4, Genetic instability

Nucleotide levelNER (nucleotide excision repair system)• Repair of pyrimidine dimers developed due to UV• If doesn’t work → skin tumors

4, Genetic instability

Chromosome level• Disrupton during the segregation of chromosomes

→ aneuploidity• Centrosome amplification• p53 is inactivated

→ CDK2 and cyclin E activated→ centrosome duplication

The function of p16 and RB proteins

Seanholton.wordpress.com

5, Hereditary genetic defects

• Genetic defect in the sperm cell → can be found inall somatic cells

• Usually the first step, increase tumor susceptibility(two hit hypothesis)

• 5-10% of human carcinomas

5, Hereditary genetic defects

Autosomal dominant hereditary tumor syndromes• Mutation of one gene (tumor supressor)• Features:

• Early age• Bilaterally• Several tumors at the same time• Family accumulation• It can also be combined with non-cancerous diseases

5, Hereditary genetic defects

Autosomal dominant recessive tumor syndromes• DNA repair problems → genetic instability• NER or posttranslation repair system• Features:

• Decreased fertility• Immundeficiency• Low body height• Glucose intolerance

• Many genetic defects, but p53 always!

6, Micro-RNA differences

MicRNAs• Functional sections, don’t take part in protein

synthesis• 18-25 bp• Negative regulation of genes• ~3% of human genes• Regulate 30% of protein genes• Regulate cell division and differentiation

6, Micro-RNA differences

Oncomirs• micRNAs, play a role in the development of certain

tumor types• At fragile chromosome areas

→ chromosomal imbalance• Oncogenes↑ (micRNA↓ less inhibited)• Tumor supressor genes↓ (micRNA↑ more

inhibited)• Tumor Therapeutic targets

The steps and signalling pathways of apoptosis

quora.com

The role of the Ras / MAP kinase cascade in theoncogenesis

Roberts and Der (2009): Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.Oncogene, 26, 3291-3310.

7, Epigenetic effects

• Affect gene expression, but the nucleotidesequence of DNA does not change

• DNA methylation• Histone modification

7, Epigenetic effects

euchromatine

heterochromatine

Switch onChromatine loose

Switch offChromatine condensated

Active transcription

inhibited transcription

7, Epigenetic effects

DNS methylation• At CpG dinucleotides• Enzyme: DNA methyltransferase• Usually at promoter region• Hypermethylation →heterochromatine (gene silencing)Hypermethylation:

• Downregulation of tumor supressor genesHipomethylation:

• Upregulation of oncegenes• Increase DNA fragility

7, Epigenetic effects

Histone modification

7, Epigenetic effects

Histone modificationHistone acetylation → transcriptionally active

• Enzyme: HAT (histone acyl transferase)↔HDAC (histonedeacetylase)

• oncogene↑

Histone methylation → transcriptionally inactive/active

• Enzyme: HMT (histone methyltransferase)• Tumor supresszor gene↓

7, Epigenetic effects

• Histone acetylation

The algorithm of the developmentof colorectal carcinomas

Thank you for your attention!