The genetic background of cancer

Question 1

Introduction

Answer 1

*Proto-oncogenes:
• Involved in the signalling pathways of cell division, cell growth: stimulatory action
• Mutation or increased expression => transformed to oncogenes =>oncogenesis(tumorigenic transformation)
* Tumor suppressor genes:
- Main functions:
• Cell division, DNA replication: inhibitory action
• Stimulatingcell differentiation
• Inducing apoptosis
- Mutation or decreased expression => inactivation => lack of protective action against cancer

Genetic defects in tumor cells
• In oncogenes/tumor-suppressor gens - qualitative → mutation
• In their regulatory system - quantitative → changes in expression

Question 2

Genetic defects

Answer 2

1. Translocation
2. Chromosomal imbalance
3. Point mutations
4. Genetic instability
5. Hereditary genetic defects
6. Micro-RNA differences
7. Epigenetic effects

Question 3

Knudson’s two hit hypothesis

Answer 3

• Genes have two alleles
• Both of them have to be defective for malign transformation (The defects may have different origin)
• Somatic mutation: sporadic cancer
• Germ cell mutation : hereditary cancer (inherited mutation)

Question 4

Translocation

Answer 4

• The whole gene migrates in the genome
• Mainly the activation of oncogens (if it loses it’s regulatory part)
• A, the oncogene migrates to the promoter of one other gene’s (expression rate changes)
• B, the oncogene is incorporated in another protein gene → chimeric genes (abnormal proteins will be produced)
• Mainly characteristic for hematologic cancers, sarcoma types

Question 5

Chromosomal imbalance

Answer 5

• different sized chromosome segment’s gain/loss
• oncogene-amplification
• tumour suppressor gene- deletion
• regulating function (i.e.: mic RNA)

Amplification
• Proto-oncogenes become oncogenes
• Gene parts involved in the regulation of the cell cycle • It plays a role in tumor progression
• It can be chromosomal or extrachromosomal as chromatin fragment(double minutes)

Deletion
• Losing suppressor genes - first, on one allele (loss of heterozygosity)
• A: losing the information on the other allele (bi-allelic deletion)
• B: the suppressor gene on the other allele will be inactivated (point mutation, hypermethylation)
• The detection of these alterations has special relevance regarding prognosis (PCR)

Question 6

Point mutation

Answer 6

• Inactivation of tumor suppressor genes

* Activation of oncogenes – members of signalling pathways are in a constant active state

Question 7

Genetic instability

Answer 7

• It affects the whole genome 
• Multiplex genetic lesions 
• Can be detected during the progression of the tumor • It may also be different in each cell within the tumor 
- Types 
• On nucleotide level 
• On chromosome level

Question 8

Genetic instability - Nucleotide level

Answer 8

Nucleotide level
• Disruption of the DNA repair system MMR (mismatch repair) system
• repair + inhibits the replication of defective DNA
• Its disorder mainly causes microsatellite instability
• eg.: hereditary nonpolyposis colon carcinomas (HNPCC)

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

Question 9

Genetic instability-Chromosome level

Answer 9

• Disruption during the segregation of chromosomes → aneuploidy (difference in the chromosome numbers
• Can be detected in various tumors (during progression)
• It is mainly centrosome amplification
• p53 is inactivated → CDK2 (cyclin dependent kinase) and cyclin E are activated → centrosome duplication

Question 10

Hereditary genetic defects

Answer 10

• Genetic defect in the sperm cell/oocyte → can be found in all somatic cells
• Usually the first step, increase tumor susceptibility (two hit hypothesis)
• 5-10% of human carcinomas

Question 11

Autosomal dominant hereditary tumor syndromes

Answer 11

• Mutation of one gene (tumor supressor)
• Features:
  • Early age
  • Bilaterally in paired organs
  • Several tumors at the same time
  • Family accumulation
  • It can also be combined with non-cancerous diseases

Question 12

Autosomal recessive tumor syndromes

Answer 12

• DNA repair problems → genetic instability 
• Disturbances in the NER (nucleotide excision repair) or in the posttranslation repair system 
- Features: 
• Decreased fertility 
• Immunodeficiency 
• Low body height 
• Glucose intolerance 
- Many genetic defects, but p53 always!

Question 13

Micro-RNA alterations

Answer 13

MicRNAs
• Functional sections, don’t take part in protein synthesis
• 18-25 bp long
• Negative regulation of genes
• ~3% of human genes
• Regulate 30% of protein genes
• Regulate cell division and differentiation

Question 14

Oncomirs

Answer 14

• micRNAs, play a role in the development of certain tumor types
• Near fragile chromosome areas → chromosomal imbalance
• A: Oncogenes↑ (micRNA↓ less inhibited)
• B: Tumor suppressor genes↓ (micRNA↑ more inhibited)
• Tumor therapeutic targets

Question 15

Epigenetic effects

Answer 15

• Affect gene expression, but the nucleotide sequence of DNA does not change
• DNA methylation
• Histone modification

euchromatin: Switch on Chromatin=> loosens
heterochromatin: Switch off Chromatin=> condensed

Question 16

DNA methylation

Answer 16

• At CpG dinucleotides 
• Enzyme: DNA methyltransferase 
• Usually at promoter region 
• Hypermethylation →heterochromatin (gene silencing) Hypermethylation: 
• Downregulation of tumor suppressor genes 
Hypomethylation: 
• Upregulation of oncogenes 
• Increase DNA fragility

Question 17

Histone modification

Answer 17

-Histone acetylation → transcriptionally active
• Enzyme: HAT (histone acyl transferase)↔HDAC (histone deacetylase)
• oncogene↑
-Histone methylation → transcriptionally inactive /active
• Enzyme: HMT (histone methyltransferase)
• Tumor suppressor gene↓