Molecular Basis of Carcinogenesis
Fundamental principles:
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3 types of mutations (lethal, neutral, altered “non lethal”).
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Carcinogenesis: is caused by non lethal mutation.
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Monoclonality is a feature of tumor which means one mutated cell is the origin of the
whole mass of tumor.
Hallmarks of cancer:
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Self-sufficiency in growth signals.
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Insensitivity to growth inhibitory signals.
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Impaired DNA repair system.
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Evading apoptosis.
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Unlimited replicative capacity.
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Sustained angiogenesis.
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Ability of the cell to invade and metastasis.
1. Self-sufficiency in growth signals:
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Normal non-cancerous cell replicates when needed only by the action of proto-oncogene.
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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.
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Mutated picture of proto-oncogene is: oncogene.
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Oncogene: allows cell proliferation even when
there is no need.
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Most common mutation seen in oncogene is RAS protein mutation.
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In oncogene, the mutation is a gain of function mutation.
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Defects in one allele are enough to change the phenotypic of the cell (Dominant gene).
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Types of mutations in oncogenes are:
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Point mutation
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Base-pair substitution
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Base-pair insertion
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Base-pair deletion
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Gene amplification
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Translocation
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Figure 1
Study guide:
2. Insensitivity to growth inhibitory signals:
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Tumor suppressor gene inhibits the cell proliferation (act as car break of the cell).
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Three most important tumor suppressor genes are Rb gene, P53 gene and APC gene.
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Mutation in tumor suppressor gene will cause the cell to proliferate without control.
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Most commonly mutated gene in all cancer is P53
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In tumor suppressor gene the mutation is a loss of function mutation.
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The defect of two alleles is required to change the phenotypic of the cell (Recessive gene).
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Types of mutation in tumor suppressor gene:
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Interstitial deletion
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Chromosomal deletion
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Point mutation
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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:
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Three types of DNA repair system exist:
4. Evading apoptosis:
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The non-cancerous mutated cell goes through apoptosis (intended self death).
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Apoptosis happens by activation of caspases pathway.
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2 types of genes seen in apoptosis:
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BAX gene (pro-apoptosis gene).
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bcl2 gene (anti-apoptosis gene).
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To promote apoptosis high expression of BAX gene and low expression of bcl-2 are present.
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In cancerous cells, these two genes are mutated so, no apoptosis:
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Mutation in BAX gene so, under expression → cell lives
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(OR) mutation in Bcl-2 gene so, over expression → cell lives.
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5. Unlimited replicative capacity:
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Normal cell has limited replicative capacity because of telomere shortening in each cell replication
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Cancerous cell has an enzyme known as telomerase, which will keep the telomere long so, unlimited replication can happen.
6. Sustained angiogenesis:
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By the presence of vascular endothelial growth factor (VEGF).
7. Ability of the cell to invade and metastasis.

References:
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Kumar, Vinay et al. Robbins And Cotran Pathologic Basis Of Disease. Print.
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Sanchez, Henry et al. USMLE Step 1 Pathology Lecture Notes. [New York, N.Y.]: Kaplan Medical,
2011. Print.
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Le, Tao et al. First Aid For The® USMLE. Print.
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YouTube,. 'Molecular Pathogenesis Of Cancer (Carcinogenesis)'. N.p., 2015. Web. 29 Sept. 2015.
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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