Etiology and Pathogenesis of Tumors

DNA repair genes and their role in antiblastoma defense

DNA repair genes form the basis of maintaining genetic stability. They act as the primary factor of antiblastoma defense at the genome level. During normal cell proliferation or under the aggressive influence of external carcinogens, the DNA structure inevitably sustains damage. The main function of DNA repair genes is to timely recognize these defects and restore the normal nucleotide sequence.

The pathogenesis of tumor growth is closely linked to the disruption of this defense system. Loss of function, somatic mutation, or an inherited congenital defect in DNA repair genes leads to a failure in correcting DNA errors. As a result, an avalanche-like accumulation of mutations begins in the cell genome, ultimately culminating in malignant transformation.

Clinical practice identifies several severe hereditary diseases directly associated with defects in the DNA repair system. The presence of these syndromes drastically increases the risk of malignancies:

• Hereditary nonpolyposis colorectal cancer.
• Xeroderma pigmentosum.
• Bloom syndrome.
• Fanconi anemia.
• Ataxia-telangiectasia.

Molecular basis of multistep carcinogenesis

Modern pathological anatomy relies on the multistep theory of carcinogenesis. According to this concept, a malignant tumor never arises spontaneously as a result of a single defect. Its development is the outcome of long-standing, strictly sequential genetic events. The foundation of this process is the complex interaction between oncogenes and tumor suppressor genes.

For a normal cell to transform into a cancer cell, the accumulation of a vast number of significant genetic anomalies is required. Statistical data from molecular studies show that colorectal carcinoma and breast cancer cells accumulate an average of about 90 mutant genes. Furthermore, approximately 11 so-called "frequently mutated genes" are present per tumor.

It is important to understand that not all genetic alterations are equivalent. All mutations in tumor tissue are divided into two fundamental categories:

1. Driver mutations — alterations directly leading to malignant transformation and further tumor progression.
2. Passenger mutations («Passengers») — entirely neutral mutations that passively accumulate in cells simply because the tumor genome is extremely unstable.

Oncogene combinations and mutation specialization

One of the key features of carcinogenesis is that complete malignant transformation is caused only by combinations of various mutations. Each individual oncogene specializes in forming a strictly defined property of the malignant phenotype of a tumor cell.

A striking example of such specialization is the action of the RAS oncogene. Its activation leads to several critical changes:

• It stimulates the cell's interaction with growth factors, sharply increasing its sensitivity to them.
• It provides anchorage independence — the unique ability of a tumor cell to grow and divide without the obligatory attachment to a solid substrate.
• It induces cellular immortality.

However, this is not sufficient for the formation of fully developed cancer. As proven in experiments on mouse fibroblasts, only the joint, synergistic action of several oncogenes — for example, the combination of RAS and MYC — is capable of causing complete malignant transformation of the tissue.

Evolutionary defense mechanisms and their evasion

The organism possesses powerful evolutionary mechanisms to suppress tumor growth. The main ones include apoptosis (programmed cell death) and cellular senescence.

Normally, when the control system is competent and functions without failures, the emergence of oncogenic signals does not lead to cancer. For instance, hyperactivation of the same RAS gene in a healthy cell will be recognized as a threat, which will immediately trigger cellular senescence or apoptosis. The cell will die or permanently lose its ability to divide, thereby protecting the organism.

For true cancer to emerge, a tumor cell must overcome these barriers. This is achieved through the mutational loss of multiple genes, including those that directly regulate apoptosis and senescence processes. It is precisely the loss of this control that leads to the acquisition of malignant phenotype progression properties and uncontrolled tumor growth.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• The role of the p53 gene in cell cycle regulation and apoptosis triggering.
• Mechanisms of anchorage independence formation in tumor cells.
• Interaction of oncogenes with growth factors and their receptors.
• Morphological manifestations of malignant phenotype progression.
• The impact of exogenous carcinogens on DNA structure during proliferation.

Other topics in the section "Tumor Growth"

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.