Cancer Genetics Dr Dawn Smallwood dawn smallwooddmu ac

Cancer Genetics Dr Dawn Smallwood dawn. smallwood@dmu. ac. uk

Learning objectives • Describe: • Proto-oncogenes • Tumour suppressor genes • Mismatch repair genes • Genetic predisposition • Knudson two hit hypothesis • Apply Knudson two hit hypothesis to retinoblastoma and other tumour suppressor genes

Genetic mutations cause cancer Processes that cause DNA mutation: • Chemicals • Radiation • Viruses

Genetic mutations cause cancer Types of genes that cause cancer when mutated: • Proto-oncogenes – mutation allows gain of the ability to cause proliferation etc. • Tumour suppressor genes – normally stop proliferation etc. but mutation means they lose that ability • Mismatch repair genes – mutation means newly replicated DNA does not get repaired when mistakes happen

Genetic mutations cause cancer • Ageing is strongest risk factor for cancer • Over time we accumulate mutations • Decline in metabolic homeostasis and gene regulation as we age For interest: Wu et al 2014 https: //www. ncbi. nlm. nih. gov/pmc/articles/PMC 3970212/

Proto-oncogenes are activated to cause cancer

Proto-oncogenes and oncogenes • Proto-oncogenes: normal genes that encode proteins involved in: • Cell division/growth/proliferation • Cell differentiation • Apoptosis (cell death) • These activities are essential for cell growth and development and to maintain healthy tissues and organs

Oncogenes were discovered in acute transforming retroviruses Peyton Rous • Showed (in chickens) cancer could be caused by infection • Used cell free sarcoma extract to cause infection • We now know the acute transforming retrovirus oncogene (v-src for viral sarcoma) caused the cancer infection https: //www. ncbi. nlm. nih. gov/pmc/articles/PMC 3256973/

https: //www. ncbi. nlm. nih. gov/pmc/articles/P MC 2185676/pdf/je 1504729. pdf

Proto-oncogenes and oncogenes • Oncogene: a proto-oncogene that has been mutated into a cancer causing gene • Mutations that turn proto-oncogenes into oncogenes are activating mutations called ‘gain of function’ (e. g. the mutation allows more protein to be produced) • Oncogene mutations are dominant: mutation of one copy is enough to stimulate proliferation Gene at this locus encodes a protein involved in cell proliferation (proto-oncogene) Single mutation creates oncogene Gene at this locus is mutated (oncogene) Mutation is gain of function (too much of the encoded protein is produced) so proliferation is stimulated Figure 23 -24 Alberts

Proto-oncogenes and oncogenes Proto-oncogene + single activation/gain of function mutation = oncogene Proto-oncogene activation is analogous to having the accelerator pedal stuck down (accelerating cell division/proliferation)

Tumour suppressor genes are deactivated to cause cancer

Tumour suppressors control the cell division cycle Cell division occurs: • During development • To replace dead or damaged cells Tumour suppressors act at checkpoints and stop (arrest) the cell cycle if DNA damage is detected. If DNA damage is severe and cannot be repaired cells are forced into apoptosis/programmed cell death G 2/M checkpoint for damaged or unduplicated DNA Mitotic spindle checkpoint for correct alignment of chromosomes S phase checkpoint for DNA damage G 1/S checkpoint for DNA damage Figure 12. 5 Read

Tumour suppressor genes • Tumour suppressor gene mutations are deactivating mutations called ‘loss of function’ (e. g. the mutation stops the encoded protein being produced) • Tumour suppressor gene mutations are recessive: mutation of both copies is needed to prevent production of the tumour suppressor protein Single mutation inactivates gene on one allele Second mutation inactivates gene on second allele Enough tumour suppressor protein is produced from one allele Figure 23 -24 Alberts

Tumour suppressor genes Tumour suppressor gene + function of both alleles lost = protein that supresses proliferation is not produced Tumour suppressor gene inactivation is analogous to having no brakes (unable to stop cell division)

