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GGE > Genetics 10 - Cancer & Genomic Medicine (lessons) > Flashcards

Genetics 10 - Cancer & Genomic Medicine (lessons) Flashcards

1
Q

learning outcomes

A
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2
Q

neoplasm

A

an abnormal mass of tissue unresponsive to normal growth controls

neoplastic cells have clonally expanded as a result of somatic mutation

BENIGN - uncontrolled growth of tumour, but cannot metastasize

MALIGNANT - acquired ability to metastasize (seed other places)

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3
Q

cell growth/division

A

Cancer is closely linked to cell cycle

Most cancers have inactivating mutations in 1+ proteins that normally function to restrict progression through G1 phase of cell cycle

Virtually all human tumours have inactivating mutations in proteins - p53 - stopping cell if previous step has occurred incorrectly or DNA has been damaged

Growth factors

Growth factor receptors

Signal transduction proteins

Transcription factors

Pro and anti apoptotic proteins

Cell cycle control proteins

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4
Q

hallmarks of cancer

A

progressive

not overnight - changes accumulate

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5
Q

role of oncogene

A

developed from protooncogene

accelerator

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6
Q

genes involved in growth, proliferation, cell cycle

A

tyrosine kinases (Src, ABL)

growth factors (PDGF-B)

receptor tyrosine kinases (ERBB2, EGFR, HER2/neu)

IC signalling cascade components (Ras)

cell cycle regulators (Myc)

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7
Q

role of TSGs

A

brakes

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8
Q

gatekeeper genes

A

APC - familial colon cancer

RB1 - retinoblastoma

inhibits tumour growth, proliferation or cell cycle progression

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9
Q

caretaker genes

A

stability genes

MLH1

MSH2

stabilise the genome (provide mutational (DNA repair) or chr stability)

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10
Q

oncogene

A

a gene that when expressed confers resistance to programmed cell death

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11
Q

protooncogene

A

can become an oncogene following

point mutation

chromosomal translocation

increase in gene expression e.g. change in promoter

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12
Q

protooncogene to oncogene - type of mutation

A

change in just 1 of 2 alleles may result in malignant transformation e.g. epidermal growth factor (EGFR)

dominant activating/hypermorphic (GOF) mutation

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13
Q

tumour suppressor genes - what do they code for

A

products of this family of genes regulate cell cycle or direct cells towards apoptosis - code for:

  1. proteins that repress expression of genes essential for continuation of cell cycle
  2. proteins that prevent cell cycle progression in presence of damaged DNA
  3. proteins that promote apoptosis if DNA is damaged
  4. proteins that promote cell adhesion (prevent metastasis)
  5. proteins involved in DNA repair
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14
Q

2 hit hypothesis - type of mutation

A

typically need change in both alleles for malignant transformation

recessive amorph/hypomorphic (LOF) mutations

Probability of 1 cell being hit is high - especially if it’s a large cell

2nd hit is unlikely

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15
Q

big TS gene

size

activity depends on…

function

A

protein - p53

gene is TP53 on chr 17 (17p13.1)

393 AAs

activity depends on forming a tetramer

multiple TS functions - growth arrest, apoptosis, DNA repair

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16
Q

hereditary mutation associated with TP53

A

Li-Fraumeni Syndrome

rare but highly penetrant

can result in tumorigenesis in different places

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17
Q

mutation in core domain of TP53

A
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18
Q

mutation in C terminal of TP53

type of mutation

A

No tetramer formed

Interferes with normal protein folding - binds in an abhorrent fashion

Monoallelic change is enough

Dominant negative mutation - antimorph

Protein with a no of subunits and a mutation in 1 allele means the tetramer cannot form properly to carry out its function

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19
Q

Vogelstein’s tumour progression model

A

e.g. Colorectal cancer

10 years to get to carcinoma stage

More and more mutations over time

Initially in DNA repair genes, TSGs, built up to oncogenes which acecelerated tumorigenesis - loss of p53 can lead to chromosomal aneuploidy

CA = change no of chromosomes in the cell - increases dysplasia (presence of abnormal cells within a tissue)

