Week 4 Flashcards

1
Q

Epidemiology ovarian cancer

A

Incidence- around 160000 new patients/year worldwide
Mortality is high- at best 30% 10 year survival

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2
Q

What do i need to know

A

1 in 2 adults will be diagnosed with cancer in lifetime
Large national screening programs- cervix, lung, breast, colorectal
Multiple specialities involved in cancer care- radiology/laboratory medicine/ surgery/ oncology/pain/palliative care/community care
Cancer contributes to multimorbidity

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3
Q

Cancer impacts more than health

A

It affects all aspects of a patients life
-work/school
-relationships/friendships
-finances
A diagnosis of cancer affects the patient but also friends and family
Holistic care of patient and family are key features of good cancer care

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4
Q

Basic uk facts on incidence

A

~375000 new cases of cancer/year
-36% are diagnosed in people ages 75 and over
-incidence rates for all cancers combined in the UK are highest in people aged 85 to 89
-estimated around 506000 new cases of all cancers combined every year in the UK by 2038-2040
Uk incidence is ranked higher than three quarters of Europe
Uk incidence is ranked higher than 90% of the world
Breast, prostate, lung, bowel cancers together accounted for more than half of all new cancer cases

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5
Q

Basic UK facts on mortality and survival

A

167142 deaths/year
-lung, bowel, breast and prostate cancers together accounted for almost half of all cancer deaths (~20% lung cancer)
-accounts for 1 in 4 deaths in the UK (2017)
-cancer causes more than one in four of all deaths 2020 UK
On average 50% of patients diagnosed with cancer survive over 10 years
-cancer survival in the UK has doubled in the last 50years
-survival rate dependent on cancer type; range 1-98%

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6
Q

worldwide cancer picture

A

There were 18.1 million new cases of cancer worldwide in 2020 it is estimated
Estimated 10 million deaths
A third contributed to by smoking
The 4 most common cancers occurring worldwide are female breast, lung, bowel and prostate cancer- more than 4 in 10 of all cancers diagnosed worldwide
Lung, bowel, liver and stomach are the most common causes of cancer death worldwide- more than 4 in 10 of all cancer deaths

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7
Q

Almost half of adult cancers are diagnosed at a late stage

A

Patients arrive at diagnosis by different pathways
Symptoms: may be specific to one cancer eg enlarged lymph nodes, may be non-specific eg weight loss, anorexia
Screened: a test given to a person with no symptoms of a disease- eg PAP (cervical) smears, FIT, PSA tests and mammograms
Incidental: picked up whilst investigating another symptom

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8
Q

Making a cancer diagnosis

A

Cancers are diagnosed by:
-history and clinical examination
-imaging eg X-rays or CT scanning or ultrasound
-blood tests- cancer biomarkers
Tissue biopsy and histological assessment
Most cancers require histological confirmation/assessment before treatment is initiated

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9
Q

Symptomatic diagnosis common symptoms that might suggest cancer- RED FLAG symptoms

A

Change in bowel or bladder habits: stomach, pancreatic, colon and ovarian cancers may change the bowel and bladder habits
A sore that doesn’t heal- unusual shape, border and crusts with a foul smelling discharge
Unusual bleeding- blood when passing urine or stools may be a warning sign of kidney, bladder and intestine cancers
Breast lump or thickening: any mass or growth in the breasts sometimes may be painful and contain blood or fluid
Indigestion or difficulty swallowing: a constant feeling of having a lump in the throat or difficulty in swallowing
Extreme fever with night sweats
Persistent cough or hoarseness: with or without chest pain, fatigue and shortness of breath

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10
Q

Examination- signs

A

Lumps
Ulcers that aren’t healing
Abdominal distension
Nodal masses
DVT

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11
Q

Lung cancer major presenting symptoms

A

Breathlessness, cough, pain, loss of appetite, coughing up blood

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12
Q

What do we explore in the history when lung cancer is suspected

A

Smoking and occupational exposure:
-no of cigarettes/day/risk of death from cancer
-chromium, arsenic, asbestos
Characterise the symptoms:
-has anything changed recently
—eg worsening of existing cough
-anorexia, weight loss, extreme fatigue
—indicate advanced (usually unresectable) disease

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13
Q

What do we look for on examination when lung cancer is suspected

A

Signs of metastatic disease: eg brain, bone , liver
Signs attributable to local spread: eg superior vena cava obstruction, horners syndrome, pancoast syndrome, pleural effusion, lymph nodes
Signs attributable to ectopic hormone production: eg Cushing’s syndrome from ACTH secretion
Non-specific cancer- related symptoms: weight loss and cachexia

