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MFM > Cancer Genetics > Flashcards

Cancer Genetics Flashcards

1
Q

3 classes of genes that contribute to oncogenesis/tumorigenesis/carcinogenesis

A
  1. oncogenes
  2. tumor suppressor genes
  3. oncomirs
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2
Q

relevant oncogenes in cancer

A

RET, MET, RAS

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3
Q

relevant tumor suppressor genes in cancer

A
  1. Gatekeepers - RB1, TP53

2. caretakers - MSH2, MLH1

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4
Q

relevant apoptotic genes in cancer

A

FAS

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5
Q

relevant antiapoptotic genes in cancer

A

BCL2 , telomerase

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6
Q

how does cancer regulate the apoptotic genes in general?

A

inactivates apoptotic genes like FAS, so cancer cells are not destroyed

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7
Q

how does cancer regulate antiapoptotic genes in general?

A

upregulate antiapoptotic genes like BCL1 and telomerase, so cancer cells survive

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8
Q

what do gatekeeper tumor suppressor genes do in general?

A

control cell growth by sensing stresses in the cell, tell cell to senesce or die

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9
Q

what do caretaker tumor suppressor genes do in general?

A

protect integrity of genome via DNA mismatch repair

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10
Q

what are oncomirs?

A

types of miRNA

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11
Q

how would cancer regulate tumor suppressor genes?

A

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

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12
Q

what is an oncogene

A

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

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13
Q

what would be the result of an oncogene?

A

the mutated cell would have increased RET, MET, and RAS activation, telling cell to proceed in cell growth and proliferation

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14
Q

general mechanism of tumorigenesis by oncogenes?

A
  1. mutation in genes involved in growth factor signaling 2. mutation in genes involved in antiapoptotic signaling
  2. mutation in genes involved in telomerase function
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15
Q

how does mutation in growth factor signaling relate to tumorigenesis?

A
  1. mutation in growth factors so that they are constantly stimulating their receptors
  2. mutation in receptors for the GF (so that they are signaling with or without GF), like RTK phosphorylating itself and always being active
  3. mutation in intracellular signaling pathway components like Ras, Raf, MET, ERK
  4. mutation in transcription factors
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16
Q

how does mutation in anti-apoptotic signaling relate to tumorigenesis

A

anti-apoptotic proteins like BCL1, BCL2, and MCL are upregulated so cancer cells are not killed

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17
Q

how does mutation in telomerase function relate to tumorigenesis?

A

upregulating telomerase makes site for replication

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18
Q

what type of mutations can turn a proto-oncogene into an oncogene?

A
  1. point mutation in coding sequences
  2. gene amplification
  3. chromosome rearrangement
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19
Q

what occurs when a point mutation is made in coding sequences?

A

a hyperactive protein is made in normal amounts

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20
Q

what occurs when a gene is amplified?

A

a normal protein is greatly overproduced

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21
Q

what occurs when chromosomes are rearranged

A
  1. a nearby regulatory DNA sequence causes normal protein to be overproduced
  2. fusion of chromosome to actively transcribed gene produces hyperactive fusion proteins
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22
Q

what type of mutation causes mutation in HER2/Neu/ERBB2?

A

point mutation

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23
Q

example of point mutation

A

HER2/Neu

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24
Q

what is HER2

A

human epidermal growth factor receptor 2 (aka ERBB2, aka Neu), a member of epidermal growth factor receptor (EGFR) family

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25
Q

what does a mutation in HER2 cause?

A

point mutations cause constitutively active protein, so EGFR signals RTK/Ras/MAPK pathway to cause constant signaling

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26
Q

cancers associated with HER2 mutation

A

sporadic breast cancer (non-inherited)

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27
Q

what gene is associated with hereditary breast cancer and ovarian cancer?

A

Brca1 and Brca2 mutations

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28
Q

what gene is associated with sporadic breast cancer?

A

ERBB2/HER2/Neu

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29
Q

example of gene amplification that causes cancer

A

Myc oncoprotein mutation

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30
Q

function of Myc

A

can inhibit P15ink48, upregulates cyclins, downregulates p21, downregulates Bcl-2

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31
Q

what is c-myc

A

expressed in almost all rapidly proliferating cells

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32
Q

what is n-myc

A

expressed in pre-B cells, kidney, brain, and intestine

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33
Q

significance of n-myc?

A

some neuroblastomas are caused by increased production (amplification) of n-myc

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34
Q

what is L-myc

A

expressed during embryogenesis and in kidney and lung

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35
Q

what is myc

A

transcription factor that has roles in controlling cell cycle progression, apoptosis, and transformation

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36
Q

what does p15ink48 do

A

inhibits cyclin D-cdk4/6, so that the cell does not enter S phase

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37
Q

what does inhibition of p15ink48 do?

A

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)

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38
Q

what does upregulation of cyclins do?

A

increases cyclin-cdk formation that assists entering of S phase and other phases of mitosis

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39
Q

what does downregulation of Bcl2 do?

A

decreases formation of Bax/Bak which indicates that no mitochondrial pore forms, therefore no cytochrome C is released into the cell

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40
Q

what does downregulation of p21 do?

