Cancer Genetics Flashcards
3 classes of genes that contribute to oncogenesis/tumorigenesis/carcinogenesis
- oncogenes
- tumor suppressor genes
- oncomirs
relevant oncogenes in cancer
RET, MET, RAS
relevant tumor suppressor genes in cancer
- Gatekeepers - RB1, TP53
2. caretakers - MSH2, MLH1
relevant apoptotic genes in cancer
FAS
relevant antiapoptotic genes in cancer
BCL2 , telomerase
how does cancer regulate the apoptotic genes in general?
inactivates apoptotic genes like FAS, so cancer cells are not destroyed
how does cancer regulate antiapoptotic genes in general?
upregulate antiapoptotic genes like BCL1 and telomerase, so cancer cells survive
what do gatekeeper tumor suppressor genes do in general?
control cell growth by sensing stresses in the cell, tell cell to senesce or die
what do caretaker tumor suppressor genes do in general?
protect integrity of genome via DNA mismatch repair
what are oncomirs?
types of miRNA
how would cancer regulate tumor suppressor genes?
would be a loss of function of caretaker and gatekeeper genes, so there would be a loss of control of cell growth and DNA repair
what is an oncogene
a dominant gain of function mutation, where only one allele has to be affected to cause abnormality, would result in inappropriate activation or constitutive activation
what would be the result of an oncogene?
the mutated cell would have increased RET, MET, and RAS activation, telling cell to proceed in cell growth and proliferation
general mechanism of tumorigenesis by oncogenes?
- mutation in genes involved in growth factor signaling 2. mutation in genes involved in antiapoptotic signaling
- mutation in genes involved in telomerase function
how does mutation in growth factor signaling relate to tumorigenesis?
- mutation in growth factors so that they are constantly stimulating their receptors
- mutation in receptors for the GF (so that they are signaling with or without GF), like RTK phosphorylating itself and always being active
- mutation in intracellular signaling pathway components like Ras, Raf, MET, ERK
- mutation in transcription factors
how does mutation in anti-apoptotic signaling relate to tumorigenesis
anti-apoptotic proteins like BCL1, BCL2, and MCL are upregulated so cancer cells are not killed
how does mutation in telomerase function relate to tumorigenesis?
upregulating telomerase makes site for replication
what type of mutations can turn a proto-oncogene into an oncogene?
- point mutation in coding sequences
- gene amplification
- chromosome rearrangement
what occurs when a point mutation is made in coding sequences?
a hyperactive protein is made in normal amounts
what occurs when a gene is amplified?
a normal protein is greatly overproduced
what occurs when chromosomes are rearranged
- a nearby regulatory DNA sequence causes normal protein to be overproduced
- fusion of chromosome to actively transcribed gene produces hyperactive fusion proteins
what type of mutation causes mutation in HER2/Neu/ERBB2?
point mutation
example of point mutation
HER2/Neu
what is HER2
human epidermal growth factor receptor 2 (aka ERBB2, aka Neu), a member of epidermal growth factor receptor (EGFR) family
what does a mutation in HER2 cause?
point mutations cause constitutively active protein, so EGFR signals RTK/Ras/MAPK pathway to cause constant signaling
cancers associated with HER2 mutation
sporadic breast cancer (non-inherited)
what gene is associated with hereditary breast cancer and ovarian cancer?
Brca1 and Brca2 mutations
what gene is associated with sporadic breast cancer?
ERBB2/HER2/Neu
example of gene amplification that causes cancer
Myc oncoprotein mutation
function of Myc
can inhibit P15ink48, upregulates cyclins, downregulates p21, downregulates Bcl-2
what is c-myc
expressed in almost all rapidly proliferating cells
what is n-myc
expressed in pre-B cells, kidney, brain, and intestine
significance of n-myc?
some neuroblastomas are caused by increased production (amplification) of n-myc
what is L-myc
expressed during embryogenesis and in kidney and lung
what is myc
transcription factor that has roles in controlling cell cycle progression, apoptosis, and transformation
what does p15ink48 do
inhibits cyclin D-cdk4/6, so that the cell does not enter S phase
what does inhibition of p15ink48 do?
allows for binding of CyclinD-cdk4/6, so that it signals the cell to enter S phase (binds to Rb which inactivates it, which then activates E2F)
what does upregulation of cyclins do?
increases cyclin-cdk formation that assists entering of S phase and other phases of mitosis
what does downregulation of Bcl2 do?
decreases formation of Bax/Bak which indicates that no mitochondrial pore forms, therefore no cytochrome C is released into the cell
what does downregulation of p21 do?
reduces the binding of p21 to cyclinD-cdk4/6 and cyclinE-cdk2, therefore, increasing amounts of active cyclin-cdk complexes, stopping cell cycle arrest
example of nearby regulatory sequences causing overproduction of normal proteins
Burkitt’s lymphoma
mutation involved in Burkitt’s lymphoma
chromosomal translocations result in fusion of heavy chain immunoglobulin gene (IgH) with oncogene myc
pathology of Burkitt’s lymphoma
B lymphocytes have a high expression of IgH, so the translocation of myc causes OVEREXPRESSION of myc, causing increased proliferation of B cells – leads to lymphoma
what is Burkitt’s lymphoma associated with?