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14
Q

What do we explore in the history when colon cancer is suspected

A

Is there a family history
Characterise presenting symptoms:
-how long
-what’s changed recently , weight
Ask directly about expected symptoms. Blood in motions

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15
Q

Major presenting symptoms colorectal cancer

A

A change in bowel habits: diarrhoea, constipation
Bright red or dark blood in the stool
Discomfort in the abdomen, bloating and cramps
Unexplained weight loss or anaemia (iron deficiency)

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16
Q

What do we explore on examination when colorectal cancer is suspected

A

Palpable mass in abdomen
Palpable mass/blood per rectum
Enlarged (lumpy) liver

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17
Q

Imaging modalities

A

Ultrasound scan
CT scan
MRI scan
Radioisotope scans:
-bone scans
-PET scans
-MIBG scans (neuroblastoma)

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18
Q

Tissue biopsy

A

Core
Fine needle
Surgical
-percutaneous, or via a ‘scope’.. colonoscopy, bronchoscopy, cystescopy etc

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19
Q

Tumour markers

A

In standard clinical practice:
-alpha-fetoprotein AFP
-cancer antigen 125 (CA125)
-cancer antigen 15-3 (CA15-3)
-carbohydrate antigen 19-9 (CA19-9)
-carcinogembryonic antigen (CEA)
-human chorionic gonadotropin (hCG or beta-hCG)
-prostate-specific antigen (PSA)
-urinary catecholamines
In experimental development
-circulating tumour cells (CTCs)
-circulation tumour DNA (ctDNA)

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20
Q

Early diagnosis improves outcomes

A

WHO steps to early diagnosis
-increasing patient awareness and accessing care
-clinical evaluation, diagnosis and staging
-access to treatment
Barriers exists at every step contributing to delays in diagnosis

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21
Q

How can we encourage early diagnosis

A

National screening programmes
-breast, bowel, cervical cancer screening
Early recognition of cancer related symptoms
-public awareness campaigns
-primary care awareness
Rapid referral and access to diagnostics

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22
Q

Increasing awareness in primary care

A

Often patients present to GPs with non specific symptoms
Signs of cancer may also not be clear or obvious
An average GP:
-has between 6000-8000 appointments/year
-sees ~8 new cancer cases/year
-has around 10 minutes per appointment to pick out warning signs that could be cancer but equally may be a symptom of a less serious condition
NICE guideline based on symptoms:
-to make its recommendations easier for GPs to use
-recommendations organised by symptoms which should prompt a 2 week wait referral and further investigation in primary care and safety netting in primary care

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23
Q

Cancer waiting times, UK countries

A

Performance standard should be 93% for a 2 week wait
2014/2015 the performance was above average 94.2%
However once patient has been sent to specialist and investigations have been started then receipt of the first treatment should be within 31 days and 62 days within the first referral
For the most part we are not meeting these targets in UK

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24
Q

Before treatment we must determine the extent of the disease

A

Staging
Categories patients into groups according to the extent of their disease
Important for:
-prognosis
-planning treatment

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25
Q

Treatment of cancer

A

Early localised disease can often be cured by surgery or radiotherapy
Importance of early diagnosis
Treatment of metastatic disease- needs a systemic approach- chemotherapy/targeted therapy/ immunotherapy
Cost of cancer care to health systems that focus on treatment of advanced disease rather than screening and prevention and early detection

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26
Q

Staging of colorectal cancer

A

Stage 1- cancer in situ located in mucosa
Stage 2- through the mucosa and invaded the muscularis
Stage 3- beyond the muscularis of the colon or rectum but has not spread to the lymph nodes
Stage 4- cancer has spread to regional lymph nodes

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27
Q

the TNM staging system

A

T-size of the primary tumour: T1(invades mucosa), T2(invades muscularis propria), T3(invades subserosa), T4(invades other organs)
N- status of lymph node metastases. No(no node metastasis), N1(1-3 pericolic nodes), N2 (>pericolic nodes), N3 (vascular trunk nodes)
M-presence or absence of metastases. Mo (no metastasis), M1- distant metastasis
G-the histological grade of tumour
Not applicable to all cancers. Eg haematological malignancies and some paediatric cancers

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28
Q

Treatment of cancer

A

Treatment modalities:
-surgery
-radiotherapy
-chemotherapy
—cytotoxics drugs
—small molecule targeted drugs
—immunotherapeutics
Aim of treatment: curative vs palliative
Multidisciplinary team approach

