Mutations & Cancer

what is a mutation?

a permanent change in the DNA nucleotide sequence, which can occur spontaneously, during DNA replication or after DNA has been damaged

somatic mutation

• occurs in body cells (skin/liver)

• not inherited by offspring, but passed to daughter cells during mitosis

Consequence:

• can contribute to cancer and sometimes mosaicism (genetically different groups of cells)

germline mutation

• occurs in reproductive cells (egg/sperm) or their precursors

• can be inherited by offspring

Consequence

• can cause genetic disorders

• can cause cancer predisposition

what are the main causes of DNA mutations?

• DNA replication errors

• Reactive oxygen species (ROS) from metabolism

• Radiation (UV and ionising)

• Environmental chemicals (cigarette smoke)

• Certain viruses

what is a mutagen and how does it cause mutations?

• an agent that can cause genetic mutations by damaging DNA

• when damage is copied, or incorrectly repaired it could lead to incorrect base substitutions, insertions or deletions

which viruses are associated with cancer?

• HPV = cervical and other cancers

• HBV/HCV = liver cancer

• EBV = certain lymphomas and nasopharynegal cancer

• HTLV-1 = adult T-cell leukaemia/lymphoma

• HHV-8 = Kaposi sarcoma

• MCPyV = merkel cell carcinoma

how do cells respond to detected DNA damage?

1. Cell cycle arrest = cell cycle pauses division to allow repair

2. DNA repair = enzymes attempt to correct the damage

3. Apoptosis = programmed cell death occurs if damage is too severe

what are the main DNA repair mechanisms?

• direct reversal of DNA damage

• base-exicision repair

• mismatch repair

• double-strand break repair (homologous recombination or end joining)

what happens if DNA repair fails?

• unrepaired DNA damage could become permanent mutations

• severely damaged cells may undergo apoptosis

• if repair and apoptosis fair, abnormal cells may survive and divide, increasing risk of cancer

what are the 3 types of point mutations?

1. silent = base substitution does not change the amino acid

2. missense = base substitution changes 1 amino acid

3. nonsense = base substitutions creates a premature STOP codon, producing a shortened protein

insertion, deletion, duplications

• insertion = addition of 1 or more nucleotides

• deletion = removal of 1 or more nucleotides

• duplication = a DNA segment is copied 1 or more times

what is a frameshift mutation?

• an insertion or deletion of nucleotides that shifts the reading frame (changes how the sequence is read in groups of 3)

• changes the downstream amino acids, and often produces a non-functional protein

what is an inversion mutation?

a DNA segment is reversed within the sequence

what is a chromosomal mutation?

large-scale changes to chromosomes, including deletions, duplications and translocations

how can a mutation affect the function of a protein?

• Neutral = little/no effect on protein function

• Harmful = important region (eg, enzyme active site affected), so protein structure/function altered

• Beneficial = may provide an advantage in certain environments

what type of mutation causes sickle cell disease?

• a missense mutation in the HBB gene, where a single DNA base substitution causes glutamic acid to be replaced by valine at position 6 of β-globin

• a hydrophillic amino acid is replaced with a hydrophobic one, promoting haemoglobin aggregation and red blood cell sickling

what mutations are associated with cystic fibrosis?

can occur from the deletion of 3 DNA bases in the CFTR gene, disrupting protein function

what mutations are associated with Huntington’s disease?

expansion of CAG gene repeats in the HTT gene, causing progressive nerve-cell degeneration

what are some examples of beneficial genetic variants?

• HBB sickle-cell trait = 1 variant copy provides some protection against severe malaria

• lactase persistence = allows lactose digestion in adulthood

• EPAS1 variants = associated with adaptation to high altitude

how is normal cell growth and division controlled?

cell population homeostasis is maintained by a balance between:

1. Positive growth regulators = promote cell division

2. Negative growth regulators = inhibits cell division

this prevents excessive cell proliferation

how can mutations in cell-growth regulatory genes cause cancer?

mutations can disrupt proteins controlling:

• cell growth and division

• DNA repair

• apoptosis

allows abnormal cells to survive and divide uncontrollably

how can accumulated mutations lead to cancer?

1. DNA damage occurs and some mutations remain unpaired

2. mutations accumulate over time

3. growth-control mechanisms become disrupted

4. cells divide uncontrollably, potentially forming malignant tumours

what is a tumour suppressor gene?

they encode proteins that limit cell divison, help repair DNA or promote apoptosis

what is a proto-oncogene?

they encode proteins that promote normal, controlled cell growth and division

what is an oncogene?

• a gene that promotes excessive cell growth

• arises when a proto-oncogene becomes overactive due to a mutation or another genetic change, potentially causing uncontrollable cell division

how can mutations in DNA-repair genes contribute to cancer?

• they reduce the cell’s ability to repair damaged DNA, allowng mutations to accumulate

• this causes genomic instability, increasing cancer risk

what is p53 and its 3 main functions?

a tumour suppressor protein, known as the guardian of the genome

responds to DNA damage by:

1. Cell cycle arrest = pauses cell division

2. DNA repair = activates repair mechanisms

3. Apoptosis = triggers cell death if damage is severe

how does p53 respond to DNA damage?

1. normally = p53 is continuously produced and rapidly degraded (quickly broken down and removed by the cell)

2. DNA damage causes p53 phosphorylation and stabilisation

3. p53 accumulates and activates transription of target genes

4. this causes cell cycle arrest at the G1/S checkpoint, allowing DNA repair or triggers apoptosis

how can mutations in TP53 contribute to cancer?

1. a mutation in the TP53 gene can produce a defective p53 protein

2. mutant p53 may fail to activate genes responsible for cell cycle arrest, DNA repair and apoptosis

3. damaged cells continue dividing, allowing mutations to accumulate and increasing cancer risk

what is a SNP (single-nucleotide polymorphism)?

• variation at a single nucleotide position, commonly found in at least 1% of the population

• usually harmless

how do SNPs contribute to genetic variation and drug responses?

• different individuals may have different bases at the same DNA position (at one point someone could have AA, another could have AG and another could have GG)

• these variations contribute to genetic diversity

• some SNP’s affect drug pharmacokinetics (what body does to a drug) or pharmacodynamics (what drug does to the body)

what is pharmacogenomics?

• studies how genetic variations affect drug responses

• helps select the right drug and dose for patient, improving effectiveness and reducing adverse effects

how can genetic and molecular findings improve cancer care?

• prevention = identify inherited cancer risks and inform screening

• diagnosis = detect genetic changes associated with cancer

• treatment = identify molecular targets and select more appropriate therapies

how can genetic testing support precision therapy?

• genetic testing identifies variations that may affect disease or drug response

• treatment can be tailored to a patients genetic characteristics

• this may improve treatment effectiveness and reduce side effects

(eg, precision therapy in epilepsy, where genetic findings may help guide treatment selection)