Lecture 3. Inherited cancer syndromes
There are nine hallmarks of cancer. 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. Cancer sustains proliferative signalling by switching on divide
and grow signals and by evading growth suppressors. To do so, cancer requires nutrients and
oxygen, inducing angiogenesis and resisting apoptosis.
Cancer is an evolutionary disease with structural rearrangements like aneuploidy and
acquisition of mutations. Somatic mutations have different prevalence in different cancer
types. These somatic mutations cause DNA damage to the cell and killing the cell, it may affect
a non-coding or inactive DNA region or it may damage a gene controlling cell growth which
has potential consequences in clonal expansion. Other somatic mutations include inactivating
a tumour suppressor gene (TSG) allowing faster cell division, it could activate an oncogene
driving faster cell division, or it could create a new fusion gene and confer a growth
advantage. Additionally, cancers typically have pathogenic variants of TP53, a gain of function
in RAS or MYC proto-oncogenes or have activated telomerase allowing cellular division.
TP53 is a TSG encoding the p53 protein. TSG normally control the rate of cell growth. Here,
the protein p53 normally activates DNA repair processes in the nucleus, arresting cell division
in case of DNA damage, initiating apoptosis in severely damaged cells and controlling cellular
senescence. Pathogenic TP53 variants exist in over half of human cancers. Other commonly
mutated genes associated with cancer predisposition are oncogenes. Proto-oncogenes
control cell proliferation but once mutated they become oncogenes, like RAS, and are
constitutively activated, driving cellular division in absence of an activation signal normally
delivered by a growth factor.
In a cell, DNA damage can either be endogenous like from oxidative deamination and
replication errors, or it can be exogenous such as due to UV, x-rays, geological particles,
carcinogens and viruses. These can cause mismatch errors, base hydrolysis, oxidation or
alkylation, single strand break, double strand break or crosslinks. These broad themes of DNA
There are nine hallmarks of cancer. 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. Cancer sustains proliferative signalling by switching on divide
and grow signals and by evading growth suppressors. To do so, cancer requires nutrients and
oxygen, inducing angiogenesis and resisting apoptosis.
Cancer is an evolutionary disease with structural rearrangements like aneuploidy and
acquisition of mutations. Somatic mutations have different prevalence in different cancer
types. These somatic mutations cause DNA damage to the cell and killing the cell, it may affect
a non-coding or inactive DNA region or it may damage a gene controlling cell growth which
has potential consequences in clonal expansion. Other somatic mutations include inactivating
a tumour suppressor gene (TSG) allowing faster cell division, it could activate an oncogene
driving faster cell division, or it could create a new fusion gene and confer a growth
advantage. Additionally, cancers typically have pathogenic variants of TP53, a gain of function
in RAS or MYC proto-oncogenes or have activated telomerase allowing cellular division.
TP53 is a TSG encoding the p53 protein. TSG normally control the rate of cell growth. Here,
the protein p53 normally activates DNA repair processes in the nucleus, arresting cell division
in case of DNA damage, initiating apoptosis in severely damaged cells and controlling cellular
senescence. Pathogenic TP53 variants exist in over half of human cancers. Other commonly
mutated genes associated with cancer predisposition are oncogenes. Proto-oncogenes
control cell proliferation but once mutated they become oncogenes, like RAS, and are
constitutively activated, driving cellular division in absence of an activation signal normally
delivered by a growth factor.
In a cell, DNA damage can either be endogenous like from oxidative deamination and
replication errors, or it can be exogenous such as due to UV, x-rays, geological particles,
carcinogens and viruses. These can cause mismatch errors, base hydrolysis, oxidation or
alkylation, single strand break, double strand break or crosslinks. These broad themes of DNA