29
Q

The concept of adjuvant (chemo) therapy

A

Neo adjuvant-> surgery, radiotherapy-> adjuvant
Neoadjuvant- shrinks tumour to encompass RT or to make surgery feasible, deals with metastatic disease
Surgery/radiotherapy - deals with bulk of disease
Adjuvant- deals with low volume residual disease

30
Q

Systemic treatments

A

Conventional cytotoxic agents:
-eg cisplatinum, doxorubicin, 5-fluorouracil
-target readily dividing cells
-relatively non-specific and therefore ‘toxic’
-but many great successes and still widely used
Targeted agents: often paired with a biomarker that identifies cohorts with increased chance of response ‘personalised medicine’
-rationally developed
-relatively specific with different toxicities, ie imatinib for CML
Immunotherapies:
-monoclonal antibodies (conjugated and unconjugated)
-checkpoint inhibitors
-oncolytic vaccines
-CAR-T cell therapy

31
Q

Stratified/personalised medicine

A

The right treatment for the right patient
Finding the golden key, the genetic lesions to which the tumour is addicted

32
Q

Example of personalised medicine: national lung matrix trial

A

Trial where patients with lung cancer were biopsied at diagnosis and then tumours screened for molecular targets
They started with getting conventional cytotoxic chemotherapy and if this fails they enter into trial to go into multiple arms that target specific molecular target with the aim of looking at resistant types of lung cancer and seeing if it can be treated based entirely on its specific molecular signature

33
Q

Palliative care

A

“Adding life to days when we can’t add days to life”
Good death- well managed and pain free

34
Q

Palliative care is multi-faceted

A

Skilled symptomatic treatment
-pain, nausea, and vomiting
Good communication: simple straight forward information, sympathetic listening
Leaving a patient in control of his own life for as long as possible

35
Q

How does damage to the DNA occur

A

Copying errors during DNA replication
Spontaneous depurination
Exposure to different agents:
-background ionising radiation
-UV light
-tobacco products

36
Q

What is a DNA adduct

A

A segment of DNA bound to cancer-causing chemical

37
Q

Five major types of DNA repair

A

Direct reversal of damage
Base excision- corrects DAN damage caused by reactive oxygen species deamination, hydroxylation, spontaneous depurination
Nucleotide excision repair- removes adducts that produce large distortions in DNA
Homologous recombination repair and non homologous end joining- repairs DNA double strand breaks
DNA mismatch repair- repairs copy errors made during replication

38
Q

7-methyl-guanine

A

Where the guanine base is methylated on the 7 position
This is typical sort of damage to the base
Methylation is caused by drugs eg alkylating drugs used to treat cancer
-the idea of treatment with these drugs is to kill the cell by damaging the DNA

39
Q

Ethyl methane sulphonate

A

Is a drug (mutagen) that can cause this
It causes an alkylation on the O6 position of guanine
This changes the pairing of guanine with cytosine to guanine and thymine
At the next round of replication, the guanine on the first strand will pair with thymine again whilst thymine on other strand will pair with adenine
Therefore overall transition from G:C-> A:T

40
Q

DNA damage

A

7-methyl guanine causes a large distortion in the DNA
This causes a problem at DNA replication, the cell dies
This is ok as long as the overall dose is not large to cause death of the whole organism
O-6 alkyl guanine does not result in cell death but is mutagenic- this is dangerous

41
Q

UV induced DNA lesions

A

The major forms of damage induced by sunshine, UV light are:
-thymine dimers (CPD)
-(6-4) photoproducts
Mechanism:
-adjacent thymine bases in presence of UV light become covalently linked to form a cyclobutane ring (thymine dimer), this causes major distortion in the DNA and causes difficulties at replication
-this a mutagenic lesion

42
Q

Thymine dimer from UV light

A

Cyclobutane ring causes distortion in DNA so sticks out in DNA structure

43
Q

DNA repair

A

Cells have several repair systems which are usually constitutive
More than 200 genes are believed to be involved in DNA repair in man
There are many different substrates for repair systems
Broadly speaking repair involves either:
-enzymatic reversal
-removal and replacement of damage

44
Q

Enzymatic reversal

A

UV induced dimers undergo monomerisation by action of visible light and photolyase
O6 alkyl guanine - alkyl transferase- removal of alkyl group
Strand breaks in sugar-phosphate backbone- ligation

