Cancer Genetics is the Best Option for Understanding Cancer

Background of Cancer Genetics

Cancer Genetics is the combination of two words (Cancer and Genetics). The first word “Cancer” describes a group of diseases, i.e., cancer is not a single disease. Cancer is a disease of uncontrolled growth and the spread of mutant body cells to other parts of the body. Metabolically these mutant body cells are more active than normal body cells. Therefore, they deprive the normal body cells of all types of nutrients and other essential requirements. Consequently, the normal body becomes weaker and subsequently dies. Cancer is the second leading cause of death after cardiovascular diseases. 

Genetics is the subject that educates us about DNA-associated characteristics of an organism that transfer from parents into offspring. These units (also known as “Genes”) define some specific characteristic of an organism. For example, genes associated with organism phenotypes. The eye color gene regulates eye color. In humans, eye color may be black, blue, green, or brown, etc. Similarly, the eye shape gene controls the shape of the eye (i.e., round, oval, etc.). According to the human genome project, the human genome consists of 20,000-25,000 genes (About the Human Genome Project, n.d.). Genes are the writers of almost all proteins, performing different cellular activities (such as cell growth, metabolism, cell cycles, DNA damage/repair, etc.) of an organism. 

Mutations Play a Leading Role in Cancer Initiation

Mutations can alter the normal functions of these genes such as cell signaling, drive cell cycles and maintain DNA in its original form like parental copy through DNA damage/repair mechanisms. Particularly mutations in those genes are responsible for altered functions and can trigger different types of cancers. These mutations can occur by exposing cells of an organism to different types of DNA damage substances, known as “Carcinogens”. Carcinogens may be external such as chemical (e.g., Benzene), biological (e.g., Viruses), physical (e.g., UV light, ionizing agents) and/or internal (such as ROS).

Therefore, Cancer Genetics is one of the most important domains of biological sciences to investigate the association between mutated genes and associated cancers. 

Classification of Cancer based on Mutations

All types of Cancers can be classified into two groups based on a mutation in the cancer-associated genes. 

1. Sporadic Cancer. Sporadic Cancers are common as compared to inherited cancer. This type of cancer occurs due to “Acquired Mutations”. Acquired mutation can occurr in the life cycle of a person and damage cancer-associated genes in specific cell types (e.g., Skin epithelial cells, brain neuron cells, etc.) of the body. Mutation remains in the specific cell type and the rest of the cells have a normal version of the mutant gene. 
2. Inherited Cancer. Inheritance Cancer is due to mutations in cancer associated-genes present in the germ cells (sperm/ova) and transferred to offspring.

Cancer Statistics According to WHO 

According to WHO, approximately 10M death occur each year due to different types of cancers. Breast, lung, colon, rectum, and prostate are common types of cancers. Early detection of cancer helps clinicians to effectively treat cancer patients. Besides adults, approximately 400000 children acquire Cancer each year (WHO, 2022). WHO data show Breast Cancer is more frequent cases among reported new cases of cancer in 2020 (Figure: 1)

Cancer Genetics Explores Mechanistic Approaches Behind DNA Damages

DNA is a double-stranded helix molecule consisting of repeated nucleotides in linear form. In the same strand, these nucleotides bind with each other by a phosphodiester bond. While hydrogen bonds are present between Nitrogen bases of nucleotides of both strands. Each nucleotide comprising of three different components as Nitrogen bases (A, C, T, G), Pentose sugar (deoxyribose sugar in the case of DNA, while in the case of RNA ribose sugar), and a Phosphate group. The nitrogen bases, a pentose sugar, and a phosphate group interact with each other through different types of Bonds (i.e., glycosidic bonds, ester bonds, hydrogen bonds, covalent bonds, etc.). DNA targeting agents target these components of DNA molecules and alter either their structure or natural sequence. These altered sequence codes for abnormal protein products (i.e., either in composition or in an expression) resulting in altered proliferation of body cells and consequently leading to tumor formation. 

Cancer Genetics Investigates Carcinogenic-mediated DNA Damage

Carcinogenic substances can target DNA molecules in two ways.

1. These substances can interact directly with DNA molecules and produce breaks in DNA strands, chromosomal translocation, deletion, insertion, and substitution etc. 
2. Despite directly targeting DNA molecules, these substances indirectly interact with water (Radiolysis) to generate Reactive Oxygen Species (ROS). ROS in turn work as a Carcinogenic agent to alter DNA compositions. 

Both direct and indirect-acting carcinogenic substances ultimately either alter the normal structure of nucleotide or sequence of a gene and subsequently lead to the cancer phenotype. 

Cancer Genetics Can Estimate Rate of Mutations per Day

Approximately DNA faces 20,000 lesions per day. DNA repair systems heal most of the mutations in DNA. Among these lesions, hydrolysis (consisting of depurination, depyrimidination, C deamination, and 5-MeC deamination) is approximately 10,000. Oxidation-mediated mutations (occurring due to 8-oxoG, ring-saturated pyrimidines, and lipid peroxidation products) are nearly 3000. Lesions due to methylations are almost 4000. However, less than one remains or becomes fixed in the genome when replication occurred. Approximately 1-2 per day remain unrepaired. In addition, approximately 100,000 up to 10,00,000 lesions occur per day during the replication process, driven by polymerases (Preston et al, 2010). Having the same rate approximately 10,000 mutations can accumulate in the genome of any human in their lifetime. 

