Lecture 5: boring one Flashcards
what is the first hereditary cancer susceptibility gene and the first tumor supressor gene discovered and when was it discovered
it is the RB1 gene and it was in 1986
what is leukocoria
a white reflexion in the pupil
what us strabismis
eye misalignment due to tumor growth
what are the 2 presenting signs of retinoblastoma
-leukocoria
-strabismus
what is usually the age of diagnosis of retinoblastoma
5ys
true or false: a retinoblastoma is always unilateral anbd multifocal
false: it could be unilateral or bi lateral aka one or 2 eyes
-it could be unifocal or multifocal aka 1 foci or multiple foci of tumor
what is a retinoblastoma
a malignant tumor of the embryonic neural retina
retinoblastoma cases occurs in…. and …. context
-familial and sporadic contect
what is a familial context
familial disease is consistent with autosomal dominant code of transmission of a highly penetrant trait
what does a sporadic disease mean
np family history
what does a multigenerational trait
it is a trait that is transmitted through the same branch of the family
what does penetrance mean
often describes the likelihood or the lifetime probability of devloping cancer in risk allele carriers
who had discovered the two hit hypothesis and when
alfred knudson in 1971
what is the name of the hypothesis that was proposed to explain the development of both familial and sporadic cases of retinoblastoma and disease presentation in these conrexts
the two hit hypothesis
what does the revised 2 hit hypothesis include
it incorporated the general theory of carcinogenesis involving putitative tumor supressor genes (1976)
what is the age of diagnosis of familial rb
12 months
what is the age of diagnosis of sporadic rb
7-10 years
what are the characteristics of familial rb
bilateral and multifocal
what are the characteristics of sporadic rb
unilateral and uni focal
truie or false: familial and sporadic form of rn is caused by the same gene
true
how is the rb1 gene transmitted
autosomal dominant mode of inheritance
what does rb1 gene encode for
a tumor supressor gene
can you inherit a mutant rb allele
yeah
you can inherit a loff of function risk rb allele from carrier parent
do you need to get the second hit in order to get rb
yeah
loss of function in rb in tumours is due to what
mutational inactivation and allele loss`
loss of pRB function in tumor cells results in what?
in loss of cell cycle regulation leading to unprogrammed cell division
pRb is regulated by what
phosphorylation
what does unphosphorylated Rb do
it physically interacts with TF an impedes their functions
could genetic testing reveal that a seemingly sporadic case was hereditary
you can because although rb has a high penetrance it is possible that the parents do not get cancer
which cancer predisposing traits can account for features in disease presentation
-young age of onset
-bilateral disease
-number of tumour foci
-familial history of cancer
cancer predisposing genes encode for what?
proteins that behave of tumour supressor
what can serve as mediacal biomarkers pedictive of rb risk
cancer predisposing gene
when were BRCA1 and BRCA2 found and by using what
1994 and 1995
genetic analyses of breast cancer
what is a germline variant
-a gene change in a reproductive cell aka sperm or egg that becomes incorporated in the dna of every cell of the kiddo
-passed from parent to offspring aka hereditary
what is a somatic mutationb
-al alteration in dna that occurs after conception and is not present within ther germline
-can occur in any cells in the body except the germ cells and is not passed to the kids
-can cause cancer or other disease
what is a pathogenic mutation
directly contributes ti the development of a disease
what is a likely pathogenic pathogen
very likely to contribute to the development of a disease but need more scientific evidence
what is a benign varuianbt
does not cause disease
the term variant is increasingly being used in place of which term
mutation
true or false: RB1 is a very rare allele
true
cowden disease can cause what
breast cancer
ataxia telangi smth can cause what
breast cancer
features of hereditary cancer often include what?