A

reduces the binding of p21 to cyclinD-cdk4/6 and cyclinE-cdk2, therefore, increasing amounts of active cyclin-cdk complexes, stopping cell cycle arrest

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41
Q

example of nearby regulatory sequences causing overproduction of normal proteins

A

Burkitt’s lymphoma

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42
Q

mutation involved in Burkitt’s lymphoma

A

chromosomal translocations result in fusion of heavy chain immunoglobulin gene (IgH) with oncogene myc

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43
Q

pathology of Burkitt’s lymphoma

A

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

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44
Q

what is Burkitt’s lymphoma associated with?

A

Epstein Barr virus infection and malaria

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45
Q

unique characteristic of Burkitt’s lymphoma

A

fastest growing human tumor

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46
Q

what is the hallmark sign of Chronic Myelogenous leukemia?

A

presence of Philadelphia chromosome

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47
Q

what is a philadelphia chromosome

A

a fusion of BCR (breakpoint cluster region) with Abl kinase `

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48
Q

what does the fusion of BCR/Abl kinase indicate

A

BCR promotes the dimerization of ABL, which is a tyrosine kinase that pushes cells to divide

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49
Q

what does RB1 gene encode

A

p110

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50
Q

what does mutated RB1 cause?

A

mutation of p110, familial retinoblastoma, sporadic retinoblastoma, SCLC, breast cancer

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51
Q

what does TP53 encode

A

p53

52
Q

what does p110 d0

A

cell cycle regulation

53
Q

what does DCC encode

A

Dcc-receptor

54
Q

what does Dcc-receptor do?

A

decreases cell survival in the absence of survival signal from its netrin ligands

55
Q

what does mutation of TP53 cause?

A

familial Li-Fraumenti syndrome, sporadic lung cancer, breast cancer, and other cancers

56
Q

what does VHL encode

A

Vhl

57
Q

what does Vhl do

A

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)

58
Q

what does mutation of VHL cause

A

familial Von-Hippel-Lindau syndrome, sporadic clear cell renal carcinoma

59
Q

what are the tumor suppressor gatekeepers?

A

RB1, TP53, DCC, VHL

60
Q

what are the tumor suppressor caretakers?

A

BRCA1, BRCA2, MLH1, MSH2

61
Q

what does BRCA1 and BRCA2 encode

A

Brca1, Brca2

62
Q

what do Brca1 and 2 do?

A

chromosome repair in response to double stranded DNA breaks

63
Q

what does mutation of DCC cause?

A

sporadic colorectal cancer

64
Q

what does BRCA1/2 mutation cause?

A

familial AND sporadic breast and ovarian cancers

65
Q

what does MLH1/MSH2 encode?

A

Mlh1 and Msh2

66
Q

what do Mlh1 and Msh2 do?

A

repair nucleotide mismatches

67
Q

what does mutation of MLH1/MSH2 cause?

A

familial hereditary nonpolyposis colon cancer, sporadic colorectal cancer

68
Q

what do oncomirs do?

A

miRNAs that regulate expression of either tumor suppressors or oncogenes

69
Q

what could result from LOSS of oncomir that acts as a tumor suppressor?

A

loss of miRNA that acts as tumor suppressor could allow overexpression of oncogenes

70
Q

what could result from overexpression of oncomir that is acting as an inhibitor of a tumor suppressor?

A

promotion of tumor progression, such as the case of miR-21 overexpression in glioblastoma multiforme, which targets p53 mRNA, degrading it

71
Q

general pathway of tumor suppressor action of oncomir?

A

binds to mRNA and targets it for degradation

72
Q

difference between sporadic and familial cancers?

A

sporadic cancer is due to accumulation of mutations over time, familial cancers are due to inherited susceptibility and environmental factors

73
Q

what type of cancer (familial or sporadic) is most common?

A

sporadic

74
Q

does having a susceptible gene mean you will get an familial cancer?

A

no, it increases the risk, but the genes do not automatically cause the cancer

75
Q

what is a familial cancer?

A

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

76
Q

what is an inherited cancer?

A

cancer that results from genetic mutations that are passed on from one generation to next, 5-10% of cancer cases

77
Q

what genes are involved in hereditary cancers?

A

TP53, VHL, BRCA1/2, MLH1, MSH2, APC, RB1, NF1, MEN1 and RET

78
Q

what features suggest hereditary cancers? (10)

A
  1. early age of onset
  2. multiple primary cancers (actual new growths, not metastases) (CRC and endometrial)
  3. bilateral cancer in paired organs/multifocal disease (bilateral breast cancer, multifocal renal cancer)
  4. clustering of same type of cancer in close relatives
  5. cancers occurring in multiple generations of a family (autosomal dominant)
  6. occurrence of rare tumors
  7. unusual presentation of cancer
  8. uncommon tumor histology
  9. rare cancers associated with birth defects
  10. geographic or ethnic populations known to be at high risk of hereditary cancers
79
Q

what are rare tumors that are most likely hereditary cancers?