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20
Q

life time risk of BC

A

molecular progression of BC is complex

different subtypes arising from different pathways

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21
Q

histology of BC

A
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22
Q

sporadic BC - risk factors

A

female gender

oestrogen exposure

age of menarche/menopause (<12/>55)

reproductive Hx

exposure to exogenous oestrogens

alcohol, obesity, radiation exposure

null parity

having 1st child > 35

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23
Q

sporadic vs familial BC

A

majority of BC is sporadic

family history of BC not synonymous with hereditary BC

13% of women have family history of BC but most do not get BC

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24
Q

what does oestrogen do

A

fuels growth and division of cancer cells, especially those with oestrogen receptors

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25
Q

triple -ve BC

A

negative for oestrogen receptors, progesterone receptors and excess HER2 protein

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26
Q

common mechanisms of genetic change in BC

A
  1. amplification of DNA sequences
  2. changes in chr number (aneuploidy)
  3. epigenetic modification
  4. point mutations
  5. changes in micro-RNA regulation
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27
Q

amplification

A

commonly of oncogenes

increase in gene copy number

results in over-expression of proteins

up to 24 ‘amplicons’ (tandemly repeated copies) in invasive BC

many genes amplified simultaneously

17q12-22 (“HER2 amplicon”) contains HER2, amplicon and Top2A, TSG (responsive to anticyclins)

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28
Q

changes in chr number

A

common

advanced tumours

significance uncertain

29
Q

epigenetic modification

A

common mechanism of genetic change

reversible

methylation of DNA and histone acetylation

regulates expression of many genes e.g. ER, PR, p16, p21, BRCA1

30
Q

point mutations

A

E-cadherin (CDH1) mutated in lobular carcinomas (putative TSG)

discrete point mutations are more common in hereditary BC

BRCA1 and BRCA2 - TSGs, transcriptional regulation, repair of double strand breaks

TP53 - TSG, guardian of genome, mutated in > 50% of BCs

Checkpoint Kinase 2 (CHEK2) - cell cycle TSG - DNA repair and cell cycle arrest

31
Q

micro-RNAs

A

non-coding ss RNA

contribute to post-transcriptional gene silencing by binding to mRNA

altered in BC by e.g. amplification, deletion

affect expression of many gene products e.g. ER, p27, Bcl-2

Abhorrently expressed in cancer, they can function as TUMOUR SUPPRESSORS and/or ONCOGENES

Oncogenes - oncomeres/oncomicroRNAs

32
Q

chr translocations in cancer - chimeric oncogenes

A

can create chimeric oncogenes (neomorphic) - Take a protoncogene and move it to another position in chromosome - usually a fusion protein with another gene

e. g. Philadelphia chr (Ph1: (t9;22)) - BCR-ABL in CML - constitutively active ABL tyrosine kinase - growth signal
e. g. PML-RARα fusion (t15;17) in APML - blocks PML TSG function and retinoic acid induced myeloid differentiation

33
Q

chr translocations in cancer - transcriptionally upregulated oncogenes

A

e.g. MYC oncogene in Burkitt lymphoma (t8;14) or occasionally (t8;2, t8;22)

MYC oncogene moved to IGH (Ig heavy chain) region (chr 14)

MYC overexpression in lymphocytes (high expression from IGH promoter)

constitutive B lymphocyte activation - characteristic lymphoma tumour in jaw

34
Q

things to remember

A
35
Q

learning outcomes

A
36
Q
A

hypermorphic - GOF - new or stronger expression

37
Q

symptoms of RB

A

white reflection in eye - leukocoria

strabismus - cross-eyed

38
Q

hereditary cancer syndromes ⇒

A

first hit in a TSG is inherited as a constitutional mutation

e.g. hereditary. RB - OMIM 180200

39
Q

gene - hereditary RB

A

RB1 TS gene on 1 copy of chr 13q14 in all cells (including retina)

subsequent 2nd hit in RB1 in retinal cells lead to retinoblastoma tumour

sporadic form of RB where 2 hits occur de novo (somatic) - 2/3 of cases

40
Q

sporadic RB difference

A

2/3 of cases

tumours are generally. UNILATERAL

in hereditary RB, tumours are BILATERAL or MULTIPLE PER EYE (multifocal)

