Week 2 - Cancer Genome, Mutation vs. Repair

A comprehensive set of practice flashcards covering normal vs abnormal genomes, chromothripsis, and carcinogens based on lecture notes.

What distinguishes normal cells from cancer cells in terms of DNA maintenance?

Normal cells maintain stable DNA with active detection and repair of damaged DNA throughout the cell’s life.

What characterizes cancer at the genetic level?

Alterations to gene structure and expression with gradual accumulation of mutations over time, including phenomena like kataegis and chromothripsis, and the presence of circular extrachromosomal DNA (ecDNA) with high copy numbers.

What are kataegis and chromothripsis?

Kataegis = localized hypermutation; chromothripsis = chromosome shattering with multiple rearrangements.

What is circular extrachromosomal DNA (ecDNA) and its features?

ecDNA is circular DNA outside chromosomes with extreme copy number amplification, no centromeres, and uneven distribution to daughter cells.

What is chromosomal instability?

High rate of chromosome mis-segregation leading to aneuploid cancer cells.

What are purines and which bases are purines?

Purines double ring nitrogenous bases. The purine bases are adenine (A) and guanine (G).

What are pyrimidines and which bases are pyrimidines?

Pyrimidines are singe ring nitrogenous bases. The pyrimidine bases are cytosine (C), thymine (T), and uracil (U in RNA).

What is the Central Dogma of Molecular Biology?

DNA replication, transcription into RNA, and translation into protein (gene expression).

What are exons and introns?

Exons are coding regions; introns are non-coding regions inside genes.

What is a promoter and where is transcription started?

A promoter is near the beginning of a gene (5' end) and is involved in regulating transcription.

What is a TATA box?

A regulatory element that, when bound by the TATA-binding protein, initiates transcription.

What is a response element (RE)?

A short DNA sequence within a promoter recognized by a specific protein, contributing to gene regulation (e.g., serum response element CCATATTAGG).

What are enhancers and super enhancers?

Regulatory DNA sequences that drive tissue- and stage-specific gene expression; enhancers can be distal from the promoter.

What is a terminator in transcription?

The end of a gene where transcription stops (3' end).

What are base substitutions and their types?

Mutations include transitions (purine-purine or pyrimidine-pyrimidine) and transversions (purine-pyrimidine exchanges).

What is a frameshift mutation?

Insertion or deletion that shifts the reading frame of the gene.

What are common mutation consequences?

Silent mutations (no protein change), missense changes, nonsense or truncated proteins, mislocalization, protein overproduction (gene amplification), or new chimeric proteins from translocations.

What is a driver mutation?

A mutation in cancer genes that provides a growth/proliferation advantage; many cancers require multiple driver mutations.

What is a mutator phenotype?

A state with an increased rate of mutations, often due to defective DNA repair.

What does Tumor Mutational Burden (TMB) mean?

The total number of mutations present in a cancer genome.

What is chromothripsis and its clinical relevance?

A single catastrophic event involving one or more chromosomes causing numerous gene rearrangements; can disrupt tumor suppressors or create oncogenic fusions; seen in 30-50% of cancers.

What are major causes of chromothripsis?

Cell division errors (micronuclei, bridge breakage), DNA damage (ionizing radiation, replication stress), repair pathway defects (loss of p53, NHEJ/HDR defects), structural abnormalities (telomere crisis, oncogene-induced stress), and external triggers (chemotherapy, viral infections).

What are polycyclic aromatic hydrocarbons (PAHs)?

Carcinogens derived from phenanthrene that form from incomplete combustion (coal, oil, wood); include benzo[a]pyrene (BP) and DMBA; metabolized by CYP1A1 to reactive intermediates that form DNA adducts with purine bases.

How do PAHs cause mutations at the DNA level?

Metabolized to highly reactive mutagenic toxic diol epoxides that form adducts with purine bases, resulting mainly in G→T transversions.

What are aromatic amines (HCAs) in carcinogenesis?

Heterocyclic amines produced by cooking meat (heating of amino acids and proteins); activated by CYP1A1 enzymes to create DNA-damaging products that form adducts, like aryl nitrenium ions.

What are nitrosamides and nitrosamines?

Carcinogenic compounds found in tobacco and formed when nitrites react with amines in fish and meats during smoking; nitrosamines require metabolic activation and can alkylate DNA (e.g., O6-guanine, which base pairs with thymine rather than cytosine).

What are alkylating agents and give an example?

Chemicals that alkylate DNA, causing intra- and inter-strand cross-links; mustard gas is a classic example.

What are asbestos and erionite, and what cancer do they cause?

Naturally occurring fibrous minerals that are carcinogenic; Asbestos exposure can cause mesothelioma; Eronite is found in volcanic ash and hollows of rock formation; Possible genetic predisposition to fibrous-material–related carcinogenesis.

How do infectious pathogens contribute to cancer?

Pathogens can produce proteins that block tumor suppressor genes or encode mutated genes with a dominant effect, or cause chronic infection; HPV is a key example that targets cervical, anal, and head/neck cancers.

What is HPV’s mechanism in promoting cancer?

Oncoproteins E6 and E7 degrade p53 and disrupt pRB, respectively, increasing genome instability and promoting translocations, deletions, and amplifications.

What percentage of cancers worldwide are associated with infectious pathogens?

Approximately 13%.

What types of skin cancers are linked to UV radiation?

Squamous cell carcinoma, basal cell carcinoma (very common and usually treatable), and melanoma (less common but deadly).

How does UV radiation affect DNA structure?

Forms cyclobutane pyrimidine dimers; this distorts (bends) the DNA structure and impairs replication by impeding DNA synthesis; Responsible for 80% of UVB-induced mutations.

Why are tanning devices classified as “carcinogenic to humans?”

UV-emitting tanning devices lead to the inactivation of p53, a tumor suppressor protein, increasing the risk of skin cancer.

What are adducts?

Adducts are chemical compounds formed when a carcinogen binds to DNA, leading to its distortion. This is the initiation of carcinogenesis

What everyday cooking practices can reduce HCA formation?

Oven-roasting, marinating, and coating food with breadcrumbs before frying

What is the carcinogenic mechanism of ionizing radiation?

Ionizing radiation converts molecules from a neutral state to a charged state (ion) by displacing electrons; Causes DNA damage by generating toxic ROS or breaking DNA double-strand.