Importance of Tumor Suppressor Genes in Cancer: An Outline

Introduction:

Nowadays, large-scale cancer genomics programs such as The Cancer Genome Atlas (TCGA), GENIE, and the International Cancer Genome Consortium (ICGC), tumor driver genes, molecular subtypes, and other features are being identified to increase the efficiency of sequencing technologies and bioinformatics. These efforts have made vast volumes of tumor genetic and clinical data available. In addition, the organized integration of several multi-genomics platforms offers a significant opportunity to understand better the fundamental genetic changes that drive cancer genesis and progression.

What Are Tumor Suppressor Genes?

Tumor suppressor genes are the most important genes that govern numerous cellular activities inside the genome. Dysregulated or abnormal cell proliferation without functioning tumor suppressor genes is a well-known pathway for cancer formation. Mutations in tumor suppressor genes that cause loss of function have been found in uterine, ovarian, head and neck, bladder, colorectal, lung, pancreatic, and breast cancer.

How Are Tumor Suppressor Genes Classified?

These genes are grouped broadly based on their roles as follows:

1. Cell growth or cell cycle progression.

2. Cell proliferation.

3. Deoxyribonucleic acid(DNA) repair processes.

4. Critical cellular signaling tasks (apoptosis induction).

What Are the Properties of Tumor Suppressor Genes?

Based on the findings, traditional tumor suppressor genes have three crucial properties:

1. First, frequently demonstrating inactivation of both alleles.

2. A single mutant allele raises the risk of developing tumors since it only takes one additional inactivating event to completely lose a gene's function.

3. The same gene is typically inactivated in sporadic cancers.

What Is the Mechanism of Tumor Suppressor Genes?

• PRB and P16 - Tumor suppressor genes encode intracellular proteins to determine cell cycle progression.

• APC and TGF - Tumor suppressor genes encode receptors or signal transducers that organize signals to suppress cell proliferation.

• P14, P16, P14, and BRCA1 Checkpoint - Control Proteins initiate cell cycle arrest in case of DNA damage or chromosomal abnormalities.

• P53 - Genes are encoding proteins involved in the induction of apoptosis.

• P53 and DNA Mismatch Repair Protein 2 (MSH2) - Genes encoding proteins involved in DNA repair.

What Are the Different Roles of the Tumor Suppressor Genes?

Retinoblastoma:

The retinoblastoma (RB) gene was the first tumor suppressor gene discovered, and mutations in this gene have been linked to infantile retinoblastoma. Compared to the general population, this is a genetic condition caused by an inactivating mutation in the RB1 gene, which raises the probability of developing retinoblastoma in both eyes 10,000-fold. They have a high risk of developing osteosarcoma and other sarcomas. On the other hand, over 60 percent of retinoblastomas develop randomly, almost invariably, in one eye. To explain this difference, the two-hit theory is presented :

• Children with inherited retinoblastoma inherit one mutant and one regular copy of the RB allele. The second hit occurs when a spontaneous somatic mutation arises in the normal retinoblastoma (RB) allele.

• In occasional cases of retinoblastoma, both normal RB alleles must undergo a somatic mutation in the same cell. This is improbable, which explains why retinoblastoma is rare in the general population. In both situations, the subsequent two impacts result in the creation of retinoblastoma.

Neuroblastoma:

• The neuroblastoma breakpoint family member 1 (NBFP1) gene is disrupted by constitutional translocation in neuroblastoma. After that, many studies discovered that the NBPF1 gene on chromosome 1p36 is extensively deleted in various human malignancies, including those of blood, epithelial, and neural origin.

• Neuroblastoma breakpoint family member 1 (NBFP1) gene levels were decreased in recurrent neuroblastomas within five years. By inhibiting the PI3K or mTOR and Akt-p53-cyclin signaling pathways, the member 1 (NBFP1) gene lowers tumor cell proliferation, growth, and cell cycle progression in cutaneous squamous cell carcinoma and cervical cancer, respectively.

• Downregulating NBPF1 in liver cancer cells, on the other hand, dramatically lowers their proliferation capability.

TP53 Tumor Suppressor Gene:

• The TP53 tumor suppressor gene, also known as the genome guardian, detects cellular stress such as anoxia (low oxygen levels) and detects DNA damage or improper signaling by mutant oncoproteins.

• The TP53 gene encodes the p53 protein, which is involved in cell cycle arrest, cellular senescence (deterioration), DNA repair, and apoptosis (cell death).

• Despite DNA damage, p53 loss can result in extended cell replication and the inability to trigger programmed cell death.

• Complexes of ATM or ATR family kinases detect DNA damage and phosphorylate p53, freeing it from inhibitors such as MDM2.

• Active p53 stimulates the synthesis of critical proteins, such as the cyclin-dependent kinase inhibitor p21, resulting in cell cycle arrest at the G1-S checkpoint.

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, cell cycle progression, and apoptosis.

• The PTEN protein also regulates migration, adhesion, and angiogenesis (formation of new blood vessels).

• It also contributes to the general stability of the genome. Unfortunately, genetic loss of function is frequent in many malignancies.

• Cowden syndrome is caused by germline loss-of-function mutations in this gene, which has been linked to an elevated risk of breast and endometrial cancer. It is also an an autosomal dominant disorder.

WT1:

• The WT1 (Wilms tumor protein) gene encodes transcription factors required for the correct development of genitourinary tissue.

• Wilms tumor, a kind of juvenile kidney cancer, has been related to a germline loss-of-function mutation in this gene.

• WT1 mutations have also been linked to sporadic Wilms tumors.

BRCA 1 and 2, PARP-1:

• Tumor suppressor genes BRCA1 and 2 produce proteins that involve the repair of DNA (homologous recombination) double-strand breaks.

• PARP-1 encodes a protein that assists in single-stranded DNA repair.

• The cell cycle continues to pass on flawed and altered genetic information without working proteins that repair DNA, resulting in malformed daughter cells.

Conclusion:

Each tumor suppressor gene has complicated processes interconnected with other cell signaling pathways. As a result, these genes are lost or inactivated in many cancers, eliminating negative regulators of cell proliferation and leading to tumor cell aberrant proliferation. Understanding the characteristics of a unique tissue environment, altered pathways, and immunological features of each cancer and subtype is essential to discern cancer's underlying dynamics and informing diagnosis, prognosis, and treatment as genomic and molecular interactions become more reliably described.