Estimated Mutations require to Trigger Malignancy

A single mutation is not enough to initiate Cancer. Because cellular repair systems work to repair immediately incorporated mutation in DNA. However, mutation in repairing genes, helps in accumulating mutations in DNA in subsequent generations.  Approximately mutations in five to fifteen genes, known as “driver mutation,” can transform normal cells into cancerous cells.

Cancer Genetics Classifies Cancer Genes into Many Groups

A cell of an organism has different cellular activities to maintain life, such as proliferation, growth, location, mortality, etc. Proliferation is the process to maintain the number of cells in an organism. Cell growth is necessary for the maturation of cells to gain normal size and to perform specific cellular activities. Each cell has a specific location (i.e., tissue) where the cell can easily perform normal but specific cellular activity along with other same cells in the tissue.

However, after spending a specific time of life or sometimes a cell can face unrepairable damages by accidents that lead to trigger a mechanism of mortality and consequently, such old or damaged cells face death. All such type of cellular activities is carried on via a specific cellular mechanism. For example, Cell proliferation can be acquired through the cell cycle. Growth and differentiation require cellular signaling etc. And mortality in a cell can be initiated through Apoptosis. 

Mutations in those genes, which products play a leading role in cell growth, differentiation, as well as in death developing cancer morphology. A significant number of genes drive these cellular activities. Systematic classification of these genes will help us to study these genes easily. Such as.

Cancer Genetics Provides Us Details Study about Oncogenes

An oncogene is the mutated version of proto-oncogenes. Proto-oncogenes mostly carry on the proliferation of cellular activity. Proliferation-associated pathways and their respective signaling molecules are well-studied products of proto-oncogenes. These genes normally perform to stimulate cell division, in parallel, to inhibit the differentiation process as well as prevent Apoptosis.  As proto-oncogenes get mutations, the product of the mutant gene consequently acquires a “gain of function”. Typically, oncogenes behave in a “Dominant” way (Hesketh, 2013). Approximately 500 genes have been identified to have an association with different types of cancers.

Cellular Functions of Proto-oncogenes

Proto-oncogenes play an essential role in regulating different cellular activities such as controlling cellular proliferation, differentiation, and death processes through intracellular signal transduction. Functionally these proteins work as growth factors, growth factors receptors, intracellular signal transduction factors, DNA-binding nuclear proteins, cell-cycle factors, apoptosis factors, etc. (Turnpenny and Ellard, 2016). 

Cancer Genetics & Conversion of Proto-oncogenes into Oncogenes 

Proto-oncogenes are converted into oncogenes using the following ways,1.) point mutation, 2.) gene amplification, 3.) chromosomal rearrangement, and 4.) autocrine activation (Pelengaris and Khan, 2013; Du and Lovly, 2018).

Point mutation-mediated Oncogene Activation

Point mutation refers to any single nucleotide change in the form of insertion, deletion, and/or substitution. Among these different types of mutations, substitution is one of the most characterized mutations in oncogenic-mediated tumour studies (Pierotti and Porta, 2022). A point mutation can occur in both regions (i.e., regulatory and coding) of proto-oncogenes. Mutations in regulatory or coding regions have different effects on their gene products. For example, mutations in regulatory regions enhance the expression of gene products. In contrast, a mutation in the coding region produces an altered product with increased cellular activity (Pecorino, 2012). It is point mutation, that is responsible for converting proto-oncogenes of the Ras family (such as k-ras, H-ras, N-ras) into oncogenes by point mutations. Most cases of lung, colon, pancreas, and thyroid carcinomas, are due to point mutation  (Pierotti and Porta, 2022).

Gene Amplification Mediated Oncogenic Tumour Formation

Gene amplification denotes the repetition of a gene or the presence of more copies in the genome of an organism. Multiple copies of a gene in the genome enrich the protein product of the said gene. Tumours of Squamous cell carcinoma, neuroblastomas, glioblastoma, and breast cancer show a significant copy number of proto-oncogenes belonging to myc, erb B and ras families (Pierotti and Porta, 2022). Receptor tyrosine kinases (EGFRs, FGFR, MET, ERBB, FLT, etc.) mediated different types of cancers (such as breast, gastric, lung, etc.) also confirm gene amplification mediated oncogenic tumours (Du and Lovly, 2018).   

Chromosomal Rearrangement is one of the leading causes of Oncogenic tumour

Chromosomal rearrangement is a phenomenon in which any change (i.e., deletion, duplication, translocation, inversions) can occur in chromosome structure. Among these changes, the most frequent change is chromosomal translocation, and less frequent is chromosomal inversions. Chromosomal rearrangement-mediated abnormality occurs in two types, transcriptional activation of protooncogene, and formation of fusion protein (Pierotti and Porta, 2022). 

Cancer Genetics Assists in Studying Tumor Suppressor Genes

Tumor-suppressor genes are involved in the regulation of cell cycle progression, protein degradation, cellular adhesion as well as mortality. Mutation in Tumor suppressor genes leads to “loss of function”. Tumor suppressor genes exhibit a recessive Mendelian inheritance pattern. Mutation in around 100 gene leads to loss of function-mediated cancers.

Cancer Genetics Ensures to Investigate Genomic Stability

Genomic Integrity is indispensable for the continuation of the generation of an organism. Different types of enzymes (i.e., DNA polymerases λ and μ, etc.) continuously proofread the genome of the replicating or resting cells and recognize any kind of damage in DNA molecules. Subsequently these enzymes repair these repairable damages through the DNA damage/repair systems driven by different types of proteins. In simple words, these proteins ensure the Genomic Integrity of an organism. However, mutations in these genes lead to loss of function, therefore, genomic instability occurs followed by Cancer.     

References

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