Carcinogenesis

Carcinogenesis is the pathogenesis of cancer. Cancer patients may have inherited mutations predisposing to cancer.

There are 3 categories of genetic mutations:

1. Autosomal dominant inherited cancer syndromes –single mutant gene, point mutations
2. Defective DNA repair syndromes –autosomal recessive pattern
3. Familial cancers –seen in close relatives, early age of onset

Non- hereditary Predisposing Conditions

a. Chronic Inflammation

Chronic inflammation predisposes to cancer, because of:

1. Production of cytokines leading to growth of transformed cells
2. Chronic inflammation may increase pool of tissue stem cells
3. Production of reactive oxygen species increasing genetic instability

b. Chronic gastritis by H. pylori

c. Environmental and geographic factors

1. Chemical carcinogens
2. Radiations
3. Age

Molecular Basis of Cancer

Non-lethal genetic damage lies at the center of carcinogenesis.

This damage may be acquired:

1. Chemical carcinogens
2. Carcinogenic viruses and other microbes
3. Radiations
4. Inherited
5. Combination –common

Regulatory genes –targets of genetic damage

Four classes of regulatory genes are present:

1. Promotors –promote proliferation
2. Inhibitors –tumor suppressor genes, p53
3. Genes causing apoptosis
4. DNA repair genes

Genetic alterations and oncogene activation

1. Loss/damage to suppressor genes
2. Duplication of promoter genes
3. Loss/damage of apoptosis genes
4. Loss/damage of DNA repair genes

Essential alterations for malignant transformation

• As a consequence of oncogene activation, tumors have capacity to proliferate without further stimuli
• Tumors are insensitive to growth inhibitory signals
• Resistance to apoptosis
• Tumors fail to repair DNA damage
• Tumor sustain blood supply by various factors
• Tumor metastases are cause of majority of cancer deaths

Tumor Clonality

• Genetic damage to single precursor cell
• Clonal expansion
• Tumor formation
• Clonality can be determined by assessment of:

1. Specific translocations in all tumor cells
2. Tumor markers
3. Immunoglobulin receptors

Tumor progression

The various components of tumor progression are:

1. Excessive growth
2. Local invasion
3. And distant metastasis

These result from:

1. Accumulation of genetic lesions
2. Defects in DNA repair