Genetics Basics and Cell Cycle Overview

Genetics Basics

• A gene is a distinct DNA sequence within a chromosome that acts as an instruction to make proteins.
• Humans have 20,000-25,000 genes (~2 million DNA bases).
• Alleles are variations of a single gene with small differences in DNA base sequences.
• Humans have 46 chromosomes (23 pairs), half from the mother and half from the father.
• A chromosome is a tightly packed structure of DNA.
• Each chromosome has two arms and is further divided into regions, bands, and sub-bands, where each gene resides.
• A nucleotide is the building block of DNA.

Cell Cycle

• The cell cycle is a series of events that take place in a cell as it grows and divides into two daughter cells.
• The G0 (resting) phase is where the cell spends most of its time.
• The cell cycle is regulated by a complex balance of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors.

Genetic Basis of Neoplasia

• Neoplasia is caused by mutations in normal regulatory genes.
• Four classes of genes are commonly targeted in cancer-causing mutations:
  • Proto-oncogenes: Growth-promoting genes
  • Tumor suppressor genes: Growth-inhibiting genes
  • Genes that regulate apoptosis (programmed cell death)
  • Genes involved in DNA repair

Proto-oncogenes

• Proto-oncogenes are normal genes that promote cell growth.
• Oncogenes are mutated proto-oncogenes.
• Oncoproteins promote cell growth independently of normal extracellular growth-promoting signals.
• The MAPK signaling pathway is altered in a large percentage of ameloblastomas.
• BRAF mutations are one of the most common oncogenes.
• BRAFV600E is a common mutation found in 90% of all BRAF mutations observed in neoplasia.

Tumor Suppressor Genes

• Tumor suppressor genes normally inhibit cell proliferation.
• Mutations inactivating tumor suppressor genes lead to a failure of growth inhibition.
• The Knudson ‘two-hit’ hypothesis states that both alleles of a tumor suppressor gene must be mutated for tumor development.
• Loss-of-function mutations render tumor suppressor proteins unable to function properly.

RB (Retinoblastoma)

• RB is a tumor suppressor gene involved in regulating cell cycle progression.
• RB is directly or indirectly inactivated in most human cancers.
• RB regulates the expression of genes necessary for dividing cells to pass through the G1/S cell cycle checkpoint.

Tumor Suppressor Syndromes

• Many cancer predisposition syndromes are characterized by germline mutations in tumor suppressor genes.
• Germline mutations are present in every cell of the body and can be passed on to subsequent generations.
• Patients with germline mutations in tumor suppressor genes are at increased risk for tumor development.
• Examples of tumor suppressor syndromes include:
  • Familial adenomatous polyposis (FAP)
  • Neurofibromatosis 1 (NF1)
  • Nevoid basal cell carcinoma syndrome (Gorlin syndrome)
  • Cowden syndrome
  • Familial retinoblastoma syndrome
  • Li-Fraumeni syndrome

PTCH (Patched 1)

• PTCH is a tumor suppressor gene that regulates the Hedgehog signaling pathway.
• The PTCH protein binds to and inactivates SMO (a proto-oncogene).
• Mutations in PTCH are associated with nevoid basal cell carcinoma syndrome (Gorlin syndrome).

APC (Adenomatous Polyposis Coli)

• APC is a tumor suppressor gene that downregulates the Wnt/β-catenin signaling pathway.
• FAP is a cancer predisposition syndrome caused by germline mutations in APC.
• FAP patients develop multiple adenomatous colonic polyps, with a high risk of transformation to colorectal carcinoma.
• APC mutations are also frequently found in sporadic colorectal carcinoma.

Gardner Syndrome

• Gardner syndrome is a subgroup of familial adenomatous polyposis syndrome.
• It is characterized by multiple epidermoid cysts, osteomas, supernumerary teeth, and multiple premalignant colorectal polyps that have a 100% risk of becoming malignant if untreated.

TP53 (Tumor Protein P53)

• TP53 is a tumor suppressor gene known as the 'guardian of genomic stability'.
• TP53 regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis.
• TP53 monitors DNA damage and cell stress, inducing growth arrest, DNA repair, or apoptosis if DNA cannot be repaired.
• TP53 is the most frequently mutated gene in human cancers.

Gene Deletions: Meningioma

• Meningioma is the most common brain tumor.
• Deletions in 22q, which contains the NF2 tumor suppressor gene, are commonly observed in meningioma.

Gene Amplification: Liposarcoma

• Gene amplification is an abnormal generation of multiple copies of a specific DNA sequence.
• 12q13-15 amplification is seen in liposarcoma.
• MDM2 is a negative regulator of TP53.
• Amplification of MDM2 can have the same effect as a TP53 mutation.

CDK4 Overexpression

• CDK4 overexpression promotes uncontrolled cell cycle progression, contributing to tumor development.

MMR (Mismatch Repair) and Microsatellite Instability

• Mismatch repair (MMR) genes are important for repairing DNA mismatches during replication.
• Lynch syndrome is a cancer predisposition syndrome associated with mutations in MMR genes.
• Lynch syndrome often leads to microsatellite instability (MSI), where repetitive DNA sequences are prone to mutations.
• MSI is associated with a higher risk of developing colorectal cancer.

BRCA1 and BRCA2

• BRCA1 and BRCA2 are tumor suppressor genes involved in DNA repair via homologous recombination.
• Mutations in BRCA1/BRCA2 are linked to a significantly increased risk of breast, ovarian, and other cancers.
• Cells lacking functional BRCA1/BRCA2 proteins are susceptible to chromosomal breaks and aneuploidy.

Carcinogenesis: Accumulation of Mutations

• Carcinogenesis typically involves the accumulation of multiple complementary driver mutations in a stepwise fashion over time.
• This process is thought to require multiple genetic alterations (e.g., both proto-oncogene activation and tumor suppressor inactivation) before malignant transformation occurs.

Key Points

• Knowing the basic concepts of genes and their roles in cellular processes is crucial for understanding cancer development.
• Tumor suppressor syndromes are important to consider in patient care and clinical management.
• Specific gene alterations are often associated with the development of certain tumors and may serve as diagnostic markers or therapeutic targets.

Explore the fundamental concepts of genetics, including genes, alleles, and chromosomes, as well as an overview of the cell cycle and its phases. Understand how these foundational principles intertwine with the genetic basis of neoplasia. This quiz will test your knowledge of essential biological processes.