Cancer genetics Flashcards
What are Mendelian diseases?
= monogenic
Disease caused by mutation in a single gene, with little or no impact from the environment
What are Oligogenic diseases?
= polygenic
Disease caused by combined effects of a few genes (oligogenic) or many different genes (polygenic)
Each gene contributes only a small proportion to total disease risk
What are multifactorial diseases?
= polygenic + environmental factors
disease or traits resulting from multiple risk genes and their interplay with the environmental stimuli
What are the different types of mendelian inheritance patterns?
(usually in monogenic disorders)
autosomal recessive autosomal dominant X-linked recessive X-linked dominant (rare) Y-linked (v. rare)
What are examples of autosomal recessive disorders?
- cystic fibrosis
- sickle cell anaemia
- spinal muscular atrophy
- phenylketonuria
- Tay Sachs disease
- Meckel-Gruber syndrome
What are examples of autosomal dominant disorders?
- Achondroplasia
- Huntington’s
- Marfan syndrome
- polycystic kidney disease
- polydactyly
- familial hypercholesterolaemia
How do X-linked recessive disorders present for inheritance?
- only males affected
- Females are carriers (as they inherit functional allele from X-chr from mother)
- there is no male to male transmission
What are examples of X-linked recessive disorders?
- red green colour blindness
- Duchenne muscular dystrophy
- Haemophiia A and B
- X-linked ichthyosis
What are examples of X-linked dominant disorders?
- cranio-fronto-nasal dysplasia
- hypophosphaaemic rickets
Where is mitochondrial DNA inherited from?
mother (in the egg)
What is penetrance?
the percentage of individuals who exhibit a particular phenotype for that genotype
[in a given generation/population]
What is phenotype expression/expressivity?
for a given genotype, what is the degree to which the phenotype is expressed?
e.g. how severe in the phenotype between different individuals with the same genotype
What are the different types of penetrance?
- COMPLETE
everybody in that family with the mutation will show clinical signs - INCOMPLETE (reduced)
- LOW
<20% of family members with the mutation show clinical signs
What is mosaicism?
when not all the cells in the body harbours the genetic defect
caused by a post-zygotic mutational event
What are the 2 cellular hallmarks of cancer?
- apoptosis malfunction
- uncontrolled cell growth
facilitated by accumulation of DNA mutations in cells
Which genes are responsible for controlling cell growth (and often mutated in cancer)?
- oncogenes
- tumour suppressor genes
- DNA repair genes
- Apoptosis genes
What kind of cancer arises from post zygotic mutations?
usually sporadic (rather than familial) similar to de novo somatic mutations
What is the two-hit theory of cancer causation?
inheritance of a gremlin mutation becomes a risk factor for cancer
It then reduces the number of further post-zygotic mutations required to cause cancer
What is the nature of cancer caused by inherited/family history?
usually
- early age at onset <50
- more than one relative with the same type of cancer
- clustering of certain cancer types
- family member with multiple cancers
- bilateral tumours
- genetic testing usually beneficial
Why does familial cancer have an earlier onset?
inherited genetic risk increases overall cancer risk and lowers threshold for additional mutations in the genome
What proportion of all cancer are sporadic? What mutations cause this?
90% of all cancers
post-zygotic mutations
What proportion of all cancer are hereditary? What mutations cause this?
10% of all cancer
germline mutations
+post-zygotic combos
What factors indicate an increased likelihood of having familial cancer?
- cancer in 2 or moe close relatives
- early age at Dx
- multiple and different types of tumours in one person
- male breast cancer
- ethnicity with known increased risk
Which genes are implicated in the hereditary breast-ovarian cancer syndrome?
BRCA1
BRCA2
Which gene is implicated in retinoblastoma?
RB1
Which gene is implicated in Cowden’s syndrome?
PTEN
Which gene is implicated in Lynch syndrome?
MSH2
MLH1
Of the BRCA genes, which confers a higher risk for ovarian cancer?
BRCA1 > BRCA2
What is the BRCA1-related familial breast/ovarian cancer syndrome an example of?
autosomal dominant inheritance
with high penetrance
lifetime cancer risk increased by 30-70%
Are family cancers always completely penetrant?
nope
Can show reduced penetrance
e.g with BRCA1 mutations
unaffected mum with risk genotype may have affected son
How may expressivity affect phenotypes for cancer mutations?
may affect:
- age of onset
- type of cancer
may vary person-person even within same family
