Genetic basis of carcinogenesis

Mechanism and nature of oncogenesis

The development of a malignant neoplasm is a prolonged and multi-step process. It is based on the accumulation of genetic changes that cause a cell to transition from a normal life cycle to unlimited division (proliferation) and the shutdown of programmed cell death mechanisms — apoptosis.

Any cancerous tissue has a clonal nature. This means that the pathological process is triggered by just a single cell that has acquired a primary mutation. As it divides, the daughter cells accumulate new genetic defects, forming aggressive invasive clones capable of surviving in other tissues and producing metastases.

In the vast majority of cases, cancer arises from somatic mutations that accumulate over a lifetime (they are more common in older adults). However, there is also a hereditary predisposition where an increased susceptibility to tumor development is transmitted. Inheritance can be monogenic dominant or complex multifactorial (for example, in certain forms of breast cancer, the risk increases in close relatives).

Oncogenes and their activation pathways

Oncogenes play a key role in stimulating cell growth. In a healthy cell, they exist as inactive precursors — proto-oncogenes — which are responsible for the strict regulation of division and encode growth factors, their receptors, and intracellular messengers. Normal cellular genes are designated as c-oncogenes. If a viral equivalent that causes cancer enters a cell, it is called a v-oncogene.

For a proto-oncogen to transform into an active oncogene that drives unregulated growth, one of three mechanisms must occur:

1. Gene mutations. These arise under the influence of carcinogens (tobacco smoke, UV rays, ionizing radiation). Point mutations in the coding regions of genomic DNA directly activate the oncogene.
2. Chromosomal translocations. Errors during cell division where a chromosome breaks and part of one gene is transferred to another. A combined (hybrid) gene is formed, falling under the control of a foreign regulatory region, which leads to its overexpression. Examples: the Philadelphia chromosome in chronic myeloid leukemia and the translocation in Burkitt lymphoma (granting B-lymphocytes an unlimited lifespan).
3. Viral stimulation. RNA-containing viruses use reverse transcriptase to synthesize cDNA and integrate it into the host genome. This can occur via insertional mutagenesis (the virus integrates directly into a cellular oncogene, activating it) or transduction (the virus captures a cellular oncogene and transfers it to a new host).

Suppressor genes and cell cycle control

Normally, oncogenes are counteracted by tumor suppressor genes (anti-oncogenes). Their main function is to limit uncontrolled cell proliferation. In the event of severe genome damage, they trigger DNA repair or apoptosis. Damage to these genes removes the molecular "brakes" from the cell.

Anti-oncogenes are closely linked to the regulation of the cell cycle, interacting with specific proteins called cyclins. The main representatives of suppressor genes are:

• The RB (Retinoblastoma) gene. Historically the first described suppressor gene. Its defects lead to the development of retinoblastoma (occurring in 1 out of every 20,000 children) and can be hereditary.
• The p53 gene. Encodes a cellular nuclear phosphoprotein with a mass of 53 kDa. It is a critical DNA-binding protein that controls the cell cycle, DNA synthesis, differentiation, and apoptosis. In a healthy cell, it functions for a short time. Upon mutation, its normal degradation (catabolism) is inhibited, and its protective functions are lost. p53 damage is detected in almost all human tumors, including lung cancer, colorectal cancer, osteosarcoma, and breast carcinoma.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanisms of apoptosis and their shutdown in carcinogenesis.
• Stages of invasive clone formation and metastasis.
• Detailed pathogenesis of Burkitt lymphoma and the role of chromosomal translocations.
• Interaction of suppressor proteins (p53, RB) with cyclins.
• Rous sarcoma virus: history of discovery and mechanism of transduction.

Other topics in the "Medical Genetics" section

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