Tumor-Suppressor Genes in Cancer

Role of tumour-suppressor gene and oncogene in tumorigenesis

The cell differentiation process in normal cells is properly controlled and regulated in a specific manner so that cells changes and divides in a normal manner. This is because inappropriate cell differentiation or cell proliferation leads to the development of cancer cell. The tumorigenesis is the result of mutation in three specific classes of genes which are tumour-suppressor genes, oncogenes and genomic stability genes. The mutation in these genes leads to cause damage repair of DNA as well as segregation and recombination of chromosome. For those seeking further guidance, biomedical science dissertation help can provide valuable support in navigating these complex genetic processes.

Tumour-suppressor genes

The Tumor-suppressor genes are those which have the key task to regulate cell growth. In this process, when the genes function effectively they are able to prevent tumour growth. However, when they are inactive or altered due to mutation, it leads them to lose their ability for making the protein which control growth of cells. This results in uncontrolled growth of cells leading to development of cancer. There are different types of tumor-suppressor genes like the TP53 gene which encoded by p53 tumour-suppressor protein that acts as a guardian for the retinoblastoma genes and genomes. These genes show abnormal functional ability as a result of genetic mutation, loss of heterozygosity and DNA methylation. The two-hit hypothesis is one of the essential hypotheses related to the abnormal functioning of tumour-suppressor genes which inform the genes cause cancer when both the alleles of the genes lose their normal functional ability (Knudson 1971). In this situation, mutation in one of the allele is inherited from the germinal cell and another from the somatic cell of the body. For instance, mutation in RB1 gene is seen to causes cancer in eye, breasts, lings and others parts of the body. The Retinoblastoma (RB) protein is seen to act like a checkpoint where they control entry of the cell for further differentiation in the S-phase and they specifically binds with the E2F family of transcription factor. The presence of a mutation is able to influence the binding of the E2F1-E2F2 transcription factors with the dismerase protein (DP) complex in the RB pathway (Thoma et al., 2011; Chen et al., 2009). Moreover, the TP53 gene which is a tumour- suppressor protein is required for regulation of the checkpoint of the cell cycle and for activation of the apoptosis and senescence. The loss of mutation in the p53 gene is found in more than half of the cancer where it results in metastasis causing cell invasion and migration (Muller et al., 2011).

Oncogene

Oncogene is the gene which has the efficiency to cause cancer by expressing at high level as a result of mutation. The proto-oncogenes are the normal genes which encode protein enhanced cell growth through stimulation of the cell division process and prevention of cell differentiation as well as impairing cell death. These genes as a result of mutation or over-expression or chromosomal translocation become oncogenes that are responsible for cancerous growth. However, in normal condition, these proto-oncogenes do not have the ability to cause cancerous growth and instead they show collaboration to work with other oncogenes. The oncogenes which are encoded by specific cellular proteins are involved chromatin remodelling, apoptosis, transcriptional factor induction, signal transduction, response to growth factor receptor, growth regulation or responses to hormone receptors (Croce, 2008). For example, RAS subfamilies which are small GTP-binding protein are seen to be involved in the regulation of cell growth and signalling along with supporting cell survival process. They with the help of tyrosine kinase receptor pathway have the ability to inhibit or activate growth factor signalling. Nearly 30% of cancers in humans are initiated as a result of mutation in RAS oncogenes (HRAS, KRAS and NRS) (Pylayeva-Gupta et al., 2011; Croce, 2008).

The viral oncogenes posses the ability to promote and initiate development of different cancer types which results from persistent presence of viral infection. They mutate the pro-oncogenes by infecting DNA of the host’s chromosome through their promoters leading towards activation of transcription factor genes. The expression of tumour- suppressor genes is latered through the over-expression of the oncogene (Ranzaniet al., 2013). For instance, retroviral Rous Sarcoma Virus (RSV) is seen to be drive mutation of the sarcoma cells (Vogt, 2012).

Genome Stability genes

The genome stability genes functions to repair the mistakes caused in the DNA during DNA replication or after DNA induction due to mutagen exposure (Negrini et al., 2010; Vogelstein and Kinzler, 2004). Moreover, this group of genes are seen to be remaining associated with the chromosomal segregation and meiotic recombination. They also include genes such as breast cancer susceptibility (BRCA1 and BRCA 2), ataxia telangiectasia protein (ATM) and Nijmegen breakage syndrome 1 (NBS 1) that is mutated in different cancer types including ovarian cancer, breast cancer, leukaemia and lymphoma (Negrin et al., 2010). The group of genes which keeps the minimum level of genetic alteration in the body on abnormal expression is seen to cause an increased rate of alteration of other genes.

Cancer-testis antigen genes

The Cancer Testis Antigen genes (CTA) are referred to the protein group which are genetically coded to remain in silence in the normal and healthy somatic tissues and are largely restricted to the tissues present in the testis. The genes are seen to be widely expressed in different tumour cells as well as cancer stem-like cells where their intrinsic characteristics are regarded to be marked as a nature of promising therapeutic target (Whitehurst, 2014; Yang et al., 2015). The "cancer-testis antigen genes" is also given the name of cancer germline antigen genes and the term is coined first by Chen et al. in 1997 (Chen et al., 1997). The cancer-testis antigen genes have the characteristics of neo-antigens in the cancer cells as a result of lack of MHC Class I antigen expression in the germ cells which is able to subsequently cause recognition of germ cell antigen by the cytotoxic T-cells. This leads the cancer testis antigen protein to show increased immunogenicity in the patients who are affected by cancer (Hirohashi et al., 2016). In 1991, the cancer-testis antigen genes were first identified by the primary technique of T-cell epitope cloning known as melanoma antigen -1 (MAGE-A1) retrieved from individuals suffering from melanoma (van der Bruggen et al., 1991).

In current years, the other cancer-testis antigen genes like MAGE-A2, GAGE-1 and MAGE-A3 are identified through methods which are similar to the process implemented in identifying MAGE-A1 (De Backer et al., 1999; Gaugler et al., 1994; Chomez et al., 2001). In order to discover more CTA genes, the SEREX (serological analysis of recombinant cDNA expression libraries) technique is used. The mentioned technique is seen to have capability for enabling analysis of immune response towards tumour–specific antigens. This approach involves the serological analysis as well as screening of the cDNA expression libraries related to tumours present in humans with the autologous sera retrieved from individuals suffering from cancer (Sahin et al; 1997). The method is seen to be advantageous for classification of CTA genes such as NY-ESO-1 (Chen et al., 1997), SCP1 (Tureci et al., 1998) and SSX (Tureci et al., 1998). Moreover, by the application of bioinformatics approaches new clinically relevant CT genes are identified which are seen to designate the meiosis-specific CT antigen genes (Sammut et al., 2014; Feichtinger et al., 2012). The Cancer Genome Atlas and cooperative schemes are seen to have identified various CTA genes by examining their profiles of expression in large number of patients suffering from cancer.