Genetic predisposition to cervical cancer

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Introduction. Statistics and relevance.The state in Russia. In 2023, cervical cancer ranked ninth among all types of tumors in men and women (4.5%). In women, it has become the third most common among tumors of the reproductive system, second only to breast cancer and cancer of the uterine body. The average age of the patients over the last decade was 52 years. There is a tendency towards rejuvenation of the disease. According to statistics, in the age group under 35, breast cancer was first detected in 46.88% of women. At the age of 35-44, this figure was 35.25%, in the perimenopausal period (45-54 years) — 18.49%, and in the postmenopausal period (after 55 years) — 18.59%. There is evidence that the highest incidence is observed among people aged 40 to 49 years. The absolute number of cervical cancer (C53) (without postmortem detection) is 15,986, as of 2023.* Calculated for the population of 2022. Mortality.In 2023, mortality from cervical cancer was 12.7%, ovarian cancer — 16.7%, uterine body — 7.0%, breast — 4.4%. These statistics indicate that mortality from cervical cancer ranks second, second only to ovarian cancer. Based on the above, it can be concluded that cervical cancer occupies a leading position in the structure of cancer morbidity and mortality. At the same time, the disease is preventable with timely detection, which makes the coverage of this problem especially relevant. In order to predict risks and develop a differentiated approach to patient management, it is necessary to identify a genetic predisposition to cervical cancer. According to current views on the causes of the disease, the genetic and epigenetic aspects are not receiving enough attention, although some studies suggest otherwise.(Referring to clinical guidelines that do not provide information about epiginetics). If the patient has a genetic predisposition to cancer, this may be the basis for an active approach to treatment, which in this case is justified already at the first stage of tumor development. Timely measures taken in most cases make it possible to completely get rid of the disease and significantly reduce the risk of death. When working with patients, it is advisable to use an advanced approach based on the concept of 4P medicine. This approach involves taking into account the individual characteristics of each person, which contributes to the prevention of diseases, as well as facilitates diagnosis and treatment. This technique is based on four main principles: Personalization — an individual approach to each patient. Predictivity is the identification of risks and the "prediction" of disease development.Prevention is the early adoption of measures aimed at preventing the progression of the disease.Participation is the motivation of all participants in the prevention and treatment process [1, 2].The aim of the work was to investigate specific genes regulating the process of cervical cancer. To analyze the information presented in modern scientific publications about the genetic predisposition of the female body to the development of cervical cancer. To consider the epigenetic mechanisms influencing the occurrence and development of cervical cancer.Materials and methods of research. Search for scientific articles in PubMed and Medline databases, as well as analysis of some medical journals.The results of the study. In the course of studying modern literary sources, it was found that the risk of developing cervical cancer may be due to a number of factors: Infection with the human papillomavirus (HPV). The main danger of this virus lies in its high oncogenicity, especially in some strains. In Russia, the majority of patients with cervical cancer are diagnosed with HPV of 16 and/or 18 oncogenic genotypes. Mechanical damage and chemical effects on cervical tissue. Such injuries include birth injuries to the cervix, damage during abortions, as well as the use of certain contraceptives. Chemicals such as bisphenol A, phthalates, and xenoestrogens can also have a negative effect on cervical tissue. Hormonal disorders. Studies show a link between cervical cancer and factors such as diabetes mellitus, oral contraceptive use, thyroid dysfunction, and hyperestrogenism. The incidence of cervical cancer increases with age and increased levels of follicle-stimulating hormone (FSH). Infectious diseases of the cervix and vagina. Among the diseases that can be distinguished in this group are infections caused by viruses and chlamydia, bacterial vaginosis, as well as a violation of the balance of microorganisms in the female genital tract. It is interesting how the microbiome affects: its imbalance can disrupt the symbiotic relationship between the body and microorganisms, which becomes a key factor in the development of various diseases, including HPV-related cervical