Cancer Genes (Tumbarello) Flashcards
What is cancer?
Cancer is a condition where abnormal cells grow and
reproduce uncontrollably.
The cancerous cells can invade and destroy surrounding healthy tissue, including organs.W
What is some evidence of cancer being a genetic disease?
Most carcinogens are also mutagens
- Not all mutagens are human carcinogens
No mini-epidemics – not contagious
- But see viral oncogenes (e.g. HPV)
Incidence increases with age as does damage to DNA
Some cancers segregate in families
- >50 forms of cancer have some degree of inherited
predisposition
Chromosomal instability a common feature and specific
chromosomal changes are found in some cancers
Defects in DNA repair increase the probability of cancer
What types of mutations are there?
Substitution (point mutations)
- Coding/non-coding
- Insertions
- Deletions
- Duplication
- Inversions
- Translocations (e.g. Philadelphia chr, BCR-ABL gene
fusion in CML/AML
Is cancer inherited?
All cancer arises from mutations in genes BUT not all cancer is inherited
Most is not inherited, only 5-10% of cancers are due to inherited mutations
Mutations can occur in the germline or somatic tissues
What is the difference between germline and somatic mutations
Germline mutations:
- Mutation in every cell of the body, including the reproductive cells
- Passed directly from a parent to a child
- Less common cause of cancer
- Cancer caused by germline mutations is called inherited cancer
Somatic mutations;
- Also known as ‘acquired mutations’
- Occur from damage to genes during a person’s lifetime
- They are not passed from parent to child
- The most common cause of cancer
- Cancer caused by somatic mutations is called sporadic cancer
What are cancer genes?
Genes have a normal biological function within normal cells
Genes can be known as ‘cancer genes’ when these genes are mutated and behave differently - causing or contributing to cancer development
Two main groups of cancer gene:
- Oncogenes
- Tumor suppressor genes
What is an oncogene?
The normal version of these are sometimes called protooncogenes when carrying out the normal cellular functions
Genes which normally function to PROMOTE cell growth/division
Mutations cause gain of function (switched on) and tend to be dominantly acting (only 1 copy required)
Mutations in these genes are not usually inherited (some exceptions)
Activated oncogene in the germ line normally affects
embryonic development so severely that it causes embryonic lethality
Family cancers linked to oncogenes (few), e.g.
- Multiple endocrine neoplasia type 2 (MEN2) – RET
- Isolated hereditary papillary renal cell cancer (HPRCC) – MET
Can be activated by;
- Amplification (e.g. Myc oncogene)
- Translocation (e.g. gene fusion BCR-ABL)
- Point mutations (e.g. Ras family genes– Kras, Nras, Hras)
What are tumour suppressor genes?
These genes normally function to PREVENT cell growth/division
Mutations in these genes inherited in family cancer syndromes
Mutations cause loss of function (switched off)
‘Recessive’ at cellular level – i.e. mutations required in both copies of the gene
Many inherited cancers are linked to tumour suppressor genes, e.g:
- Retinoblastoma - RB1
- Familial adenomatous polyposis (FAP) – APC
- Li-Fraumeni syndrome - TP53
What is required to make a mutation in an oncogene?
Point mutation – a single base pair change enough to give
transforming function
Position of mutations in oncogenes
Oncogenes and tumour suppressor genes differ in the distribution of mutations within them
Oncogenes tend to have mutations in few codons affecting particular domains
They also have a bias towards missense mutations
Position of mutations in tumour suppressor genes
Tumour suppressor genes tend to have mutations more
widely spread across the gene
They have more evenly missense mutations and mutation inducing premature termination codons
What are the further classifications of tumour suppressor genes?
Gatekeeper
- Act directly
- Restrain cell proliferation
- e.g. Classical tumour suppressors (RB1) and some
oncogenes (RET)
Caretaker
- Act indirectly
- Maintain integrity of genome, disruption leads to genomic instability
- DNA repair genes; A subgroup of tumour suppressor genes (e.g.
BRCA1,BRCA2)
Landscaper
- Act indirectly
- Control the environment in which cells grow, creating a
microenvironment aiding cancer cell growth (e.g. extracellular matrix genes)
DNA Repair gene mutations
Often thought of as a subclass of tumour suppressor genes: Targeted by loss of function mutations, similar to classical tumour suppressor genes
However;
- Classical tumour suppressor genes are directly involved
in growth inhibition or differentiation (gatekeeper function)
- DNA repair genes are indirectly involved in growth
inhibition or differentiation (caretaker function)
Inactivation of DNA repair genes by mutations;
- results in DNA damage going un-repaired
- leads to accumulation of mutations in the other cellular
genes
- Increasing the likelihood of damaging mutations in other
critical genes (i.e. other tumour suppressors or proto-oncogenes)
What is retinoblastoma?
