Cancer and Tumor Suppressor Genes: An Overview

Introduction

Tumor suppressor genes work on the inverse side of cell growth regulation, inhibiting cell proliferation and tumor formation. These genes are grouped broadly based on their roles in the following processes:

• Cell growth.

• Cycle progression.

• Deoxyribonucleic acid (DNA) repair processes.

• Cell proliferation.

• Apoptosis induction.

Without functioning tumor suppressor genes, dysregulated cell proliferation is a significant likelihood, a well-known pathway for cancer formation.

How Are Tumor Suppressor Genes (TSGs) Classified?

Tumor suppressor genes are functionally classified into the following categories:

1. Genes encode intracellular proteins that are essential for determining cell cycle progression - (e.g., pRB and p16).

2. Genes encode receptors or signal transducers that organize signals that suppress cell proliferation (e.g., APC and TGF-).

3. Checkpoint-control proteins [e.g., p16, p14, and breast cancer type 1 susceptibility protein (BRCA1)] encode genes important in inducing cell cycle arrest in the event of DNA damage or chromosomal abnormalities.

4. Genes encoding proteins are involved in the induction of apoptosis (e.g., p53).

5. Genes encode proteins in DNA repair [for example, DNA mismatch repair protein 2 (MSH2) and p53].

Which Cancers Occur Due to Mutations in Tumor Suppressor Genes?

Loss of function mutations in tumor suppressor genes has been found in various malignancies, including:

• Ovarian cancer.

• Lung cancer.

• Colorectal cancer.

• Head and neck cancer.

• Pancreatic cancer.

• Uterine cancer.

• Breast cancer.

• Bladder cancer.

Familial cancer syndromes are also linked to loss of function germline mutations in specific tumor suppressor genes, such as Li-Fraumeni syndrome with TP53 deficiency.

What Is the Retinoblastoma (RB) Gene?

The retinoblastoma (RB) gene was the first tumor suppressor gene, and mutations in the retinoblastoma (RB) gene cause infantile retinoblastoma. This is a hereditary syndrome caused by an inactivating mutation in the RB1 gene, which increases the likelihood of developing retinoblastoma (frequently in both eyes) 10,000-fold compared to the general population. These people are also more likely to develop osteosarcoma and other sarcomas. Surprisingly, over 60 % of retinoblastomas develop randomly (nearly invariably in one eye), and these people are not at greater risk for different types of cancer.

What Are the Properties of Tumor Suppressor Genes (TSGs)?

Tumor suppressor genes (TSGs) have three crucial properties:

1. First, classic tumor suppressor genes (TSGs) are recessive at the cellular level, with tumors often exhibiting inactivation of both alleles.

2. Inheritance of a single mutant allele improves tumor susceptibility because the complete loss of gene function requires one different inactivating event.

3. In sporadic tumors, the same gene is frequently inactivated.

What Is the Mechanism of Action of Various Tumor Suppressor Genes(TSGs)?

• Retinoblastoma (RB): The retinoblastoma (RB) gene, often known as the 'governor of the cell cycle,' encodes the retinoblastoma (RB) gene protein, which binds and suppresses E2F transcription factors when hypophosphorylated. These transcription factors control genes that cells need to go from the G1 to the S phases of the cell cycle. RB hyperphosphorylation and inactivation are caused by typical growth factor signaling, resulting in cell cycle advancement. Several mechanisms, including loss-of-function mutations affecting the retinoblastoma (RB) gene, CDK4, and cyclin-dependent kinase inhibitor loss (p16/INK4a), cyclin D gene amplification, and inhibition of RB by viral oncoprotein binding (E7 protein of HPV), might revert retinoblastoma (RB) genes antiproliferative action in malignancies.

• TP53 Tumor Suppressor Gene: The TP53 tumor suppressor gene is also known as the ‘guardian of the genome.’ It monitors for cellular stress like anoxia and identifies DNA damage or inappropriate signaling by mutated oncoproteins. The TP53 gene encodes for the p53 protein, which controls the expression of proteins and their activity in cell cycle arrest, cellular senescence, DNA repair, and apoptosis. Loss of p53 can cause continued cell replication despite DNA damage and failure to activate programmed cell death.

• ATM or ATR Family Kinases: DNA damage is perceived by complexes comprising the ATM or ATR family kinases. These kinases phosphorylate p53, releasing it from inhibitors such as MDM2. The active p53 upregulated the expressions of essential proteins like cyclin-dependent kinase inhibitor p21, which causes G1-S checkpoint arrest of the cell cycle. In instances where the DNA damage is not repairable, p53 induces events like activating the BAX gene, which encodes a pro-apoptotic protein that finally lead to cellular apoptosis. The active p53 boost the production of critical proteins such as the cyclin-dependent kinase inhibitor p21, causing the cell cycle to stop at the G1-S checkpoint. When DNA damage is irreparable, p53 activates the BAX gene, which encodes a pro-apoptotic protein that eventually leads to cellular death.

• Phosphatase and Tensin Homolog (PTEN) Gene: The PTEN gene encodes a lipid phosphatase that adversely controls the PI3K-AKT and mTOR signaling pathways. These pathways are essential for cell proliferation, progression through the cell cycle, and apoptosis. The PTEN protein also regulates migration, angiogenesis, and adhesion. It also contributes to the general stability of the genome. Biallelic loss of function is frequent in a wide range of malignancies. For example, Cowden syndrome is an autosomal dominant illness caused by germline loss-of-function mutations in this gene that are associated with an increased risk of breast and endometrial cancer.

• CDH1 (E-cadherin): When normal cells come into contact with nearby cells, they stop growing, preserving the shape and architecture of the tissue, a process known as contact inhibition. Cadherins are a family of proteins that mediate cell-to-cell interaction in various tissues. E-cadherin (epithelial cadherin) controls contact inhibition by attaching to ß-catenin, a crucial component of the WNT signaling (wingless-related integration site) cascade. This interaction stops E-cadherin from translocating to the cell's nucleus and initiating transcription of pro-growth target genes. This interaction generally governs the form and structure of epithelial cell linings. A germline loss-of-function in this gene is linked to autosomal dominant familial gastric cancer.

Why Is Retinoblastoma Rare in the General Population?

Children with hereditary retinoblastoma inherit one mutant RB allele (germ-line mutation) and one regular copy. Sometimes, it occurs when the normal retinoblastoma (RB) allele receives a spontaneous somatic mutation. Both normal RB alleles must experience a somatic mutation in the same cell in sporadic occurrences of retinoblastoma. This is unlikely, which explains why retinoblastoma is rare in the general population.

Conclusion:

Tumor suppressor genes either suppress or inhibit the cell cycle or induce apoptosis. The more specialized roles of tumor suppressor proteins are that mitogenic signaling pathways are inhibited, cell cycle progression and pro-growth metabolic activity are inhibited, and DNA repair factors in the genome are stabilized along with apoptosis induction. To find innovative targets for particular cancer types, extensive research needs to be conducted to understand these genes better and their association with cancer.