Genetic research as a method for assessing susceptibility to prostate cancer

Introduction

Many oncological diseases are caused by dysregulation of the cell cycle due to dysfunction of regulator genes, which leads to uncontrolled cell division. The study of these mutations can be useful for calculating the risks of cancer pathogenic pathways, determining the degree of malignancy and tumour biological behaviour, assessing the metastatic potential, choosing a treatment method, and clarifying the effectiveness of therapy.

It is believed that the individual risk of carcinogenesis is determined by the individual susceptibility, which, in its turn, is determined by gene polymorphism that regulates the carcinogenic substance metabolism, cell cycle, inflammation, and many other key events of carcinogenesis and the risks of malignant tumours [1].

It is known that there are 6 – 14 key changes in the cell genome [2], while there may be thousands of tumour cell mutations. The key changes occur in signalling cellular pathways. Protein genes of signalling cascades are protooncogenes. More than 100 protooncogenes have been described, including HER2/neu, EGFR, VEGFR, Bcl-2, genes of the RAS, RAF, Pi3K family, and many others.
There are also anti-oncogenes, or tumour suppressor genes, which include more than 20 representatives, the most famous of which are ER, PR, Bax, P53, BRCA1/2, etc.) [2].

Prostate cancer (PCa) is currently one of the most common cancers in the world. PCa is  the most widespread one in the structure of oncological pathology in men In the USA and some European countries. More than 50% of patients visit a doctor having an already advanced disease in the T3 – T4 stage with metastases [3]. In the Russian Federation, the incidence of PCa was 93.7 per 100 000 in 2012, and almost every fifth tumour was diagnosed at stage 4 [4].

By 2015, the main genetic markers of PCa susceptibility were identified.

The HOXB13 gene

The HOXB13 gene is a regulator gene for other gene transcription. This being the case, the protein expressed with the HOXB13 gene sequence is a transcription factor. The HOXB13 protein belongs to a large group of transcription factors called the homeobox protein family. It acts as a tumour suppressor, which means that it interferes with rapid and uncontrolled cell growth and division. Members of the HOXB gene group are expressed in the posterior part of an embryo including the developing genitourinary system. The HOXB13 gene transcripts are widely represented in the human prostate tissue [5]. In 2009, the study concluded that this gene plays a role in the normal development of the prostate gland by affecting the DNA-binding transcription domain of androgen receptors [6].

Many studies have been carried out to investigate the mutation of this gene, for example, 251G/A (rs138213197) pathogenic allele, which was most often found in patients with early onset of the disease and hereditary background [7]. G84E pathogenic allele of the HOXB13 gene possesses the same characteristics [6]. Also, in 2015, a study was conducted where almost 30% of patients had overexpression of the HOXB13 gene, which is directly related to the activity of androgen receptors [8]. C.K. Park et al. conducted studies proving the relationship between overexpression of the HOXB13 gene with a higher Gleason score, disease stage and biochemical relapse occurrence [9], which demonstrates the significance of the HOXB13 gene determination in predicting PCa.

The BRCA1 gene

The BRCA1 gene encodes a protein that is also a tumour suppressor. The BRCA1 protein is involved in the repair of damaged DNA, restoring DNA breaks through homologous recombination [5]. The BRCA1 protein plays an important role in maintaining the stability of the cell’s genetic information by participating in DNA repair synthesis.

There are many mutations in the BRCA1 gene that are associated not only with PCa, but also with breast cancer, ovarian cancer, pancreatic cancer, and other kinds of it [10]. Patients have BRCA1 germline mutations in PCa diagnostics usually have higher Gleason scores ≥8, T3/T4 stage of the disease, metastases availability, and a relatively early onset of the disease [11].

