Genetics - A. V. Sivolob 2008

Human Genetics
Genetics of Cancer

Cancer refers to a large group of diseases (over 200) caused by The Emergence of altered (transformed) somatic Cells in the Organism. Such cells are characterized by A number of biological features: uncontrolled division, immortality, impaired differentiation, The ability to infiltrate and destroy neighboring normal cells, and the capacity to migrate through the body and form metastases—secondary colonies in Organs and Tissues. The Development of the disease (carcinogenesis) is a lengthy process, all stages of which

(from initiation to metastasis formation) are associated with Genome Rearrangements in transformed cells. In most cases, all populations of transformed cells in the body descend from a single altered somatic Cell. Therefore, oncological diseases represent a type of hereditary disorder—specifically, Hereditary diseases of somatic cells.

Genome alterations leading to cell transformation affect genes responsible for the Regulation of the Cell Cycle, differentiation, and programmed cell death. In addition to Mutations, transformed cells undergo a redistribution of epigenetic markers, which alters the expression of certain genes. Genes involved in carcinogenesis are generally divided into three groups:

1. Proto-oncogenes (conventionally denoted as c-onc)—genes whose normal function is to stimulate Cell Division. This group also includes genes for Proteins that inhibit apoptosis, stimulate angiogenesis (the sprouting of Blood Vessels into an organ or tissue under conditions of insufficient nutrients or oxygen), and promote cell mobility. Mutations in these genes, or epigenetic changes leading to their overexpression, drive the development of neoplasms (turning proto-oncogenes into oncogenes). These mutations are typically dominant—a single event is sufficient to stimulate the corresponding stage of carcinogenesis.

2. Antioncogenes (or tumor suppressor genes)—genes whose normal function is to arrest cell division, activate differentiation processes, stimulate apoptosis, and inhibit angiogenesis. In most cases, the development of a neoplasm requires the inactivation of both alleles of suppressor genes (the two-hit mechanism), meaning that oncogenic mutations in these genes are recessive.

3. Mutator Genes (genome caretaker genes)—genes whose normal function is to maintain genome integrity (for example, genes encoding proteins of DNA Repair systems). Their inactivation due to mutations or epigenetic changes leads to an increased frequency of any mutations in any genes, including proto-oncogenes and suppressor genes. As a result, The Cell acquires the so-called mutator phenotype. Mutations in mutator genes are recessive.

It is believed that the acquisition of a mutator phenotype by a cell is often a key stage in carcinogenesis. Mutations or the inactivation of DNA repair protein genes significantly increase the probability of other oncogenic mutations, thereby accelerating the progression through all stages of carcinogenesis.

Similar to other diseases, neoplasms develop due to a combination of environmental factors and genetic predisposition. About 80% of all cancer cases are classified as sporadic (accidental), 15% as familial (where the relative contributions of environment and genotype are difficult to disentangle), and only 5% as purely hereditary.

Environmental factors that induce the development of neoplasms (carcinogens) include any mutagenic agents (see Chapter 4) and Oncogenic Viruses. They transform infected cells by means of oncogenes present in the viral genome. Viral Oncogenes (designated as v-onc) may be of cellular origin (captured c-onc genes from the host, as seen in many oncogenic Retroviruses) or represent viral genes encoding proteins essential for the virus's life cycle (DNA oncoviruses, such as papillomaviruses, Epstein-Barr virus, etc.).

Environmental factors alone account for only a small fraction of cancer cases. The development of most neoplasms (even sporadic ones) depends on genetic predisposition. However, unlike many of the hereditary diseases discussed above, hereditary cancer syndromes exhibit several unique phenotypic features that complicate their Diagnosis. While in other hereditary syndromes a complex of symptoms results from the pleiotropic action of a single mutant Gene, inherited oncogenic mutations serve merely as "initiators" of a neoplasm. Further disease progression requires additional genome alterations in individual somatic cells.

Many hereditary cancer syndromes display a peculiar inheritance paradox: at THE CELLULAR LEVEL, the inherited mutation is recessive (most genes causing hereditary cancer syndromes are Tumor Suppressors), whereas at the organismal level, it behaves as dominant. This occurs because any neoplasm is a disease of somatic cells, the development of which is a stochastic event. Naturally, in the presence of an inherited mutation, the probability of disease initiation—namely, mutating and consequently losing the remaining allele of a tumor suppressor gene in any somatic cell that can subsequently give rise to a transformed clone—is orders of magnitude higher than in the absence of such a mutation (the probability of mutating one allele is 10^-5-10^-7, whereas mutating both is 10^-10-10^-14).

Despite the considerable difficulties in identifying a genetic predisposition to cancer, a set of criteria has been developed to reliably detect hereditary forms. The main hallmarks of hereditary cancer syndromes are:

✵ the presence of identical or similar forms of cancer in two or more close relatives;

✵ early-onset cancer (under the age of 45) in at least one close relative;

✵ bilateral tumors in paired organs;

✵ multiple primary tumors in a single patient;

✵ a dominant inheritance pattern.

Naturally, certain hereditary cancer syndromes have additional diagnostic confirmation criteria.

Research into the molecular causes of cancer syndromes provides a vital source of information regarding genes whose functional impairment leads to the initiation and progression of oncological diseases. Population screening for mutations in these genes helps identify high-risk groups and allows for more effective Prevention and early diagnosis of cancer. Studying polymorphic variants of proto-oncogenes, tumor suppressor genes, and genes that determine an organism's sensitivity to environmental carcinogens helps uncover the causes of many cancers and assess an individual's risk of developing malignant neoplasms.