cancer. Immune status disorders. Epigenetic mechanisms involved in the development of cervical cancer: DNA methylation: This is the process of adding a methyl group to cytosine in the context of CpG dinucleotides. Methylation of promoter regions of genes can lead to their suppression. In the case of cervical cancer, methylation of certain tumor suppressor genes (IDH1 and IDH2 genes) can promote uncontrolled cell growth. Histone modifications: Histones are proteins that have DNA wrapped around them in the cell nucleus. Histone modifications such as acetylation, methylation, and phosphorylation can affect the availability of DNA for transcription factors and, consequently, gene expression. In the context of cervical cancer, histone modifications can affect the expression of genes related to the cell cycle, cell apoptosis. Non-coding RNAs: Some non-coding RNAs, such as microRNAs and long non-coding RNAs, can regulate gene expression at the post-transcriptional level. In the case of cervical cancer, some microRNAs may be involved in regulating the expression of genes associated with proliferation, apoptosis, and angiogenesis.The role of epigenetics in the development of cervical cancer: Inactivation of tumor suppressor genes: Epigenetic changes can lead to the inactivation of genes that normally inhibit tumor growth. This can contribute to uncontrolled cell division and cancer development. Oncogen activation: Epigenetic mechanisms can also lead to the activation of genes that promote tumor growth (oncogenes).Changes in the expression of genes related to the immune response: Epigenetic changes may affect the expression of genes involved in the immune response to tumor cells, which may contribute to tumor evasion from immune surveillance. The study of epigenetic mechanisms in the development of cervical cancer may help in the development of new approaches to the diagnosis, treatment and prevention of this disease. Currently, the field of tumor genetics includes a new type of regulation using epigenetics. More and more studies are demonstrating the importance of DNA methylation and hydroxylation in certain genes for the development of cervical cancer. Determining the methylation and hydroxylation profiles of these genes will help in early prevention and diagnosis, monitoring of recurrence, prognosis and treatment of patients with cervical cancer. Although most cases of cervical cancer are infected with the human papillomavirus (HPV), additional genetic and epigenetic changes are required for the development of the disease. Previously, it was believed that only a genetic mutation plays a key role in the development of cervical cancer. But recent advances in the biology of cervical cancer have shown that epigenetic changes are common in the carcinogenesis and metastasis of cervical cancer. Epigenetic changes caused by abnormal DNA methylation and histone modification have been extensively studied in cervical cancer. Modern research strategies allow us to gain insight into non-coding RNAs, especially microRNAs and long non-coding RNase DNA methylation as a marker in cervical cancer screening: 23 studies were included, of which almost 65% were cohort and population studies. Most of the analyzed women were Dutch, and the most studied genes were CADM1, FAM19A4, MAL, and miR124-2. The total sensitivity and specificity were 0.68 (95% CI 0.63–0.72) and 0.75 (95% CI 0.71–0.80) for detecting cervical intraepithelial neoplasia (CIN) 2+, respectively. When CIN3+ was detected, the combined sensitivity and specificity were 0.78 (95% CI 0.74–0.82) and 0.74 (95% CI 0.69–0.78), respectively. The combined prevalence of PPV in the detection of CIN2+ and CIN3+ was 0.514 and 0.392, respectively. In addition, the NPV for detecting CIN2+ and CIN3+ was 0.857 and 0.938, respectively. This meta-analysis confirmed the great potential of DNA methylation-based biomarkers as a sorting tool for women who tested positive for HPV during cervical cancer screening. However, standardization and more thorough verification are required. Nevertheless, these markers can be an excellent alternative to cytology and genotyping for referral to colposcopy for women who test positive for HPV, which will allow for more cost-effective screening programs. The literature describes genes associated with cervical cancer: HLA-DQB1, HLA-DQA1, HLA-B7, IL-1B, TNFA tumor necrosis factor gene, TP53, TTC34, MICA, MTHFR, CYP1A1 gene mutations. HLA-DQB1/HLA-B7 (co-carriage increases the risk!) They encode proteins that damage the process of elimination of epithelial cells infected with the human papillomavirus (HPV), which leads to tumor changes. HLA-DQA1 Encodes the alpha chain of the HLA-DQ protein. HLA-DQ refers to the proteins involved in the antigen-presenting cell complex of the main histocompatibility complex, namely MHC II.The research results have shown that this gene can cause cell mutation. IL-1B Normally