frequency of any mutation at the indicated residues. The vertical axis represents p53 protein starting with the N-terminus at the top. p53 protein contains transcriptional activation domains I and Il (TAD 1 , 20-40; TAD Il, 40-60), the proline domain (PP, 60—90), the sequence-specific core DNA-binding c%main (DNA-binding core, DBD; residues 100—300), the linker region (L, 301—324), the tetramerization domain (Tet, 325—356), ard the lysine-rich basic C-terminal domain (+4, 363—393). The most common mutations or hotspots are indicated in bold; residues RI 75, G245, R248, R273, and R282 are the five common hotspots for both germline and somatic mutations (Indicated as a lollipop). Pie charts illustrate the tumor site distribution of five hotspot TP53 mutations (left, germline; right, somatic). Malignancies of breast, brain, soft tissues, and bone are the most commonly seen for the five hotspot gamine mutations; malignancies from these tumor sites are also cfstributed in the same five hotspots of TP53 somatic mutations (indicated in bold).

The p53 gene and the protein it produces have a wide range of functions, and new roles are continually being discovered. For example, mutated p53 can activate various so-called ‘drivers’ of cancer formation through multiple pathways (Fig. 3). As shown in the image below, it remains unclear how (or whether) p53 plays a role in suppressing the immune system. Normally, the immune system also has a defensive role in clearing out malignant cells.

 

Evading growth suppressors p73 p63 NF-Y REG} p53 N-terminal e.g. MYC AXL EGFR Sustaining proliferative signaling Activating invasion & metastasis p63 PDGFRB SMADs let-7i To be discovered Avoiding immune destruction Tumor-promoting inflammation NF-KB DAB21P IL-IRa Inducing angiogenesis VEGFR2 ID4 E2F1 - 7------------0 TERT Enabling replicative immortality e.g. MREII BRCAI : Dysregulating cellular metabolism e.g• AMPK 4 GLUTI SREBPs C-terminal p63 p73 : BCL-XL : miR130-b : Genome instability & Resisting cell death mutation Trends in Phmnacological Sciences Figure 3. Mutant p53 Gain-of-Function Cancer Driver Mutations and Halmarks of Cancer. Dfferent mutatims in p53 protein (structural domains are described in Figure 2) arm p53 with new weapons (downstream targets indicted in the figure) to drive cancer development and progression. Each (Db-coded node indicates gain-of-function of a specific mutation in TP53 which further drives cancer through various hallmark properties of cancer cells.

Tot slot biedt het LFS een perfect model voor onderzoek voor therapieën tegen alle soorten kanker waar p53 een rol in speelt. Er zijn verschillende soorten diermodellen (Fig. 4) ontwikkeld waarin p53 gemuteerde kankers in worden gebracht /  worden ontwikkeld waarna specifieke behandelingen getest kunnen worden. Het testen van therapieën op zogenaamde organoiden (opgekweekte klompjes cellen met specifieke mutaties) is een recent voorbeeld waar prof. Clevers in Utrecht een wereld leidende positie inneemt. Ook het ‘knippen en plakken’ in (zieke) genen met de CRISPR-CAS techniek is in een stroomversnelling geraakt en biedt reële oorzakelijke behandelingsmogelijkheden voor de toekomst.

Li-Fraumeni syndrome Current disdase model Engineered mouse model Precise genome editing CRISPR TALENs ZFNS Specific p53 mutations Zebrafish model Patient primary cell lines Patient derived iPSCs "disease in a dish" Human ESCs Preclinical trails in vitro LFS patients O Mutant p53 associated tumors Yamanaka four factors 00 oo Patient derived Reprogramming Somatic cells Differentiated cells Patient organs-on-chip iPSCs p53 mutant ESCs Drug screening Drug discovery Toxicity test Potential targets identifying Precision therapy 3D organoid culture

Finally, LFS (Li-Fraumeni Syndrome) provides an ideal model for researching therapies against all types of cancer in which p53 plays a role. Various animal models (Fig. 4) have been developed in which p53-mutated cancers are introduced or allowed to develop, enabling the testing of specific treatments. Testing therapies on so-called organoids (cultured clusters of cells with specific mutations) is a recent example, with Prof. Clevers in Utrecht holding a world-leading position in this field. Additionally, the “cutting and pasting” of (disease-causing) genes using CRISPR-CAS technology has gained significant momentum and offers real potential for causal treatments in the future.

Bron: Trend Pharmocol Sci 2017 Oct;38(10):908-927. doi: 10.1016/j.tips.2017.07.004. Epub 2017 Aug 14.

Voor het volledige artikel: http://www.sciencedirect.com.eur.idm.oclc.org/science/article/pii/S0165614717301438?via%3Dihub