Carcinogenesis Flashcards
What are the categories of human carcinogens?
- Chemicals e.g. PAHs, nitrosamines
- Infectious agents e.g. human papilloma virus, Helicobacter pylori
- Radiation e.g. UV light, radon
- Minerals e.g. asbestos, heavy metals
- Physiological e.g. oestrogen, androgens
- Chronic inflammation – free radicals and growth factors
What is a carcinogen?
Any agent that significantly increases the risk of developing cancer. May be an initiator, promoter or both?
What is an initiator?
Genotoxic i.e. can chemically modify or damage DNA
What is a promoter?
Non-genotoxic e.g. induce proliferation and DNA replication
What is a complete carcinogen?
Both a promoter and an initiator.
How does the initiation of DNA damage occur?
Chemical modification of the nucleotides involved in base-pairing can occur through environmental insult or through the action of endogenous reactive molecules such as free radicals produced by normal physiological processes
E.g. Addition of a methyl group to guanine occupies one of the three hydrogen bonds G usually makes with C. G now mis-pairs with T (C->T substitution). After two rounds of replication the mutation is fixed (promotion).
How might promoters contribute to carcinogenesis?
Can stimulate two rounds of replication needed for mutation fixation.
Can stimulate clonal expansion of initiated cells which allows the accumulation of further mutations.
What common genetic abnormalities are seen in cancer?
Chromosomal translocations Deletions Frameshifts Gene amplification Chromosomal inversion Aneuploidy
How might CpG methylation be relevant to cancer progression?
CpG methylation within promoters leads to gene inactivation. Gene promoters can become abberantly methylated in tumours - tumour suppressor genes may be inactivated.
What is an oncogene?
Gene in which a mutation leads to a gain of function (base pair substitutions, amplifications, translocations, inversions)
What is a tumour suppressor gene?
Gene in which a mutation leads to a loss of function.
(Base pair substitutions, frameshifts, deletions, insertions, chromosomal rearrangements, chromosome loss, promoter methylation)
What is the relevance of metabolic activation in carcinogens?
The majority of carcinogens that we ingest require metabolic activation by enzymes that normally function in the detoxification and excretion of toxic chemicals. This introduces a genetic influence on the extent to which we are sensitive to genotoxic attack by different agents. For example, people who activate a particular chemical more efficiently are more likely to get cancer, while those that excrete the activated chemical less efficiently are also more likely to get cancer.
Which disease is caused by inherited defects in the NER repair pathway
Xeroderma pigmentosum (XP), a group of rare autosomal-recessive inherited disorders characterized by extreme skin sensitivity to ultraviolet (UV) light, abnormal skin pigmentation, and high frequency of skin cancers, especially on sun-exposed skin. Dermatologic changes are the most conspicuous findings and are mandatory for the diagnosis
Which disease is caused by inherited defects in the ATM gene involved in recombinational repair pathway.
Ataxia telangiectasia (A-T), an autosomal recessive disorder. These patients have an elevated incidence of cancers, approximately 100-fold in comparison to the general population. In children, more than 85% of neoplasm cases are acute lymphocytic leukaemia or lymphoma. In adults with A-T, solid tumours are more frequent. One basic defect associated with the malady is the abnormal sensitivity of A-T cells to x-rays and certain radiomimetic chemicals, which lead to chromosome and chromatid breaks The ATM gene product interacts with the products of tumour suppressor genes such as TP53 and BRCA1, both of which play an important role in the predisposition to breast cancer. Studies of A-T families have consistently reported an increased risk of breast cancer in women with one mutated ATM gene.
Why may people experiencing the same levels of exposure to a carcinogen exhibit different effects?
Genetic polymorphisms in genes encoding metabolic activation, detoxifying, or DNA repair enzymes may confer greater or lesser susceptibility to the effects of carcinogenic exposure.
