caarcinogenesis

Chromosomes, Genes, and Alleles

• APC gene is located at 5q21 on a chromosome
• Allele is a version of a gene
• Chromosome is tightly packed DNA
• Nucleotide is the building block of DNA
• Gene contains instructions to make a protein
• Chromosome has two arms
• Most human cells have 46 chromosomes
• A human chromosome usually has two chromatids

Cell Cycle

• The cell cycle is a series of events that take place in a cell as it prepares for division (grows) and then divides into two daughter cells.
• G0 is the resting phase where the cell spends most of its time
• Cyclins are proteins that turn on kinases
• Kinases are enzymes called cyclin-dependent kinases (CDKs) that increase in activity in response to elevated cyclin levels
• CDK inhibitors, which are chemicals, inhibit CDK function

Signal Transduction Pathways

• Proteins encoded by genes participate in signaling pathways
• Chemical or physical signals are transmitted through a cell as a series of molecular events
• Many genes that are mutated in neoplasia encode proteins that are part of signal transduction pathways
• Transmembrane receptors bind extracellular signaling molecules
• Signal transduction pathways modulate many different cellular functions

From Gene to Signaling Pathway...to Gene

• Mutations in genes that encode proteins participating in signal transduction pathways can change gene expression or activate cell signaling/division independent of external stimuli

Neoplasia is Genetic

• Carcinogenesis is a result of non-lethal genetic damage
• Tumors are formed by clonal expansion of a single precursor cell that experienced genetic damage
• Tumors are clonal
• Genomic alterations may be inherited, arise from environmental influences, or occur stochastically
• Driver alterations contribute to the development of a malignant phenotype
• Passenger alterations are much more frequent than driver alterations but are not relevant to the development of a malignant phenotype
• Carcinogenesis results from the step-wise accumulation of complementary driver mutations over time
• Tumors continue to evolve genomically during outgrowth and progression

Genetic Mutations

• Genetic mutations are permanent changes in the DNA sequence
• Mutations that arise in germ cells (egg, sperm) are transmitted to offspring and can give rise to inherited diseases
• Mutations that arise in somatic cells are important in giving rise to cancers and some congenital malformations
• Mutations interfere with gene expression

Germ and Somatic Cells

• Germ cells have 23 chromosomes

Regulatory Genes and Cancer Causing Mutations

• There are four classes of normal regulatory genes that are the main targets of cancer-causing mutations: proto-oncogenes, tumor suppressor genes, genes that regulate programmed cell death/apoptosis, and genes involved in DNA repair.

Oncogenes

• Oncogenes are mutated proto-oncogenes that promote autonomous cell growth in cancer cells.
• Oncogenes are gain-of-function mutations
• They encode mutant proteins called oncoproteins
• Oncoproteins have gained function to promote cell growth independently of normal extracellular growth-promoting signals

MAPK Pathway Alterations and BRAF Mutations

• The MAPK (mitogen activated protein kinase) pathway is present in 78-88% of ameloblastomas
• BRAF mutations are most common
• BRAFV600E mutations account for 90% of all BRAF mutations seen in neoplasia
• The BRAFV600E mutation results from BRAF c.1799T>A: Thymine (T) is replaced by adenine (A) at coding DNA sequence (nucleotide) 1799, which is a point mutation and activating mutation
• The BRAF protein consists of 766 amino acids

Oncogenic Proteins

• Growth factors
• Growth factor receptors
• Proteins involved in the signaling cascade
• Nuclear regulatory proteins
• Cell cycle regulators

RAS and MYC Mutations

• RAS is the most commonly mutated oncogene
• MYC is an oncogene that activates expression of many genes involved in cell growth
• MYC can reprogram plain somatic cells into pluripotent stem cells
• MYC upregulates telomerase in some contexts
• MYC contributes to stem-cell like immortalization of tumor cells

Telomerase

• Telomerase is an enzyme that lengthens telomeres, which results in limitless replicative potential and contributes to 'cell immortality'

Oncogene Description

• Driver

Evasion of Programmed Cell Death (Apoptosis)

• Apoptosis is programmed cell death in response to pathologic conditions such as carcinogenic mutations
• The Bcl-2 family consists of 25 pro-apoptotic or anti-apoptotic genes
• Relative expression of Bcl-2 family proteins determines cell fate

Follicular Lymphoma evades Cell Death

• Follicular lymphoma has overexpression of Bcl-2 via a chromosomal translocation
• Two-thirds of chromosomal translocations arise from erroneous repair of DNA double-strand breaks

Philadelphia Chromosome

• The Philadelphia chromosome is the most famous translocation, t(9;22), which is characteristic of chronic myelogenous leukemia

Chromosomal Translocation

• Chromosomal translocations are a "shortcut" to cancer
• Mucoepidermoid carcinoma of the hard palate with (11;19) CRTC1-MAML2 translocation is associated with both CRTC1 and MAML2, which are transcription co-activators

Common Mechanisms of Genetic Damage

• Point mutations
• Gene deletions
• Gene amplifications
• Chromosomal translocations

Genomic Instability

• Defects in genes involved in DNA repair are often the source of genomic instability
• Genetic aberrations increase mutation rates which contribute to tumor progression
• TP53 is a tumor suppressor gene that, when mutated, cannot arrest cell division to repair DNA damage or initiate apoptosis in irreversibly damaged cells
• Humans are surrounded by mutagenic environmental agents like sunlight, radiation, and chemicals
• Cancer is a rare outcome of these exposures due to:
  • Ability of normal cells to repair DNA damage
  • Apoptosis as a protective response
  • Normal surveillance mechanisms of the immune system

Xeroderma Pigmentosum

• Xeroderma pigmentosum is a cancer predisposition syndrome where individuals have an impaired ability to repair UV-induced DNA damage
• UV radiation frequently causes abnormal cross-linking of pyrimidine bases
• Normal, error-free DNA replication cannot occur with UV damage
• UV-induced DNA damage is normally repaired by the nucleotide excision repair (NER) system
• The NER system does not work properly in individuals with xeroderma pigmentosum
• Xeroderma pigmentosum is an autosomal recessive syndrome caused by inherited mutations in genes that encode NER proteins
• Individuals with xeroderma pigmentosum have a 1000-fold increased risk of skin cancers, a median age of tumor development of 8 years old, and an increased risk of squamous cell carcinoma of the lower lip and tip of tongue

Hereditary Nonpolyposis Colon Cancer Syndrome (Lynch Syndrome)

• During DNA replication, DNA mismatch repair (MMR) proteins act as "spell-checkers" to detect, excise, and repair defects
• If the MMR protein's proofreading function is lost, genetic mutations are more likely to accumulate and a greater mutational load contributes to the accumulation of complementary driver mutations
• MMR proteins are encoded by MSH2, MLH1, MSH6, PMS2, EPCAM genes
• Germline mutations in these genes:
  • Increase risk of colorectal cancer
  • Increase the risk of other cancers (endometrium, stomach, brain, skin, etc.)

This quiz explores the fundamental concepts of chromosomes, genes, and the cell cycle. You'll learn about the structure of DNA, the role of alleles and genes, and the phases of the cell cycle, including important proteins like cyclins and kinases. Test your understanding of these key biological processes!