- Most common eye tumour in children
- Tumour of retinal stem cell
- Affects 1 in 20,000 children
- Males and Females equally affected
- Signs and symptoms of retinoblastoma include “white pupil” and eye pain or redness
- Treatments include surgery, chemotherapy, radiation therapy
- Identifying at-risk infants substantially reduces morbidity and mortality
- Diagnosed in the first few years of life
- Two forms; inherited and sporadic (non-inherited)
Differences between inherited and sporadic retinoblastoma?
- 60% of retinoblastoma is sporadic
- 40% of retinoblastoma is inherited
- Sporadic shows unilateral tumour
- Inherited is bilateral
- Sporadic shows no family history
- Inherited shows family history
- Sporadic diagnose before 2 years
- Inherited diagnosed before 1 year
- Sporadic shows no risk of second tumour
- Inherited shows elevated risk of second tumour
Bilateral have a much earlier age of diagnosis by 20 months ~80% have already been diagnosed
By 20 months only ~20% of those who go on to get the unilateral form have been diagnosed
Bilateral have a much higher incidence of other cancers in their lifetime indicating that they have some predisposition to cancer in all their cells (germline)
Retinoblastoma genetics
Autosomal dominant transmission
Gene localised to chromosome 13 in 1978
RB1 gene cloned in 1986
Gene encodes Rb protein which is a negative regulator of the cell cycle
Large gene spanning 27 exons, with more than 100 known
mutations – spread across the gene
Why do inherited forms of retinoblastoma occur faster?
Knudson mathematically showed that with a certain mutation rate you could explain this discrepancy by assuming that the sporadic cases needed two somatic mutations and the inherited cases only one
This assumes;
- Recessively acting alleles
- The inherited cases had already inherited 1 mutation in the germline
What is loss of heterozygosity?
Sporadic retinoblastoma - following single mutation, cell is left heterozygous (Rb +/-) and would exhibit wild-type phenotype, therefore loss of 2nd allele is required for cancer
These types of mutational events in a single cell are highly unlikely
Second allele is not hit by a mutation – instead a recombination event occurred leading to loss of wild-type allele (allelic deletion or LOH)
What is haploinsufficiency?
Haploinsufficiency is where having only one functional copy of a gene (due to the loss or inactivation of the other copy) is not enough to produce the normal phenotype
Why does p53+/- still produce cancer?
‘Dominant-negative’ effect
p53 subunits form a functional tetramer
Mutated subunit still forms tetramers but 15/16 lack normal function
The mutated alleles ‘cancel out’ the effects of the normal alleles
What is the multi-step model?
Most cancers involve multiple acquired mutations leading towards cancer
Known as ‘Multi-Step Tumourigenesis’
Formation of tumours is complex and usually progresses over decades
Epidemiological studies show age is a large factor in the incidence of cancer
Cells acquire increasing cancer-like qualities
Pathology provides evidence of a multistep process
What is colorectal cancer mechanism?
The development of sporadic colorectal cancer provides an excellent example of multi-step tumourigenesis
Cells of the intestinal wall have a high turnover, each day
~15-20% of the epithelial cells of the colon die and are
replaced
Changes occur in mucosal surface of the intestinal wall during a persons lifetime
~10% of all adenomas become cancerous can take ≥10 years to develop
Estimated that mutations in ~5 critical genes are required
Involves both tumour suppressor genes and oncogenes
What are the two types of somatic mutations in cancer?
Driver mutations
Passenger mutations
Drivers give the clone a selective advantage and contribute to oncogenesis
Passengers have no effect on oncogenesis
Cancer cells have few drivers (<20) but many passengers
Do tumours have heterogeneity/clonality?
Cancer is clonal:
- A set of cells that all descend from a common ancestor cell characterised by one or more somatic driver mutations
Within tumours, mutations may be fully clonal (founder mutation present in all cells) or subclonal (secondary mutations present in a proportion of cells)
Evolution of cancer
Cancer clones accumulate mutations some of which advantage tumour development
Cells undergo selective pressures from their microenvironment, or external pressures such as cancer treatment
Likely not simply a linear process, but shows a branched architecture
‘Subclones’ acquiring new genetic and epigenetic changes
What is the advantage of tracking clonal evolution?
Understanding which mutations occurred when may help to understand why some cancers are resistant to specific treatments and how to prevent this
Chemotherapy acts as a selective bottleneck
The ‘fittest’ subclones survive and dominate the tumour
Relapsed malignancies are usually more aggressive and resistant to treatment and this could be partly due to chemotherapy
Treatment should therefore aim to treat multiple mutations at the evolutionary trunk rather than branches
Therefore tracking clonal evolution to the trunk of the tumour is important