45
Q

Base excision repair BER

A

Substrates:
-spontaneous hydrolytic depurination of DNA
-deamination of cytosine
-formation of DNA adducts after exposure to reactive small metabolites
Process:
-removal of base via DNA glycosylase (breaks glycosyl bone between base and sugar)
-the resulting Abasic site is corrected by the concerted action of apurinic endonuclease, removal of apurinic site
-addition of new nucleotides via DNA polymerase
-ligation via DNA ligase

46
Q

Removal and replacement of damage

A

Removal of base
Removal of apurinic site (sugar and phosphate)
Addition of new nucleotides
Ligation

47
Q

DNA glycosylases

A

There are many glycosylases
- for 7-methyl-guanine: N-methylpurine-DNA glycosylase (MPG)
-for 8-oxo-guanine: OGG1
-for 3-methyl-adenine: N-methylpurine-DNA glycosylase MPG
-for uracil incorporation into DNA: UNG1, UNG2

48
Q

Nucleotide excision repair NER

A

Operates on double stranded DNA
Cannot act on single stranded DNA eg does not act during DNA synthesis
Non specific. It recognises distortions rather than specific adducts via glycosylases
Will remove and repair large adducts eg thymidine dimers
Very efficient and error free
Principle:
-endonuclease- chops DNA on one side of dimer and then chop other side of dimer
-exonuclease- removes several or tens of nucleotides
-polymerase- fills gap with new nucleotides using other strand as template
-ligase- ligates both ends

49
Q

Xeroderma pigmentosum

A

Autosomal recessive disorder (1-4 per million)
Patients show extreme sun sensitivity
Patients develop many skin tumours (may be hundreds)
Neurological abnormality in some patients
Cultured skin fibroblasts show increased sensitivity to UV light
Cells can be shown to have a defect in DNA nucleotide excision repair

50
Q

Repair (unscheduled DNA synthesis- UDS) following UV exposure

A

Was a diagnostic assay for XP
Take cells expose to UV light and give radiolablled nucleotides
When get the fill in step the cell incorporates radio labelled nucleotides
Defect in XP: in excision deficient XP patients there is a failure to excise the damage. Therefore the thymine dimer remains in situ- potential for mutation during subsequent replication

51
Q

Xeroderma pigmentosum forms

A

8 different forms
All have different levels of DNA repair
All forms have a defect in nucleotide excision repair
However the variant form is different: has same clinical features but underlying reason is different- they have same defect in daughter strand gap repair

52
Q

Nucleotide excision repair NER

A

NER on double stranded piece of DNA that contains a cyclobutane ring
XPC (protein product) important in recognising this dimer
XPC recognises it in context of XPE protein
XPC proceeds to bind to dimer
This allows recruitment of a TF called TF2H complex which contains 2 important proteins (XPB and XPD)
These now together with XPA come to site of dimer
XPA is responsible for damage verification
XPB and XPD are helicases that unwind the DNA - one works in one direction other the opposite (3’-5’ vs 5’-3’)
We now have unwinding of DNA and exposure of thymine dimer
No recruit two more protein components XPF and XPG
These are nucleases which cut at one side and the other of the length of DNA around 20 bases long
We now have removed piece of DNA containing dimer
Recruitment DNA polymerase and accessory factors required to re synthesise DNA across excised region

53
Q

Mutation and cancer in XP

A

XP cells show a high mutation rate
Mutation probably due to unexcised dimers and therefore incorrect bases incorporated opposite damage
This mutation represents a step towards cancer development

54
Q

Mutations of PTCH1 gene (basal cell naevus syndrome)

A

Occurs without person having been exposed to UV light
Lots of basal cell carcinoma
Caused by inheritance of a mutated PTCH1 gene
In 20-30% of sporadic basal cell carcinoma BCC
73% of BCCs from XP patients have mutations in PTCH1

55
Q

Daughter strand gap repair

A

Part of double stranded DNA is exposed to UV light -> thymine dimers formed on ds DNA
If this then goes through replication you get a replication fork
You get replication of each new strand in opposite directions
However in every region there is a thymine dimer no new bases are added during replication
Later on gap gets filled but still gap at end replication
Alternative polymerase used for lesion bypass
Dimers remain after repair
A tolerance mechanism
Dimers removed later from double stranded DNA by excision repair

56
Q

XP variants

A

Not deficient in nucleotide excision repair NER
Not very sensitive to killing by UV but cells are hyper mutable by UV
Sensitivity to UV can be enhanced by caffeine
Defect in replication of DNA following UV exposure of cells (daughter strand gap repair)
Deficient in an enzyme DNA polymerase eta (hRad30) which is able to replicate DNA past UV photoproducts- translesion synthesis