The most frequent pathogenic alleles found in the Russian population are 5382insC, 185delAG, 4153delA, 3819delGTAAA, 3875delGTCT, 300T/G, 2080delA [5]. In the Republic of Bashkortostan, an analysis of pathogenic alleles of the BRCA1 gene was carried out, which showed an increased frequency of 5382insC mutation carriage among patients diagnosed with PCa [12]. At the same time, the study of this pathogenic allele of the BRCA1 gene was carried out in Novosibirsk, as a result of which the 5382insC mutation was not found in any of the patients with PCa [13], which may be due to the ethnic characteristics of patients in different groups. In the study conducted in the Republic of Bashkortostan, both patients with the pathogenic allele were ethnic Russians, and in the study conducted in Novosibirsk, ethnicity was not indicated.

The BRCA2 gene

The BRCA2 gene has the same characteristics as the BRCA1 gene but it is noted that the carriage of pathogenic alleles of the BRCA2 gene is more critical for the prostate carcinogenesis than the carriage of pathogenic alleles of the BRCA1 gene.
The IMPACT study demonstrated that the frequency of detecting PCa of intermediate and high risk in these subgroups was higher than in individuals without the pathogenic alleles carriage. Herewith, prognostically unfavourable tumours were detected in 2.3% of patients with pathogenic alleles of the BRCA1 gene and 3.3% of patients with pathogenic alleles of the BRCA2 gene [14].

The CHEK2 gene

The CHEK2 gene encodes a protein kinase that blocks cell division in G1 phase. This protein inhibits the work of CDC25C phosphatase, as a result of which the cell does not enter mitosis. Protein
kinase interacts with the BRCA1 gene protein involved in DNA repair synthesis and stabilizes the p53 gene protein [5]. Pathogenic alleles of this gene are associated with the thyroid, colon, and breast cancers [15]. Back in 2003, X. Dong et al. determined the possibility of a direct relationship between CHEK2 gene mutations and PCa [16]. Other studies have identified a direct relationship between cytidine deletion at 1100 (1100delC) position and the replacement of isoleucine for threonine at 157 (I157T) nucleotide and the risk of prostate carcinogenesis [17].

The ELAC2 gene

The ELAC2 gene encodes a ribonuclease that removes the 3’-end from the tRNA precursor. This protein interacts with SMAD2, which interacts with transforming growth factor-beta (TGFb) and thereby regulates cell growth and division. S.V. Tavtigian et al. [18] did not confirm the relationship between the carriage of the Leu217 allele and the risk of prostate carcinogenesis in a 2001 study. In 2002, Nicola J. Camp and Sean V. Tavtigian proved the relationship between the carriage of the pathogenic Thr541 allele of the ELAC2 gene separately or in combination with the Leu217 allele and the risk of prostate carcinogenesis [19]. At the same time, a new study was conducted in 2019, which confirmed a high-risk availability of PCa in patients with the Leu217 allele. It was established the risk is higher with the carriage of two Leu21 alleles in comparison with the heterozygous variant (OR = 6.080 and 1.030, respectively) in residents of the Republic of Cameroon [20], which indicates a possible lack of studies of this mutation before. Also, concerning the carriage of the Leu217 and Thr541 alleles, it is known that the carriage of the 650T and 1618A alleles of the ELAC2 gene increases the risk of prostate carcinogenesis [(OR = 1.13 and 1.22, respectively).

The CDH1 gene

The CDH1 gene encodes epithelial cadherin or E-cadherin, which is located on the epithelial cell membranes and is involved in cell adhesion. Also, E-cadherin is involved in signal transduction in the cells, regulates cell growth, maturation and movement. E-cadherin dysfunction plays a role in malignant tumour metastasis [5]. This is due to the ability of cells to avoid “anoikis” (one of the apoptosis pathways that occurs in response to impaired cell adhesion, or a complete loss of the ability of cells to adhere) with the loss of E-cadherin. The most studied single nucleotide substitution is 160C/A and the availability of A allele in homozygous or heterozygous variants increases the risk of developing PCa in comparison with the homozygous C/C genotype [21][22].