Mutated mismatch repair genes cause cancer

Mismatch repair genes • DNA replication is not perfect • When cells divide, DNA must be replicated and billions of nucleotides copied • The mismatch repair (MMR) pathway repairs DNA errors that occur during normal DNA replication • Without MMR, cells would accumulate mutations • Mutation of MMR genes occurs in Lynch Syndrome which is hereditary and involves increased risk of bowel and other types of cancer

Genetic predisposition • A genetic predisposition is an increased likelihood of developing a particular disease based on genetic makeup • Results from specific genetic variations (often inherited) • Genetic changes contribute to the development of disease but do not directly cause it • Some people with a predisposing genetic variation will never get the disease while others will • In people with a genetic predisposition, risk also depends on lifestyle and environmental factors • Genetics cannot be altered, but lifestyle modifications (regular screening, healthy weight, physical exercise etc. ) may reduce risk https: //ghr. nlm. nih. gov/primer/mutationsanddisorders/predisposition

Genetics of retinoblastoma (Rb) • Inheritable form of cancer • Non inheritable form cancer • Most cases diagnosed before 5 years

Retinoblastoma – rare eye cancer that develops in the retina https: //www. allaboutvision. com/resources/anatomy. htm

Retinoblastoma protein (p. RB) • Tumour suppressor • p. RB binds E 2 F to inihibit E 2 F activation of S phase genes • Loss of function of the p. Rb means retinal cells divide uncontrollably Figure 23 -22 Alberts

Detection of retinoblastoma The red reflex refers to the reddish-orange reflection of light from the back of the eye, or fundus, observed when using an ophthalmoscope https: //meded. ucsd. edu/clinicalmed/eyes. htm https: //en. wikipedia. org/wiki/Leukocoria

Detection of retinoblastoma https: //www. bartshealth. nhs. uk/retinoblastoma

Untreated retinoblastoma Honavar SG, Manjandavida FP, Reddy VAP. Orbital retinoblastoma: An update. Indian J Ophthalmol. 2017; 65(6): 435 -442. https: //www. ncbi. nlm. nih. gov/pubmed/28643706

Treated retinoblastoma Retinoblastoma ophthalmoscope images (A) before, (B) after 6 cycles chemotherapy http: //www. djo. org. in/printerfriendly. aspx? id=459

Knudson two hit hypothesis (1971) For interest in statistics: https: //www. ncbi. nlm. nih. gov/pmc/articles/PMC 389051/pdf/pnas 00079 -0129. pdf https: //en. wikipedia. org/wiki/Alfred_G. _Knudson

Knudson two hit hypothesis (1971) • Knudson studied retinoblastoma (Rb) • Noted that: • Rb can be sporadic or run in families • Children with bilateral Rb, first presented earlier (average 1 year) and had Rb in the family • Children with unilateral Rb, presented later (average 2. 5 years) and were sporadic • He hypothesised two mutations (hits) are needed in the same cell line for all p. RB to be lost and for cancer to occur • In the familial form, the first hit is inherited, the second happens by chance • In the sporadic form, both hits happen by chance

Knudson two hit hypothesis (1971)

Chromosome 13 Retinoblastoma gene RB 1 • In cancer, both copies of the gene are lost • Loss of function of the Rb protein results from mutation or deletion of RB 1 gene on both alleles RB 1 https: //ghr. nlm. nih. gov/gene/RB 1#resources

Genetic mechanisms underlying retinoblastoma By chance, one RB 1 alleles is mutated One mutated RB 1 allele in every cell of the body, by chance the other allele is mutated By chance, both RB 1 alleles are mutated in the same cell line Figure 23 -26 Alberts

Genetic mechanisms underlying retinoblastoma

Learning objectives • Describe: • Proto-oncogenes • Tumour suppressor genes • Mismatch repair genes • Genetic predisposition • Knudson two hit hypothesis • Apply Knudson two hit hypothesis to retinoblastoma and other tumour suppressor genes

Resources Chapter 23 Chapter 12