57
Q

Repair of DNA double strand breaks

A

Caused by errors in replication
Reactive oxygen species (cellular metabolism)
BRCA1 and BRCA2

58
Q

BRCA1 and BRCA2- 2 very different primary sequences

A

BRCA2- there are BRC motifs (about 8) which bind to rad51. These are not present in BRCA1
BRCA1 BRCA1 C-terminal= BRCT ~110aa
BRCT domains are found in many repair proteins- as pairs or with an FHA domain

59
Q

BRCA1 and BRCA2 in the cellular response to DNA damage

A

Increased sensitivity to gamma rays: this means there is a defect in DNA ds break repair
Increased gamma ray sensitivity of BRCA 1 and 2 -/- (null) human cells and BRCA 1 and 2 deficient mice suggests that these proteins are involved in the repair of DNA ds break

60
Q

BRCA1 and BRCA2 in the cellular response to DNA damage

A

DNA double strand breaks are repaired by two processes
Non-homologous end joining
Homologous recombination repair (BRCA1/2 are involved here)

61
Q

Homologous recombination repair

A

Catalytic activity of Rad51 is central to this form of DNA DSB repair
Rad51 coats ssDNA to form nucleoprotein filament that invades and pairs with homologous DNA duplex->initiating strand exchange
Availability and activity of Rad51 is regulated by BRCA2
BRCA2 shows direct interaction with Rad51
Binding of Rad51 occurs through the 8 BRC repeats in BRCA2
BRCA2 controls intracellular movement and function of Rad51
Release of Rad51 triggered by DNA damage by phosphorylation of Rad51 or BRCA2
BRCA1 is also required for HRR (homologous recombination repair)
Mechanism through interaction with and removal of 53BP1 at sites of DSB prior to resection and recombination

62
Q

Although both BRCA1 and BRCA2 are involved in DNA damage responses their roles are different

A

Involvement of BRCA2 may be thought of occurring quite specifically through control of the Rad51 recombinase in homologous recombination (DNA DSB repair)
Involvement of BRCA1 occurs on a much wider front: but links upstream sensing/signalling of damage, through 53BP1 in recombination repair
BRCA1 has also has roles in cell cycle checkpoints
Cell deficient in BRCA1/2 are unusually sensitive to PARP inhibitors

63
Q

PARP inhibitors

A

Unrepaired SSBs can lead to the formation of DSBs due to collapsing replication forks
Treating cells with inhibitors of SSBR will increase the number of DNA double strand breaks produced during normal DNA synthesis
DNA DSBs generated during DNA synthesis are repaired with HR due to the presence of a homologous template

64
Q

Treating HRR deficient tumour cells with PARP1 inhibitors

A

PARP auto ADP ribosylation is required to remove PARP from a DNA lesion
PARP inhibitors trap PARP on DNA which blocks DNA replication. Removal of trapped PARP1/2 requires DNA end processing and homologous recombination repair of a DSBs that arise as a consequence of replication fork collapse

65
Q

Non homologous end joining

A

DNA DSB repair also occurs via a second repair process- Non homologous end joining
DNA double strand break formation and resolution is part of one particular normal cellular process
Formation of antibodies (B lymphocytes) and T cell receptor (T lymphocytes)
V(D)J recombination-undertaken by components of NHEJ system
Rad51 independent
BRCA2 is not required for DNA DSB by NHEJ
V(D)J recombination is normal in BRCA deficient mice
NHEJ is an error prone process

66
Q

DNA mismatch repair

A

Repairs copy errors made during DNA replication

67
Q

HNPCC (hereditary non polyposis colorectal cancer)

A

Mutation in mismatch repair gene
-repairs base-base mismatches
-repairs insertion deletion loops which arise as a consequence of polymerase ‘slippage’ during replication. Slippage causes gains or losses in repetitive DNA eg (C-A)n
Also called microsatellite instability (MSI)
Genes that have microsatellites in their coding region have an increased risk of mutation in HNPCC
Most frequently mutated genes are MLH1, MSH2, MSH6

68
Q

Mutator phenotype hypothesis

A

Microsatellite instability- led to ‘mutator phenotype’ hypothesis
Postulates that mismatch repair defects lead to mutation in other genes, including those known to play a role in the adenoma-carcinoma sequence
Therefore the increased mutation rate is then the cause of accelerated tumorigenesis
The mutator phenotype plays a role in tumour progression rather than in initiation

69
Q

Microsatellite instability

A

Frameshift mutations have been observed in different genes all affecting growth, in HNPCC cancers
TGF-betaRII, TCF4, IGF2R, BAX, MSH6, MSH3