-multiple primary tumors in the same or different organs
-bilateral primary tumors in paired organs
-multifocal tumors in a single organ
-younger than usual age at cancer diagnosis
-family history of cancer; either same or specific cancer types and often autosomal dominant mode of inheritance
-tumors with rare histology
true or false: breast cancer is often multigenerational
true
true or false: breast cancer is often bilateral
true
BrCa Risk – BRCA1 PV carriers:
50-80% - lifetime (80 yrs)
15-30% - age 50 yrs
populztion brca risk
11% - lifetime (80 yrs)
2% - age 50 yrs
Mean age Dx = 56 yrs
true or fakse: RB1 is dominant
yeah it is
cancer predisposing genes are more likely associated with what?
the genetic transmission of an autosomal dominant trait
true or false: ATM is recessive
true
what does atm cause
leukemias
BRCA1 and 2 are dominant or recessive
they are recessive
what type of cancer does BRCA1 abnd BRCA2 cause
breast and ovary cancer
how many gene are autosomal dominant
65
homany genes are autosomal recessive
28
how many genes are x linked
4
how many genes are y linked
1
autosomal recessive characteristics
-heterozygous carriers may express other manifestations of the disease
-carriers are biallelic for mutations
-at risk alleles are inherited fromn both parents
are cancer predisposing genes always tomor supressors
no
what is the difference between tumor supressor genes and oncogenes
-tumor supressor gemes: mutations results in loss or reduced function
-oncogene: mutations result in activatuon of encoded protein
true or false: cancer predisposing genes inactivated by loss of function variants are more common than those genes modified by gain of fucntion variants
true
aka usually the second hit is the inactivation of wt allele inorder for cancer to be like hey girlie
give examples of tumor supressors
-p53
-pRB
-BRCA1-2
what is the mmr pathway and which gene uses it
-mismatch repair dna repair pathway affecting single base mismatches or short insertions/deletions
-MSH2 and 6, MLH1
what is the CIN pathway and which genes are using it
chromosomal(genomic) instability aka deletions or duplicatins affectingwhole or parts of the chromosomes
-brca1-2
what is brca1 involved in
-homologous recombination reoair
-repliucation fork repair
-dna damage checkpoiunt control
-tumors from pathogenic brca1 variants carriers display extensive genetic damage (CIN)
name tumor supressor genes involved in the apc pathway
-apc
-axin2
cdh1
-gpc3
the apc pathway affects what
-cell processes including:
-cell migration and adhesion
-transcriptional activation
-apoptosis
RET encodes for what
-receptor tyrosine kinase
-cell surface that transduces signals for cell growth and differenciation
-rendered constitutively active by cancer predisposing mutation
cancer predisposing hgenes have been associated with a variety of molecular pathways found implicated in the developmemnt of which tyoe of disease
sporadic disease
which tyoe of variuants have been recently founbd in rare oediatric cancers
germline variants in dicer (mrna processing)
how many genes are found in biwth cancer genes with somatic driver mutations and cancer predisposition with germline mutations
49
which gene is the most somaticallu mutated gene in epithelial cancers
tp53
which gene is implicated in li fraunmeni syndrome caner families
tp53
true or false: tp53 has asn autosomal dominant mode of inheritabce
teah
true or false: li fraumeni syndrome cancer fam is common
false it is rare 1/5000 are heterozygoys carriers of tp53
true or false: tp53 can affect breast cancer
yeah
what is genetic heterogeneity of hereditary cancer
a phenomenin in which a single phenotyoe or disorder bay be associated with a germline risk (pathogenic) allele in any one of a multiple number of genes
true ot false: rb is monogenic
true
true or false: titty cancer is heterogenic
yeah
brca1 and brca2
what are the roles of brca1-2
-homologous recombination repair
-replication fork repair
-dna damage checkpoint control
hereditary breast cancer is a genetically…. disease asssociated with …. mode of transmission of……. in. avariety of rare clinically defined cancer syndromes
heterogenous
-autosomal dominant mode of transmission
-of loss of funstion variants
can li fraumeni cause sarcomas