The AR gene

The AR gene encodes a receptor against androgen. A feature of this gene is the availability of triplet or trinucleotide CAG nucleotide repeats, which normally ranges from 10 to 36. A metaanalysis was carried out, proving that the number of CAG triplets less than 20 is associated with a higher risk of PCa [23]. There is also an ethnic feature of this gene polymorphism: African Americans, on average, have a smaller number of CAG triplets, which may indicate a higher risk of developing PCa in African Americans [24].

The VDR gene

The VDR gene encodes a receptor against vitamin D. Back in 1992, G.J. Miller et al. in an experiment with the LNCaP cell line proved that calcitriol stimulates the differentiation of prostate cells [25]. Many polymorphisms of the VDR gene have been studied, which are associated with a high risk of developing PCa, for example, rs1544410, rs10875692, rs7301552, rs7975232, rs731236 [26, 27, 28]. At the same time, ambiguous results are showing that African Americans do not have a relationship between the carriage of the rs1544410 mutation and a high risk of developing PCa [28]. The absence of relationships between the rs2228570 (FokI) and rs2238135 substitutions in the VDR gene and the risk of developing PCa in the West Siberian region of Russia were also noted [29].

The GST family genes

The GST family genes encode various types of glutathione-S-transferases that catalyze the conjugation of reduced glutathione with various hydrophobic compounds and are phase II enzymes for xenobiotic detoxification [5]. The polymorphism of this gene is due to the availability or absence of a deletion, which leads to a violation of the synthesis of the glutathione-S-transferase protein. In this case, the gene in which there is a deletion is referred to as the “null allele” [5]. Numerous studies have shown a link between the availability of a null allele and the risk of developing PCa. Dajun Liu et al. conducted a systematic review and meta-analysis and concluded that the availability of the GSTM1 null allele and GSTT1 significantly increased the risk of PCa in Asians, with the availability of a “double null allele” associated with a higher risk of developing PCa [30]. In the Algerian population, an association between the availability of the GSTM1 gene null allele and the risk of developing PCa was also noted. However, the availability of a significant relationship between the risk of developing PCa and the carriage of the GSTM1 gene null allele among the Algerian population has not been confirmed. [31]. The GSTP1 gene polymorphism is associated with the availability of two single nucleotide substitutions, 313A/G (I105V, rs1695) and 341C/T (A114V, rs1138272) [32]. An association was found between the carriage of the GSTP1 gene 341C/T polymorphism and the risk of developing cancer, including PCa, which may be associated with a decrease in detoxification activity [33]. The availability of 313A/G polymorphism is associated with the risk of PCa, not in all ethnic groups (Caucasians have this relationship, but Asians and African Americans do not) [34].

The Bloom syndrome gene

The possible connection between mutations in the Bloom syndrome gene and the risk of developing PCa was also studied. This gene encodes RecQ helicase, which is involved in DNA repair synthesis and maintaining genome stability. Previously, an association was established between heterozygous carriage of the Bloom gene mutations and breast cancer, but the link was not found between the carriage of the Bloom gene mutations and the risk of prostate carcinogenesis [35].

Conclusion

This literature review highlights only a subset of the genetic mutations associated with an increased risk of PCa. Undoubtedly, there is a hereditary susceptibility to PCa, and this important issue requires even more research. There is no doubt that the popularization of genetic screening is possible, especially in families with cases of PCa, ovarian cancer and breast cancer. So, L. Davenport published an article “Men with the BRCA2 gene pathogenic alleles carriage should be examined for PCa” in 2019, in which he proved both an increased incidence of PCa in carriers of the BRCA2 gene pathogenic alleles and a high prognostic value of the positive biopsy result (31% among carriers versus 18% among noncarriers) [36]. On the other hand, these mutations are rare among patients with PCa, which means they cannot be used as the only method for assessing the risk of prostate malignant tumour growth. It is also important to continue research on the relationship between the mutation and the ethnicity of the patient, and the role of this mutation in the prostate carcinogenesis in different populations.