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Genetics 10 - Cancer & Genomic Medicine (lessons) Flashcards

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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
triple -ve BC
negative for oestrogen receptors, progesterone receptors and excess HER2 protein
26
common mechanisms of genetic change in BC
1. amplification of DNA sequences 2. changes in chr number (aneuploidy) 3. epigenetic modification 4. point mutations 5. changes in micro-RNA regulation
27
amplification
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)
28
changes in chr number
common advanced tumours significance uncertain
29
epigenetic modification
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
point mutations
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
micro-RNAs
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
chr translocations in cancer - chimeric oncogenes
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
chr translocations in cancer - transcriptionally upregulated oncogenes
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
things to remember
35
learning outcomes
36
hypermorphic - GOF - new or stronger expression
37
symptoms of RB
white reflection in eye - leukocoria strabismus - cross-eyed
38
hereditary cancer syndromes ⇒
first hit in a TSG is inherited as a constitutional mutation e.g. hereditary. RB - OMIM 180200
39
gene - hereditary RB
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
sporadic RB difference
2/3 of cases tumours are generally. UNILATERAL in hereditary RB, tumours are BILATERAL or MULTIPLE PER EYE (multifocal)
41
tumour suppressor gene
typically need change in both alleles for malignant transformation recessive amorph/hypomorphic (LOF) mutations
42
Knudson's 2 hit hypothesis
43
loss of heterozygosity
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
how does LOH occur
acquired UPD - copy neutral monosomy (by nondisjunction) - hemizygous gene conversion (copy neutral) - hybrid chr mitotic recombination between parental homologs (copy neutral) deletion
45
46
inactivating mechanisms in 2nd hit
47
proportion of children with RB with a +ve family history
10% - 95% risk for RB
48
de novo mutation for RB
in the parental (USUALLY PATERNAL) germ line accounts for the other (3/4) of hereditary retinoblastoma
49
what are hereditary cancer syndrome patients also prone to
other forms of cancer for RB this includes pineoblastoma, osteosarcoma and melanoma
50
3 other hereditary cancer syndromes
familial adenomatous polyposis Lynch syndrome - hereditary non polyposis colon cancer - HNPCC Li-Fraumeni syndrome
51
FAP gene symptoms
OMIM 175100 - APC - chr5q21 colon polyps that become malignant at 40 extracolonic manifestations
52
Lynch syndrome
HNPCC usually MLH1 (chr3p22) or MSH2 (chr2p21) early age of onset (44) colon cancer, often multiple tumours and often multiple forms of cancer
53
Li-Fraumeni syndrome
OMIM 151623 - TP53 - chr17p13 multiple forms of cancer 50% have cancer by 30, 90% by 65
54
are hereditary syndromes inherited in a dominant or recessive pattern
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
hereditary BC - 5% of BC suggested if multiple 1st degree relatives affected germline mutations in cancer susceptible genes
56
cancer susceptibility genes
BRCA1 or 2 - mutations in 25% HBC others: ATM, CHEK2, p53, PTEN, LKB1 many susceptibility genes unknown
57
BRCA1 - type of gene
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
summary of BC
multiple mutations must accrue for cancer to develop
59
cancer progression - the result of importance of balance
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
match the cancer to the oncogene
61
should screening for BRCA1/BRCA2 be encouraged to prevent breast cancer
62
BreastCheck Screening in Ireland
US Tumour found - staging - TNM, type of tumour, is it in any lymph nodes, biopsy (look under microscope - how poorly differentiated it is)
63
BC - molecular (gene expression) profiling
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
how does NGS work
65
RNA sequencing (NGS)
66
whole exome sequencing
67
NGS allows for
personalised medicine causation progression recurrence treatment response risk prediction therapeutic development
68
challenges of NGS in clinical medicine and public health
69
things to remember

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