yeah
what does cowdens cause and which gene is affected
titty and thyroid cancer
pten
true or false; there is breast ovarian cancer
yeah
what does peutz jeghers cause and which gene
titty and it is stk11
what does hereditary diffuse gastric cancer cause and which gene does it affects
-diffuse gastric cancer and titty
-cdh1
true or false: colon cancer is homogenic
false it is heterogenic
what is the variable penetrance
probability of devloping cancer in carriers of pathogenic variants in cancer predisposing genes during their lives
what is the % of carriers that have rb and get rb cancer
95%
true or false: breast cancer risks depemnds on the oenetrance of the genes
true
what is the lifetime risk of not carriers to get titty cabcer
10%
what is variable expressivity
a cancer predisposing gene that also confers increased risk to different cancer type
carriers of pathogenic variuants of brca1-2 are also at significantly increased to which cancer
ovarian cancer
cancer familt phenotype of ovarian cancer
-breast cancer syndrome family with ovarian cancer
-autosomal dominant mode of inheritance of genetic trait
OvCa Risk in BRCA1 PV or
BRCA2 PV carriers:
15-60% - lifetime (80 yrs)
<2% - age 50 yrs
Population OvCa risk:
1.2% - lifetime (80 yrs)
«_space;1% - 50 yrs
Mean age Dx = 60 yrs
true. orfalse: penetrance is significantlyt higher for female ovarian cancer than boobie cancer
false boobie cancer is more penetrant
Male carriers of pathogenic variants in B…… are a increased risk for breast cancer and penetrance is significantly ….. than for female carrier
RCA1 or BRCA2 (risk alleles)
lower
BrCa risk for males:
BRCA1 PV carriers:
1-2% - lifetime risk (80 yrs)
BRCA2 PV carriers:
6% lifetime risk (80 yrs)
Population BrCa risk for males:
<1% - lifetime (80 yrs)
Mean age Dx > 55 yrs
what is the magnitude absolute risk for brca1-2 carriers for prostate
we dunno
what is the magnitude absolute risk for brca1-2 carriers for pancreas
less than 10%
non retinal tumors of retinoblastoma patients: bilateral %
36%
non retinal tumors of retinoblastoma patients: unilateral %
5.69&
Carriers of RB1 PV (risk alleles) are at significantly increased risk for other cancer types like which ones
-lung
-all neoplasms
genotype: phenotype corrolation def
A statistical relationship between genotype (risk variant) and phenotype (cancer or type of cancer) predictive of a physical trait in carriers of pathogenic variants in cancer predisposing genes
Most germline RB1 PV confer high risk (….) for developing retinoblastoma
> 95%
rb: …. % result in premature termination codon
85-95%
Most germline RB1 PV confer high risk (>95%) for developing retinoblastoma give them lil facts
- Transcripts cleared by nonsense mediated decay (NMD)
- Often found in bilateral disease
what is the penetrance of unilateral rb
30%
Pathogenic variants in ….. region of BRCA2 is associated with conferring
higher risk for ovarian cancer
“OCCR”
Frequency of carriers of pathogenic variants in high-risk cancer predisposing genes accounts of how many cancers
3%
Estimates based on research often derived in populations in high resource areas as
defined by:
ü World Bank income categories
ü health care system robustness
ü status of universal health
coverage and/or
ü research capabilities
which is one of the most rare cancer and give lil deets
-Thyroid
-Multiple Endocrine
Neoplasia
1/500,000
RET
>92%
Fewer than…. of female breast cancer cases carry a pathogenic variant in a known high risk cancer predisposing gene
15%
-10% for brca1
Chance of carrying a pathogenic variant in BRCA1 or BRCA2 depends on
personal and family history of cancer and ancestry: true. orfalse
true
which people are more likely to get cabncers
ashkenazi jews and french canadians and hispanics
80% of BRCA1/BRCA2 PV carriers in the French Canadian cancer families from Quebec harbor recurring pathogenic variants due to …..
common ancestors
what is the candidate gene approach
Proteins that interact in the same pathways as known genes are obvious candidates to pursue in BRCA1/BRCA2 variant-negative cancer families
true. orfalse: Distribution of other pathogenic breast and ovarian cancer
variants in French Canadian cancer families is the same between the two camcer
FALSE THEY HAVE DIFFERENT RATIOS