Epstein Barr virus infection and malaria
unique characteristic of Burkitt’s lymphoma
fastest growing human tumor
what is the hallmark sign of Chronic Myelogenous leukemia?
presence of Philadelphia chromosome
what is a philadelphia chromosome
a fusion of BCR (breakpoint cluster region) with Abl kinase `
what does the fusion of BCR/Abl kinase indicate
BCR promotes the dimerization of ABL, which is a tyrosine kinase that pushes cells to divide
what does RB1 gene encode
p110
what does mutated RB1 cause?
mutation of p110, familial retinoblastoma, sporadic retinoblastoma, SCLC, breast cancer
what does TP53 encode
p53
what does p110 d0
cell cycle regulation
what does DCC encode
Dcc-receptor
what does Dcc-receptor do?
decreases cell survival in the absence of survival signal from its netrin ligands
what does mutation of TP53 cause?
familial Li-Fraumenti syndrome, sporadic lung cancer, breast cancer, and other cancers
what does VHL encode
Vhl
what does Vhl do
forms part of cytoplasmic destruction complex with APC that normally inhibits induction of blood vessel growth when oxygen is present, tumor suppressor (makes sure not too much BV growth)
what does mutation of VHL cause
familial Von-Hippel-Lindau syndrome, sporadic clear cell renal carcinoma
what are the tumor suppressor gatekeepers?
RB1, TP53, DCC, VHL
what are the tumor suppressor caretakers?
BRCA1, BRCA2, MLH1, MSH2
what does BRCA1 and BRCA2 encode
Brca1, Brca2
what do Brca1 and 2 do?
chromosome repair in response to double stranded DNA breaks
what does mutation of DCC cause?
sporadic colorectal cancer
what does BRCA1/2 mutation cause?
familial AND sporadic breast and ovarian cancers
what does MLH1/MSH2 encode?
Mlh1 and Msh2
what do Mlh1 and Msh2 do?
repair nucleotide mismatches
what does mutation of MLH1/MSH2 cause?
familial hereditary nonpolyposis colon cancer, sporadic colorectal cancer
what do oncomirs do?
miRNAs that regulate expression of either tumor suppressors or oncogenes
what could result from LOSS of oncomir that acts as a tumor suppressor?
loss of miRNA that acts as tumor suppressor could allow overexpression of oncogenes
what could result from overexpression of oncomir that is acting as an inhibitor of a tumor suppressor?
promotion of tumor progression, such as the case of miR-21 overexpression in glioblastoma multiforme, which targets p53 mRNA, degrading it
general pathway of tumor suppressor action of oncomir?
binds to mRNA and targets it for degradation
difference between sporadic and familial cancers?
sporadic cancer is due to accumulation of mutations over time, familial cancers are due to inherited susceptibility and environmental factors
what type of cancer (familial or sporadic) is most common?
sporadic
does having a susceptible gene mean you will get an familial cancer?
no, it increases the risk, but the genes do not automatically cause the cancer
what is a familial cancer?
cancer that occur in families more often than what would be expected by chance, inherited susceptibility of genes that are NOT mutations in oncogenes or tumor suppressors, 15-20% of cancer cases
what is an inherited cancer?
cancer that results from genetic mutations that are passed on from one generation to next, 5-10% of cancer cases
what genes are involved in hereditary cancers?
TP53, VHL, BRCA1/2, MLH1, MSH2, APC, RB1, NF1, MEN1 and RET
what features suggest hereditary cancers? (10)
- early age of onset
- multiple primary cancers (actual new growths, not metastases) (CRC and endometrial)
- bilateral cancer in paired organs/multifocal disease (bilateral breast cancer, multifocal renal cancer)
- clustering of same type of cancer in close relatives
- cancers occurring in multiple generations of a family (autosomal dominant)
- occurrence of rare tumors
- unusual presentation of cancer
- uncommon tumor histology
- rare cancers associated with birth defects
- geographic or ethnic populations known to be at high risk of hereditary cancers
what are rare tumors that are most likely hereditary cancers?
retinoblastoma, adrenocortical carcinoma, granulosa cell tumor of ovary, ocular melanoma, duodenal cancer)
example of unusual presentation of cancer
male breast cancer
example of uncommon tumor histology
medullary thyroid carcinoma
what rare cancers are associated with birth defects?
wilms tumor and GU abnormalities
what cancers cause multiple primary cancers in a single individual?