41
Q

tumour suppressor gene

A

typically need change in both alleles for malignant transformation

recessive amorph/hypomorphic (LOF) mutations

42
Q

Knudson’s 2 hit hypothesis

A
43
Q

loss of heterozygosity

A

a TSG locus that is heterozygous in a normal cell becomes homozygous or hemizygous (lose good allele and only left with bad one) in derived cancer cell

most important mechanism of 2nd hit in hereditary cancer syndromes

44
Q

how does LOH occur

A

acquired UPD - copy neutral

monosomy (by nondisjunction) - hemizygous

gene conversion (copy neutral) - hybrid chr

mitotic recombination between parental homologs (copy neutral)

deletion

45
Q
A
46
Q

inactivating mechanisms in 2nd hit

A
47
Q

proportion of children with RB with a +ve family history

A

10% - 95% risk for RB

48
Q

de novo mutation for RB

A

in the parental (USUALLY PATERNAL) germ line accounts for the other (3/4) of hereditary retinoblastoma

49
Q

what are hereditary cancer syndrome patients also prone to

A

other forms of cancer

for RB this includes pineoblastoma, osteosarcoma and melanoma

50
Q

3 other hereditary cancer syndromes

A

familial adenomatous polyposis

Lynch syndrome - hereditary non polyposis colon cancer - HNPCC

Li-Fraumeni syndrome

51
Q

FAP

gene

symptoms

A

OMIM 175100 - APC - chr5q21

colon polyps that become malignant at 40

extracolonic manifestations

52
Q

Lynch syndrome

A

HNPCC

usually MLH1 (chr3p22) or MSH2 (chr2p21)

early age of onset (44) colon cancer, often multiple tumours and often multiple forms of cancer

53
Q

Li-Fraumeni syndrome

A

OMIM 151623 - TP53 - chr17p13

multiple forms of cancer

50% have cancer by 30, 90% by 65

54
Q

are hereditary syndromes inherited in a dominant or recessive pattern

A

DOMINANT, even though technically recessive

1 hit already there

Increased chance because mutations occur all the time

What would usually be recessive becomes dominant because if you already have 1 hit then you don’t have a good allele to balance it

55
Q

hereditary BC - 5% of BC

suggested if multiple 1st degree relatives affected

germline mutations in cancer susceptible genes

A
56
Q

cancer susceptibility genes

A

BRCA1 or 2 - mutations in 25% HBC

others: ATM, CHEK2, p53, PTEN, LKB1

many susceptibility genes unknown

57
Q

BRCA1 - type of gene

A

TSG

germ line inherited non-functioning allele in 1 homolog of chr 17

subsequent somatic mutation in BRCA1 in the other homolog of chr 17 of 1 breast cell

potential for neoplastic transformation

58
Q

summary of BC

A

multiple mutations must accrue for cancer to develop

59
Q

cancer progression - the result of

importance of balance

A

cancer is the result of the accumulation of several genetic and chr changes

often accompanied by reversible epigenetic modifications which perturb the function of 100s-1000s of genes

impact cellular control pathways

BALANCE

uncontrolled growth (tumour) is common and not equal to cancer

if balance between cell division/growth and apoptosis is disrupted can get undifferentiated tumour - more likely to become malignant

60
Q

match the cancer to the oncogene

A
61
Q

should screening for BRCA1/BRCA2 be encouraged to prevent breast cancer

A
62
Q

BreastCheck Screening in Ireland

A

US

Tumour found - staging - TNM, type of tumour, is it in any lymph nodes, biopsy (look under microscope - how poorly differentiated it is)

63
Q

BC - molecular (gene expression) profiling

A

evaluation of multiple genes/proteins in parallel

ER, PR, HER2 etc

expressive microarray profiling, quantitative RT-PCR for multiple genes e.g. oncotype DX

genome sequencing

immunohistochemistry

basic science + high throughput clinical studies

helps to guide patient management - surgery? Radiation? Hormone therapy? Chemo?

64
Q

how does NGS work

A
65
Q

RNA sequencing (NGS)

A
66
Q

whole exome sequencing

A
67
Q

NGS allows for

A

personalised medicine

causation

progression

recurrence

treatment response

risk prediction

therapeutic development

68
Q

challenges of NGS in clinical medicine and public health

A
69
Q

things to remember

A

GGE (33 decks)

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