encodes interleukin 6, which can act as a pro- and anti-inflammatory cytokine, as well as stimulate angiogenesis and tumor growth, depending on the specific situation. If a mutation occurs, for example, the replacement of the guanine nucleotide with cytosine in the regulatory region of the gene, the level of interleukin 6 production decreases, which leads to a violation of its functions. This variant is called 174C, and its presence increases the risk of cervical cancer due to the presence of oncogenic human papillomavirus (HPV).The TNFA tumor necrosis factor (G-308A) gene Normally encodes tumor necrosis factor alpha, which is responsible for pro-inflammatory function, activating the body's inflammatory response, and is involved in the control of cell proliferation and differentiation, apoptosis, blood clotting, and lipid metabolism. In the presence of a mutation, all functions of α TNFA (G-308A) are disrupted, and one of the mutation variants is called 308A. Variant 308A increases the risk of developing cancer by mutating the TP53 gene (TP53 Arg72Pro, HPV-TP53-MALAT1, TP53 rs1042522) TP53 normally has many mechanisms of anti-cancer function, is responsible for apoptosis, maintaining genomic stability and inhibiting the tumor process. In the case of a hereditary TP53 mutation, there is a predisposition to a wide range of malignancies.The TP53 tumor suppressor gene is often mutated in cancer. MTHFR (methylenetetrahydrofolate reductase, genetic marker — A1298C) It encodes the intracellular enzyme methylenetetrahydrofolate reductase, which is involved in the conversion of homocysteine to methionine in the presence of cofactors – pyridoxine (vitamin B6), cyanocobalamin (vitamin B12) – and a substrate – folic acid.One of the mutation variants associated with the risk of cervical cancer is MTHFR A1298C (replacement of adenine (A) base with cytosine (C) at position 1298) (Glu429Ala is the substitution of glutamic acid for alanine at position 429 in the amino acid sequence of the MTHFR protein). These changes in DNA lead to the replacement of an amino acid in the enzyme, and, consequently, the biochemical properties of methylenetetrahydrofolate reductase change. The MICA gene, which is associated with the major histocompatibility complex class I, encodes a protein that performs immune functions. This protein is called NKG2D.However, human tumor cells, secreting a soluble form of MICA, inhibit the activity of NKG2D, which leads to a violation of the antitumor immune response. CYP1A1 (cytochrome P450 1A1) It encodes cytochrome P450 enzymes, which are monooxygenases that catalyze many reactions involved in drug metabolism and the synthesis of cholesterol, steroids, and other lipids. The synthesis of CYP1A1 is induced by polyaromatic hydrocarbons (including those contained in tobacco smoke). Subsequently, it converts aromatic hydrocarbons into carcinogenic derivatives. TTC34 (tetratricopeptide repeating domain 34)There is little data on this gene, but there is evidence that it is associated with the risk of cervical cancer [3,4,5].Conclusion. We conducted an analysis of scientific papers that investigate the influence of various genetic factors on predisposition to cervical cancer (cervical cancer).All the studies reviewed have shown that the presence of genetic risks of developing this disease significantly increases the likelihood of its occurrence compared to those who do not have such risks. It is important to note that without infection with the human papillomavirus (HPV), these risks are not realized. However, in patients with mutations in certain genes, the probability that the virus will persist and cause malignant degeneration of the epithelium is much higher.We also studied the epigenetic mechanisms influencing the occurrence and development of cervical cancer.Breast cancer is a serious disease that can be fatal in young women. Therefore, it is extremely important to understand the causes of this pathology, identify it in a timely manner and prevent it. Identifying genetic factors that affect the likelihood of developing cervical cancer plays an important role in maintaining the health and life of many women.

About the authors

Zemfira Abduragimovna Ramazanova

Burdenko Voronezh State Medical University

Email: ramazanovazemfira15@mail.ru
ORCID iD: 0009-0008-1619-7967
Russian Federation, 10 Studenchskaya Street, 394036, Voronezh, Russian Federation

Ilya Eduradovich Tarasov

Burdenko Voronezh State Medical University

Email: itaraasov@mail.ru
ORCID iD: 0009-0003-4445-6202
Russian Federation, 10 Studenchskaya Street, 394036, Voronezh, Russian Federation

Olga Viktorovna Khoperskaya

Burdenko Voronezh State Medical University

Author for correspondence.
Email: akushervsmabyrdenko@mail.ru
ORCID iD: 0000-0003-1255-293X
Russian Federation, 10 Studenchskaya Street, 394036, Voronezh, Russian Federation

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