4 Cancer in Families and Individuals Flashcards
Q: What do mutations allow the development of? (6)
A: hallmarks of cancer
- dysregulated growth
- evasion of apoptosis
- limitless replication
- sustained angiogenesis
- invasion/metastasis
Q: What is angiogenesis?
A: new blood vessels form from pre-existing vessels
Q: What causes dysregulated growth? (2)
A: autologous progrowth signalling
insensitive to antigrowth signalling
Q: Why is cancer called the master of evolution? (3)
A: -cumulative changes
- cells in tumour are not clones (one tumour is polyclonal)
- confer a selective advantage to cell but fatal to organism
Q: What are driver mutations? arrive from? Function? In relation to tumour?
A: typically somatic mutations, i.e. they arise de novo in cancer cells -> drive the development of cancer are defined as driver mutations. Driver mutations allow cancer to grow and invade the human body
since its in the first cancer cell and every cell in tumour derives from it-> is central mutation of tumour
Q: Why are driver mutations key to the genetic research of cancer? (4)
A: -understand how disease develops
- diagnose more accurately
- devise targeted therapy
- monitor response therapy
Q: What are proto oncogenes? Role? 3 examples of proteins?
A: proto-oncogene is a normal gene that could become an oncogene due to mutations or increased expression.
Proto-oncogenes code for proteins that help to regulate cell growth and differentiation
- growth factors
- transcription factors
- tyrosine kinases
Q: What are tumour suppressor genes? How can they lead to cancer?
A: normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (a process known as apoptosis or programmed cell death). When tumor suppressor genes don’t work properly, cells can grow out of control, which can lead to cancer
Q: Explain knudson’s two-hit hypothesis.
A: -most tumour suppressor genes require damage to both alleles
- hit 1 reduces transcript/protein level but is insufficient to cause phenotypic effect
- requires inactivation of second allele (hit 2) causing total loss of transcription -> malignant potential
Q: What is a retinoblastoma protein (pRB)? Function? Damage?
A: tumor suppressor protein
One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide
- normally is a red light protein that binds to a green light protein: E2F
- stops progression of cell cycle
- until releases E2F-> goes into S phase and continues
means can’t halt cell division and it will go ahead unplanned
Q: What is familial RB? Sporadic?
A: child is born with one RB mutation (hit 1) -> acquires second somatic mutation (hit 2)
acquire one somatic mutation (hit 1) -> get hit 2= second somatic mutation in same cell
Q: What is loss of heterogeneity?
A: -normal sequencing= have 2 different bases at one point (eg AG)
- heterozygous SNP-> one chromosome has A and one has G
- can get lots of SNPs in genome -> causes genetic variety (can lose whole sections as part of a mutation-> one hit)
one allele is lost, leading to part of the genome appearing homozygous in the tumour where heterozygous in matching normal DNA
Q: What are oncogenes? Role in cancer?
A: no gene is inherently one
-activated oncogenes ‘override’ apoptosis -> damaged cells survive and proliferate
Q: Inherited cancer syndromes are?
A: rare but important
risk of cancer from them = high but not 100%
Q: What causes an inherited predisposition to breast and cervical cancer? (3)
A: -BRCA1 and 2 (2-4% of breast cancers are caused by germline mutations in them)
- age above 90 (60% risk)
- BRCA2 - predispose breast cancer in men
Q: What are BRCA mutations in? Role? Why are they susceptible to mutation?
A: -tumour suppressor genes
- gene repair, homologous recombination (takes out wrong bits and inserts correct
- very large (lots of room for it)
Q: What causes an inherited predisposition to colorectal cancer? (2)
A: -FAP familial adenomatous polyposis (<1% of all cases but virtually 100% lifetime risk of cancer)
-HNPCC lynch syndrome (3% of all cases and life… 80% and not just colorectal)
Q: What are polyps? What can happen to them?
A: abnormal growth of tissue projecting from a mucous membrane
can become cancerous
Q: Which genes are affected in HNPCC?
A: DNA mismatch repair genes (when point mutation is present= cut it out and replace)
Q: What does patient management for inherited cancer syndromes involve? (5)
A: -first need positive family history-> genetic screening and counselling
-if positive-> surveillance, chemoprevention, preventative measures in other family members possibly,
Q: What percentage of breast cancer cases have no family history? Explore?
A: around 80, could be polygenic
can explore this possibility with GWAS
Q: Why are some rare variants called mutations?
A: variance occurs in <1% of pop
Q: How can GWAS be used to investigate the polygenic possibility cancer? (hows it conducted?) (3) Effect?
A: -SNP fishing for SNPs near area of interest
-large cohort studied
-identifies possible candidate genes/genomic regions
often very small individual effect
Q: How can transciptome analysis be used to investigate the polygenic possibility cancer? (hows it conducted?) Useful when? Can’t?
A: -compares expression prfile of malignant vs normal tissues
- large patient cohort studied
- identifies possible candidate genes
when finding dysregulated pathways
can’t determine whether upregulation of that gene causes it to become malignant or vice versa
