4. Inherited Predisposition to Cancer Flashcards
what are the 2 signs of retinoblastoma?
- Leukocoria –> white reflection in eye
- Strabismus –> tumour causes misalignment of eye
how does the risk of retinoblastoma change with age?
usually diagnosed <5 years old, then risk decreases a lot by adolescence
2 types of characteristics of retinoblastoma tumour?
- unilateral/bilateral –> 1 eye or both
- unifocal/multifocal –> 1 tumour or many
what is familial retinoblastoma?
autosomal dominant transmission of a highly penetrant genetic trait
what is autosomal dominant transmission?
only 1 parent needs to have the altered gene for it to be passed on –> i.e. 1 normal allele, 1 abnormal allele
why does the familial/sporadic ways of obtaining retinoblastoma correspond to the disease presentation for each? (2)
- familial disease occurs at younger age than sporadic bc higher chance of getting only 1 somatic mutation vs 2
- sporadic disease is usually unilateral bc more rare for many cells to getting 2 somatic mutations
what are the 4 assumptions of the two-hit theory?
- constant mutation rate
- both forms (familial/sporadic) caused by same gene
- gene transmitted by autosomal dominant
- gene encodes tumour suppressor
how do tumours rise due to Rb?
complete inactivation/loss of function of Rb = tumour
does a tumour cell ever have normal Rb?
no! only mutated Rb
what is positional cloning?
- identify location in chromosome where gene is
- make physical map by cloning pieces of genome
- make cDNA library to match genes in the region where you think the gene is
what happens when there is a loss of Rb?
loss of cell cycle regulation –> unprogrammed cell division
in familial retinoblastoma, where do we see the mutation?
mutation in normal/germline cells
in sporadic retinoblastoma, where do we see the mutation?
mutation only in tumour
could genetic testing reveal that a seemingly sporadic case be hereditary?
if parents don’t express the disease but we see mutation in the blood cells –> it is actually familial retinoblastoma
what does it mean for Rb mutation to not be completely penetrant?
family history doesn’t tell the whole story
- if you inherit mutation doesn’t mean you will develop the disease –> parents may not have the disease but can pass on the mutation
what 5 things did we learn from Rb1 discovery?
- cancer predisposition could be heritable
- cancer predisposing traits account for features of disease presentation
- cancer predisposing genes encode proteins that act as tumor suppressors
- cancer predisposing genes are involved in sporadic disease
- cancer predisposing genes act as medical biomarkers that predict retinoblastoma risk
what are BRCA1 and BRCA2?
major breast and ovarian cancer predisposing genes
how were BRCA1 and BRCA2 found?
genetic analyses of rare breast and breast-ovarian cancer families
how many moderate to high risk cancer predisposing genes have been identified having rare disease associated pathogenic variants since RB1?
> 100
what is a germline variant?
gene change in reproductive cell that incorporates into DNA of every cell –> HEREDITARY
what is a somatic mutation?
gene change after conception and not in germline, can occur in any cell except germ cells –> not hereditary!
what is a genetic variant? 5 types
alteration in most common DNA nucleotide sequence
- pathogenic
- likely pathogenic
- uncertain significance
- likely benign
- benign
how many cancer predisposing genes are associated with disorders?
> 50 cancer predisposing genes associated with disorders
what are 6 features of hereditary cancer?
- multiple primary tumours
- bilateral primary tumors in paired organs
- multi-focal tumors within single organ
- younger-than-usual age at cancer diagnosis
- family history of cancer
- tumors with rare histology
carriers are _______ for ___________ pathogenic variant of BRCA1
carriers are HETEROZYGOUS for LOSS OF FUNCTION pathogenic variant of BRCA1
phenotypes of breast cancer syndrome in family with pathogenic variant of BRCA1 (6)
- younger age of onset
- many cases within family
- bilateral cancer
- multigenerational
- autosomal dominance mode of transmission
- highly penetrant gene
are cancer predisposing genes more likely associated with genetic transmission of autosomal dominant trait or recessive trait? how does this cause cancer?
cancer predisposing genes more likely associated with autosomal dominant trait
all inactivation of WT allele
3 examples of cancer predisposing genes associated with autosomal dominant transmission?
- Rb
- BRCA1
- BRCA2
is autosomal recessive possible? what does it mean?
yes
both parents without disease are heterozygous and pass on the risk allele –> child gets disease
is autosomal dominant or autosomal recessive more common?
autosomal dominant
are cancer predisposing genes always tumour suppressors?
no!! - can be activated oncogenes
are tumour suppressors or oncogenes more common as cancer predisposing genes?
tumour suppressors
3 pathways that loss of function variant genes are typically involved in
- cell cycle pathways
- DNA repair pathways
- cell growth and repair pathways
how does loss of function variants of genes involved in DNA repair pathways affect the cell?
affects chromosome integrity leading to genome disorganization
What do loss of function variants of MSH2, MLH1, MSH6, and PMS2 lead to?
affects mismatch DNA repair pathway for a single base mismatch or short insertion/deletion
What do loss of function variants of BRCA1 and BRCA2 lead to?
chromosomal instability –> deletions or insertions of entire chromosome or parts of chromosome
specifically, what does a loss of function of BRCA1 affect? (3)
- homologous recombination repair
- replication fork repair
- DNA damage checkpoint control
how does loss of function variants of genes involved in cell growth and function pathways affect the cell?
