Essay questions 6BBYG307
Lecture 1. Mechanisms of carcinogenesis
Lecture 2. Models for studying cancer
Lecture 3. Inherited cancer syndromes
Lecture 4. Genetics of leukaemia
Lecture 5. Uncovering the cancer genome
Lecture 6. Genetic epidemiology of cancer
Lecture 7. New technological platforms in cancer genetics
Lecture 8. The genetics of breast cancer
Lecture 9. Targeted therapies in cancer
Lecture 10. Epigenetics and cancer
Lecture 11. The genetics of chronic lymphocytic leukaemia (CLL)
Lecture 12. Viral oncogenes
Lecture 13. Targeted therapies in solid tumours
Lecture 14. Molecular pathogenesis of melanoma
Lecture 15. Novel agents to treat lymphoma
Lecture 16. Genetics of myeloproliferative disorders
Lecture 17. Cutaneous T cell lymphoma genetics
Lecture 18. Clinical genomics of solid cancer
,Lecture 1. Mechanisms of carcinogenesis
The lifetime risk for any individual to develop cancer is 50%. 38% of these cases are
preventable, including melanoma, lung cancer and breast cancer. 15% of cancer cases are
related to smoking and 3%-10% are related to obesity. Predisposing factors to cancer include
toxins, inflammation and immunity, genetic mutations, hormones and ethnicity. Risk factors
include occupation, family and medical history, age, gender, ethnicity, genes, immunity and
lifestyle.
There are nine hallmarks of cancers. These are sustained proliferation, resistance to cell
death, replicative immortality, dysregulated differentiation, invasion and metastasis,
angiogenesis, inflammation that promotes tumour growth, genomic instability and mutation,
and dysregulated metabolic states. Whiteman and Wilson (2016) investigated cancers
attributable to potentially modifying factors like tobacco smoke, alcohol and obesity. The
population attributable fraction was calculated to quantify how many cancers might be
avoided if exposure to causal factors di not occur. They found that the number of upper-
digestive tract cancers attributable to tobacco smoking was consistently high, with the PAF
for cancers attributable to tobacco and alcohol being higher in men.
Toxins are absorbed in the mucosa and tend to damage DNA. If this damage is extensive, cells
will be unable to repair it, causing mutations. These mutations may occur in tumour
suppressor genes, causing uncontrolled tumour growth. Mutations may also occur in proto-
oncogenes which transform into oncogenes, driving cellular growth. Alcohol is a toxin and its
direct inflammatory effect increases cancer risk. It also acts as a solvent to tobacco, promoting
the absorption of carcinogens. Factors like elevated oestrogen and adiposity can affect
alcohol absorption.
Asbestos and shift work are significantly associated with carcinogens. Asbestos has a 40-50
year latency and causes inflammatory reactions in the lung as well as the release of pro-
inflammatory cytokines like IL-1beta. Asbestos kills tissue and sets up a chronic inflammatory
environment in the lung. This will damage DNA, setting up a positive feedback of
inflammatory reaction. As mutations continue to accumulate over time, cancer develops.
,Higher than expected standardised incidence ratios in melanoma, prostate and other cancers
and statistical significance of early arrival with cancer risk was observed in 9/11 World Trade
Centre responders. Dust inhalation led to non-pulmonary cancers as it set up a chronic
inflammation. Cytokines produced and inflammatory cells circulated, affecting multiple
tissues.
Patients with primary immunodeficiency are at increased risk of cancers, especially
lymphoma. Patients with poorly controlled HIV infections are more prone to virally driven
cancers like EBV. Post-transplant lymphoproliferative disease occurs when
immunosuppressed patients develop lymphoma associated with an EBV infection. A study of
two groups of mice, 1 immunocompetent and 1 immunodeficient, were injected with a
carcinogen. A greater number of cancers arose in the immunodeficient mice. Thus, the lack
of appropriate immune response can cause an immune failure.
Inheritance of one mutated copy of RB1 was studied in 1971. This mutation was compatible
with life. However, if the other copy acquires a mutation and certain cells lose all RB1
function, this will cause an uncontrollable tumour growth. Similarly, in non-inherited cancers,
acquired mutation in, for instance, TP53, is compatible with life. A mutation in the second
copy is sufficient for certain cells to lose all TP53 function. Alternatively, loss of the piece of
chromosome carrying the WT alleles of TP53 also results in loss of TP3 function. This leads to
an accumulation of mutations without cellular apoptosis.
The inherited condition Fanconi Aneamia is an inherited condition characterised by a short
stature, limbs and other developmental disability. They develop bone marrow failure by 40 in
90% of cases. Many genes are mutated and all of these genes are involved in DNA repair
pathways. FANCA is the most commonly mutated gene (66%), BRCA2 is uncommonly mutated
though increasing the risk of breast to 80% and ovarian cancer to 30% in females. Not all FA
patients however will develop cancer, those that do develop myelodysplastic syndrome (10-
20%) or AML. 5% of FA patients develop a solid tumour, often in the head and neck. FA
patients are predisposed to cancer because their cells cannot repair DNA properly. Additional
somatic hits are required for actual cancer development.
, Older age is the main risk factor for cancer, such as DNA damage accumulates in cells over
time. Damage can result from biological processes or exposure to risk factors during the
individual’s lifetime. Sometime in breast cancer, young women are affected and are more
likely to develop triple negative aggressive cancer that is difficult to treat. BRCA1 pathogenic
variant often increases this risk. As well, in AML, older patients tend to have more adverse
genetics that are difficult to treat compared to younger patients.
Clonal haematopoiesis of intermediate potential (CHIP) links ageing to blood cancers.
Mutation in haematopoietic stem cells may confer a survival advantage to the cell, allowing
their growth and clonal expansion. The older the individual gets, the more likely they are to
acquire a mutation in their HSC that has a significant survival detectable advantage. However,
this association between AML, for instance, and CHIP is not uniform.
When a mutation in a normal cell occurs, the cell dies and the mutation does not expand. A
very deleterious mutation even in a stem cell leads to cell death. For the mutation to cause
cancer, it must occur in the right cell type such as a long-lived cells and has to not cause too
much damage, has to not get flagged to the immune system and has to give some survival
advantage to the cell. This will contribute to the clone getting fitter and expanding, increasing
the risk of getting cancer. These cells don’t necessarily become cancerous or grow
uncontrollable because they only have one allelic variant. Accumulation of several mutations
overtime may cause cancer development. In AML, normal blood cells acquire one mutation
causing CHIP, then another which causes MDS, and finally a last one such as TP53, causing
AML. Loss of TP53 function enables tolerance of significant DNA damage.
Hormones regulate normal cell proliferation and differentiation. Many tumours retain
sensitivity to hormonal regulation, such as in oestrogen positive breast cancer. This allows the
manipulation of treatments via hormonal therapy. Tamoxifen for instance binds the
oestrogen receptor, inhibiting oestrogen binding in the cytosol. This result in inhibition of cell
proliferation. In obesity, chronic low level inflammation and DNA damage, as well as excess
oestrogen from adipose tissues, and increased insulin and IGF1 may increase cancer risk.