A

retinoblastoma, adrenocortical carcinoma, granulosa cell tumor of ovary, ocular melanoma, duodenal cancer)

80
Q

example of unusual presentation of cancer

A

male breast cancer

81
Q

example of uncommon tumor histology

A

medullary thyroid carcinoma

82
Q

what rare cancers are associated with birth defects?

A

wilms tumor and GU abnormalities

83
Q

what cancers cause multiple primary cancers in a single individual?

A

CRC, endometrial cancer

84
Q

what cancer presents at an unusually early age?

A

premenopausal breast cancer

85
Q

what gene is involved in li-fraumenti syndrome?

A

TP53

86
Q

what gene is involved in von hippel-lindau syndrome

A

VHL

87
Q

what gene is involved in hereditary breast-ovarian cancer syndrome?

A

BRCA1/2

88
Q

what gene is involved in hereditary nonpolyposis colon cancer aka lynch syndrome

A

MLH1/MSH2

89
Q

what gene is involved in familial adenomatous polyposis?

A

APC

90
Q

what gene is involved in retinoblastoma

A

RB1

91
Q

what gene is involved in neurofibromatosis

A

NF1

92
Q

what gene is involved in multiple endocrine neoplasia type 1

A

MEN1

93
Q

what gene is involved in multiple endocrine neoplasia type 2

A

RET

94
Q

what is multiple endocrine neoplasia?

A

inherited cancer syndrome that features tumors of endocrine glands

95
Q

what is MEN1?

A

a tumor suppressor that regulates transcription of genes involved with cell proliferation - makes menin

96
Q

what is RET?

A

RTK that is an oncogene, gain of function mutations lead to persistent proliferative signal

97
Q

what is the most common mutation in cancers?

A

tumor suppressor mutation

98
Q

chance of cancer if multiple endocrine neoplasia gene mutations are inherited?

A

100%

99
Q

what occurs if MEN1 is mutated?

A

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

100
Q

what is Li-fraumenti syndrome?

A

extremely rare inherited cancer syndrome associated with breast, brain, leukemia, sarcomas and adrenal cancinomas, person usually inherits 1 mutated TP53

101
Q

cellular response to p53

A

apoptosis, cell cycle arrest, DNA repair, differentiation, senescence

102
Q

risk of cancer if mutated TP53 inherited?

A

90%

103
Q

what does RB1 do?

A

tumor suppressor gene that encodes for Rb, control of cell cycle, loss of Rb means E2F is not inhibited, pushing cell to cycle

104
Q

what is mutation of RB1 associated with?

A

retinoblastoma

105
Q

risk of cancer if RB1 mutation is inherited?

A

99%

106
Q

evidence of sporadic retinoblastoma?

A

single tumor, unilateral, later onset

107
Q

evidence of mendelian retinoblastoma?

A

multiple tumors, bilateral, early onset

108
Q

what is von hippel-lindau syndrome?

A

mutation in tumor suppressor gene VHL that predisposes to tumors of eye, brain, spinal cord, kidney, pancreas, adrenal glands

109
Q

what does VHL do

A

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

110
Q

hallmark of VHL mutation

A

highly vascularized tumors

111
Q

risk of cancer if VHL mutation is inherited

A

40%

112
Q

what does Brca1/2 do?

A

promotes assembly of Rad51, Brca2, Brca1, and BARD1 to repair DNA damage

113
Q

mutation in Brca1/2?

A

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

114
Q

characteristic of lynch syndrome/hereditary nonpolyposis colon cancer?

A

sessile serrated adenomas in the colon, RER+ phenotype

115
Q

what does inactivation of MLH1/MSH2 lead to?

A

increase in point mutations and genetic instability in microsatellite regions, leading to Replication Error Positive (RER+) phenotype

116
Q

what is microsatellite polymorphic marker?

A

long stretches of DNA sequence repeats (simple or tandem repeats)

117
Q

how to identify mutations in mismatch repair genes

A

gel electrophoresis to ID RER+ phenotype, mutations result in increase or decrease in SIZE of microsatellite regions in DNA

118
Q

what is lynch syndrome?

A

hereditary nonpolyposis colon cancer, predisposes individuals to colon cancer and endometrial cancer

119
Q

risk of cancer if MLH1/MSH2 mutation inherited?

A

80%

120
Q

what is familial adenomatous polyposis?

A

associated with APC mutations, predisposing individual to CRC

121
Q

what is APC

A

tumor suppressor gene that normally inactivates beta catenin, so the cell does not activate myc transcription

122
Q

result of mutated APC

A

APC cannot inactivate beta catenin, so overexpression of myc genes (and other genes regulated by beta catenin)

123
Q

risk of cancer if APC mutation inherited?

A

100%

124
Q

what is neurofibromatosis?

A

tumors of the nervous system (wherever there are nerves), usually benign, associated with NF1 mutations

125
Q

what does NF1 do

A

negative regulator of Ras signaling, mutation would cause increased Ras/lack of negative regulation

126
Q

explain autosomal dominant inheritance pattern of cancer syndromes?

A

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)

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