CRC, endometrial cancer
what cancer presents at an unusually early age?
premenopausal breast cancer
what gene is involved in li-fraumenti syndrome?
TP53
what gene is involved in von hippel-lindau syndrome
VHL
what gene is involved in hereditary breast-ovarian cancer syndrome?
BRCA1/2
what gene is involved in hereditary nonpolyposis colon cancer aka lynch syndrome
MLH1/MSH2
what gene is involved in familial adenomatous polyposis?
APC
what gene is involved in retinoblastoma
RB1
what gene is involved in neurofibromatosis
NF1
what gene is involved in multiple endocrine neoplasia type 1
MEN1
what gene is involved in multiple endocrine neoplasia type 2
RET
what is multiple endocrine neoplasia?
inherited cancer syndrome that features tumors of endocrine glands
what is MEN1?
a tumor suppressor that regulates transcription of genes involved with cell proliferation - makes menin
what is RET?
RTK that is an oncogene, gain of function mutations lead to persistent proliferative signal
what is the most common mutation in cancers?
tumor suppressor mutation
chance of cancer if multiple endocrine neoplasia gene mutations are inherited?
100%
what occurs if MEN1 is mutated?
menin is not made or is ineffective, meaning that it cannot bind to DNA and inactivate TGF-beta/BMP signaling, leading to increased cell proliferation/transcription
what is Li-fraumenti syndrome?
extremely rare inherited cancer syndrome associated with breast, brain, leukemia, sarcomas and adrenal cancinomas, person usually inherits 1 mutated TP53
cellular response to p53
apoptosis, cell cycle arrest, DNA repair, differentiation, senescence
risk of cancer if mutated TP53 inherited?
90%
what does RB1 do?
tumor suppressor gene that encodes for Rb, control of cell cycle, loss of Rb means E2F is not inhibited, pushing cell to cycle
what is mutation of RB1 associated with?
retinoblastoma
risk of cancer if RB1 mutation is inherited?
99%
evidence of sporadic retinoblastoma?
single tumor, unilateral, later onset
evidence of mendelian retinoblastoma?
multiple tumors, bilateral, early onset
what is von hippel-lindau syndrome?
mutation in tumor suppressor gene VHL that predisposes to tumors of eye, brain, spinal cord, kidney, pancreas, adrenal glands
what does VHL do
a tumor suppressor, contains ubiquitin ligase E3 activity, so involved in degradation of hypoxia inducible factor (HIF1) to inhibit formation of blood vessels ,,forms part of cytoplasmic destruction complex with APC that normally inhibits induction of blood vessel growth when oxygen is present
hallmark of VHL mutation
highly vascularized tumors
risk of cancer if VHL mutation is inherited
40%
what does Brca1/2 do?
promotes assembly of Rad51, Brca2, Brca1, and BARD1 to repair DNA damage
mutation in Brca1/2?
failed repair of p53 or other checkpoint genes that results in proliferation of cells OR failed repair of most other genes, leading to increase in p53, induction of p21, cell cycle arrest and apoptosis
characteristic of lynch syndrome/hereditary nonpolyposis colon cancer?
sessile serrated adenomas in the colon, RER+ phenotype
what does inactivation of MLH1/MSH2 lead to?
increase in point mutations and genetic instability in microsatellite regions, leading to Replication Error Positive (RER+) phenotype
what is microsatellite polymorphic marker?
long stretches of DNA sequence repeats (simple or tandem repeats)
how to identify mutations in mismatch repair genes
gel electrophoresis to ID RER+ phenotype, mutations result in increase or decrease in SIZE of microsatellite regions in DNA
what is lynch syndrome?
hereditary nonpolyposis colon cancer, predisposes individuals to colon cancer and endometrial cancer
risk of cancer if MLH1/MSH2 mutation inherited?
80%
what is familial adenomatous polyposis?
associated with APC mutations, predisposing individual to CRC
what is APC
tumor suppressor gene that normally inactivates beta catenin, so the cell does not activate myc transcription
result of mutated APC
APC cannot inactivate beta catenin, so overexpression of myc genes (and other genes regulated by beta catenin)
risk of cancer if APC mutation inherited?
100%
what is neurofibromatosis?
tumors of the nervous system (wherever there are nerves), usually benign, associated with NF1 mutations
what does NF1 do
negative regulator of Ras signaling, mutation would cause increased Ras/lack of negative regulation
explain autosomal dominant inheritance pattern of cancer syndromes?
most tumor suppressors are inherited in autosomal dominant fashion, meaning, only need to inherit one abnormal copy of gene to get disease, but both ALLELES of tumor suppressor must be inactivated in order for the cancer to form.(recessive at genotypic level, dominant at phenoytpic level). even though only one allele is mutated in an inherited pattern, the change that the other allele will undergo mutation at some point in the person’s life is very high (chance of LOH or 2nd hit is very high)
