Molecular Basis of Carcinogenesis

Fundamental principles:

3 types of mutations (lethal, neutral, altered “non lethal”).
Carcinogenesis: is caused by non lethal mutation.
Monoclonality is a feature of tumor which means one mutated cell is the origin of the

whole mass of tumor.

Hallmarks of cancer:

1. Self-sufficiency in growth signals:

Normal non-cancerous cell replicates when needed only by the action of proto-oncogene.
Proto-oncogene is a group of genes: growth factor gene, growth factor receptor gene, transducer protein, responder gene, cyclin gene, cyclin dependent kinase (CDK) -> all these act together to phosphorylate Rb protein to release E2F protein to start the DNA synthesis arrangement.
Mutated picture of proto-oncogene is: oncogene.
- Oncogene: allows cell proliferation even when
  
  there is no need.
Most common mutation seen in oncogene is RAS protein mutation.
In oncogene, the mutation is a gain of function mutation.
Defects in one allele are enough to change the phenotypic of the cell (Dominant gene).
Types of mutations in oncogenes are:
- Point mutation
  - Base-pair substitution
  - Base-pair insertion
  - Base-pair deletion
- Gene amplification
- Translocation

Figure 1

Study guide:

2. Insensitivity to growth inhibitory signals:

Tumor suppressor gene inhibits the cell proliferation (act as car break of the cell).
Three most important tumor suppressor genes are Rb gene, P53 gene and APC gene.

Mutation in tumor suppressor gene will cause the cell to proliferate without control.
Most commonly mutated gene in all cancer is P53
In tumor suppressor gene the mutation is a loss of function mutation.
The defect of two alleles is required to change the phenotypic of the cell (Recessive gene).
Types of mutation in tumor suppressor gene:
- Interstitial deletion
- Chromosomal deletion
- Point mutation

DNA Repair Systems

DNA mismatch repair system mutated in: HNPCC

Nucleatide excision repair system mutated in: Xeroderma Pigmentosum

Homlogus recombination repair system mutated in: breast and ovarian cancer

3. Impaired DNA repair system:

4. Evading apoptosis:

The non-cancerous mutated cell goes through apoptosis (intended self death).
Apoptosis happens by activation of caspases pathway.
2 types of genes seen in apoptosis:
- BAX gene (pro-apoptosis gene).
- bcl2 gene (anti-apoptosis gene).
To promote apoptosis high expression of BAX gene and low expression of bcl-2 are present.
In cancerous cells, these two genes are mutated so, no apoptosis:
- Mutation in BAX gene so, under expression → cell lives
- (OR) mutation in Bcl-2 gene so, over expression → cell lives.

5. Unlimited replicative capacity:

Normal cell has limited replicative capacity because of telomere shortening in each cell replication
Cancerous cell has an enzyme known as telomerase, which will keep the telomere long so, unlimited replication can happen.

6. Sustained angiogenesis:

7. Ability of the cell to invade and metastasis.

References:

Kumar, Vinay et al. Robbins And Cotran Pathologic Basis Of Disease. Print.
Sanchez, Henry et al. USMLE Step 1 Pathology Lecture Notes. [New York, N.Y.]: Kaplan Medical,

2011. Print.
Le, Tao et al. First Aid For The® USMLE. Print.
YouTube,. 'Molecular Pathogenesis Of Cancer (Carcinogenesis)'. N.p., 2015. Web. 29 Sept. 2015.
Members.drnajeeblectures.com,. 'Members'. N.p., 2015. Web. 29 Sept. 2015. (10 videos).

Written By: Rawan Al-Tuwaijri

Reviewed By: Roaa Amer

Haneen Al Farhan

Format Editor: Adel Yasky