- cell migration and adhesion
- transcriptional activation
- apoptosis
what is RET? what happens when there is a mutation?
encodes receptor tyrosine kinase –> mutation makes it constitutively active (gain of function = oncogene)
what is the function of the receptor tyrosine kinase encoded by RET?
cell surface molecule that transduces signals for cell growth and differentiation
what 3 cancers are RET mutations involved in?
- thyroid cancer
- parathyroid cancer
- adrenal cancer
are p53 mutations usually somatic or hereditary?
somatic
when does germline p53 mutation occur?
for LI-FRAUMENI SYNDROME (but rare)
is Li-Fraumeni Syndrome autosomal recessive or autosomal dominant?
autosomal dominant
what is li-fraumeni syndrome?
carriers are at high risk for breast cancer, sarcomas, and brain tumours bc gene has high penetrance!
is li-fraumeni syndrome treatable?
yes, some carriers are sensitive to radiation
is somatic Rb mutation more common than somatic p53 mutation?
somatic Rb mutation less common than somatic p53 mutation
are somatic BRCA1 mutations common or rare?
rare!
what is genetic heterogeneity of hereditary cancer?
1 phenotype/genetic disorder is associated with a risk allele in multiple different genes
is retinoblastoma heterogenous? why?
no, only Rb is involved in the disease
is breast cancer heterogenous? why?
yes, either BRCA1 or BRCA2 can give breast cancer
why is it unsurprising that either BRCA1 or BRCA2 can be involved in breast cancer?
both are involved in DNA repair
are only BRCA1 and BRCA2 involved in breast cancer?
no - other syndromes caused by other genes can also give the breast cancer phenotype
what is another example of a cancer that is genetically heterogenous?
colorectal cancers
what is variable penetrance?
probability of developing cancer in carriers of pathogenic variants of cancer predisposing genes (i.e. lifetime risk)
is retinoblastoma high penetrance? explain
high penetrance –> 95% of carriers of Rb1 loss of function pathogenic variant will develop retinoblastoma
why is it rare to develop retinoblastoma as an adult?
eye has developed –> no more replicating so reduced chance of the second hit
which gene has the highest penetrance for breast cancer?
p53
what is variable expressivity?
when a cancer predisposing gene gives increased risk to different cancer types
describe variable expressivity in the context of BRCA1 and BRCA2 pathogenic variants
carriers of BRCA1/2 pathogenic variants are also at increased risk of ovarian cancer
is penetrance of BRCA1/2 pathogenic variants for breast cancer higher than ovarian cancer?
penetrance is higher for breast cancer
describe male carriers with pathogenic variants of BRCA1/2
have increased risk of breast cancer, but penetrance is significantly lower compared to females so lower risk
describe variable expressivity of carriers of pathogenic variants of Rb1
carriers of pathogenic variants of Rb1 are at significantly higher risk for other types of cancers (but not all high penetrance)
is there a relationship between the genotype (risk variant) and phenotype?
yes –> the relationship predictive of a physical trait in carriers of pathogenic variants in cancer predisposing genes
can a specific mutation have an effect that is different than another variant in the same gene?
yes
what do most germline retinoblastoma mutations lead to?
premature termination codon which knocks out the function of a gene to prevent anything functional from being made –> specific proteins can’t be made bc the body will naturally clear the transcript by nonsense mediated decay
do all Rb1 variants cause the same risk of retinoblastoma?
no - can have diff presentations, transmission, etc
describe the rare low penetrance pathogenic variant of Rb1
- % chance of disease
- how is it caused
- is it good or bad?
only gives 30% chance of disease
caused by mutation in promoter region that causes leaky transcription of Rb
better than other retinoblastoma bc lower penetrance
do all mutations in a gene cause the same risk?
no - mutations in diff parts of genes cause diff risk
describe the pathogenic variant of BRCA2 that causes a higher risk of ovarian cancer
mutation in Ovarian Cancer Cluster Region of BRCA2 is associated with higher risk of ovarian cancer
- lower penetrance for breast cancer so there are more cases of ovarian cancer
what percent of all cancers are caused by carriers of pathogenic variants in predisposing genes?
only 3%
why is it difficult to estimate frequency of carriers?
hereditary cancer syndromes are rare and carriers are also rare –> also access to genetic testing and management is not equitable
do all populations studied for BRCA1/BRCA2 mutations have the mutation?
yes and penetrance is consistent
what are the causes of breast cancer?
90% - unknown genetic risk factor
10% BRCA1/BRCA2
<1% P53, PTEN, etc
describe BRCA1/BRCA2 on a plot of risk for cancer in carriers vs frequency of carriers
BRCA1/BRCA2 have high risk AND high frequency
which ethnic population has higher frequency of breast cancer than ppl with western european ancestry?
Ashkenazi Jewish population
BRCA1 pathogenic variant causes higher rates of:
breast and ovarian cancer
BRCA2 pathogenic variant causes higher rates of:
breast cancer
why do we know that BRCA1/BRCA2 are not the only genes involved in breast and ovarian cancer/breast cancer?
WT BRCA1 and WT BRCA2 are common in each, so other predisposing genes are involved
describe French Canadian BRCA1/BRCA2 pathogenic variant carriers
have similar pathogenic variants due to common ancestors
