This document discusses principles of oncology including cell number control, growth disorders, cancer classification, tumor spread and metastasis, stages of cancer, and an overview of carcinogenesis. It defines key terms like neoplasia, benign and malignant tumors, dysplasia, carcinoma and sarcoma. It also summarizes the hallmarks of cancer including self-sufficiency in growth signals, evasion of apoptosis, unlimited replicative potential, sustained angiogenesis, and genetic instability.
2. 2
CELL NUMBER CONTROL
Cell number is the
balance of:
• cell production (due to proliferation via
the cell cycle)
and
• cell loss via a number of means including
cell death by the process of apoptosis
5. 5
Perspective
• About 250,000 people every year are
diagnosed with cancer in the UK:
– about 120,000 die every year
– about 1 in 3 of all deaths.
• The annual cost of diagnosing and
treating cancer is about £1.5 billion for
the NHS every year.
6. 6
Basic definitions
Rupert Willis 1930s A neoplasm
• is an abnormal mass of tissue,
• the growth of which is uncoordinated with that of
normal tissues,
• and that persists in the same excessive manner after
the cessation of the stimulus which evoked the
change“
An important additional component is
• "the presence of genetic alterations that alter cell
growth"
7. 7
Basic definition
An alternative OPERATIONAL definition
of neoplasia is;
"a growth disorder characterised by
genetic alterations that lead to loss of
the normal control mechanisms that
regulate cell growth, morphogenesis and
differentiation"
8. 8
DYSPLASIA
• A spectrum of abnormal growth
conditions with many of the
morphological and genetic changes of
neoplasia BUT without any invasion of
spread
• Half way to neoplasia
9. 9
DYSPLASIA IN THE COLON
Associated sometimes with the
formation of polyps
Can be flat
Pre malignant
Associated with some familial
types of colon cancer
FAP or Familial Adenomatous Polyposis
Also associated with inflammatory
bowel disease
10. 10
DYSPLASIA IN THE CERVIX
Abnormal maturation of squamous epithelial cells
Associated with HPV infection
Varying degrees of abnormality . . . . .
. . . . ultimately can become invasive and become a frank
CARCINOMA
11. 11
The purpose of classification
• is to provide an aid to diagnosis
• to allow the accurate exchange of information
• to define clinical sub-groups who have
different biological or clinical features
– will benefit from particular types of treatment
– have different outcomes (prognosis)
– to facilitate epidemiological analysis
12. 12
Why is classification important?
PRECISE CLASSIFICATION
OF A NEOPLASM FROM A PATIENT
IS ESSENTIAL FOR THE
CORRECT AND APPROPRIATE
PLANNING OF TREATMENT
13. 13
Two key elements of
classification of a neoplasm
Behavioural
classification
• based upon the
probable behaviour
of a tumour
– E.g. benign or
malignant
Histogenetic
classification
• based upon the
presumed cell of
origin a tumour
– E.g. epithelium or
connective tissue
14. 14
Behavioural classification
• Spectrum of behaviour
e.g. benign or malignant
• Essentially a prediction of likely natural
history
• Pathologists use a range of morphological
features in an attempt to categorise a
tumour as benign or malignant
15. 15
Benign Malignant
Slow growing Variable and may be rapid
Few mitoses Variable but may be many mitoses
Usually resemble tissue of origin
Variable, but may only poorly
resemble tissue of origin
Nuclear morphology is usually normal
Nuclear morphology may be variable
and can be very abnormal with
hyperchromasia, pleomorphism and
nucleolomegaly
Usually have a well circumscribed or
encapsulated
Often poorly defined or irregular
Necrosis is rare Necrosis is common
Ulceration is rare Ulceration is common
Never invade May invade surrounding tissues
Never metastasise May metastasise
16. 16
Histogenetic classification
• Histogenesis refers to the presumed cell of origin of
a tumour
• Tumours from a specific histological tissue often
have microscopic features similar too that tissue
• The basis of this aspect of classification is
HISTOLOGY.
• Thus
– tumours arising in squamous epithelia have a squamous pattern
– tumours arising from the glandular epithelium of the gastro-
intestinal tract have a glandular pattern.
17. 17
Two main histogenetic sub
groups of malignant tumours
CARCINOMA SARCOMA
Derived from epithelium Derived from connective tissue
Always malignant Always malignant
Common Rare
Spread by lymphatics Spread by blood
May have a pre-malignant phase
(or in situ phase)
Not believed to have a pre-
malignant phase
Older patients Younger patients
19. 19
SUFFIXES
Suffix Meaning
-oma
Tumour (benign
or malignant)
-carcinoma
Epithelial
malignancy
-sarcoma
Connective
tissue
malignancy
-aemia
malignancy of
bone marrow
derived cells
(exceptions
exist eg.
anaemia)
20. 20
Grade
• the degree of differentiation of a tumour.
• It is the degree to which a tumour cell resembles its presumed
normal counterpart as assessed by its morphological appearances
by a pathologist.
• In general
– a low grade [or well differentiated] tumour has a less aggressive
course
– than a high grade [or poorly differentiated] tumour.
• ANAPLASTIC –
– This word implies that histological examination shows a very poorly
differentiated neoplasm that does not resemble any normal tissue.
– These tumours are always malignant and usually behave very
aggressively.
21. 21
Stage
Stage refers to the extent of spread
of a tumour.
Stage is informed by both
• clinical and radiological assessment (clinical
stage)
as well as
• pathological examination of surgical specimens
(pathological stage)
22. 22
Classification of epithelial tumours
• Benign tumours of epithelium
– Adenoma benign tumour of
glandular epithelium
– Papillomas benign tumour of
non-glandular epithelium
• Malignant tumours of epithelium
– These are always carcinomas.
– Qualifying terms needed like
• Adeno-carcinoma
• Transitional cell carcinoma
24. 24
THE PROBLEMS OF EXCEPTIONS . . . . . .
• For example
– MELANOMA
– MESOTHELIOMA
– LYMPHOMA
• EPONYMS
– Hodgkin's disease (a kind of lymphoma)
– Ewing's sarcoma (a malignant tumour of bone in children and
young people)
– Burkitt's lymphoma (a kind of lymphoma)
25. 25
Relevance
• Classification, grade and stage
• are important as they enable the
clinician to make some prediction of the
likely prognosis of a patient
AND
• are essential information for the logical
planning of treatment.
26. 26
A case history
• A 48 year old man presents with a history of
blood in his stool.
• He has lost weight (2 stone over 8 months).
• His brother had colon cancer a the age of 35.
27. 27
• On examination middle aged man with evidence of weight loss,
pale skin.
• Abdominal examination: ? Irregular liver edge and suggestion of
mass in lower abdomen
• Rectal examination: blood on finger but no mass
• Differential diagnosis:
– Piles
– Inflammatory bowel disease
– Diverticular disease
– Tumour
• Referred to Consultant Surgeon.
• Sigmoidoscopy shows a mass at 20 cm which is biopsied
28. 28
• Flexible sigmoidoscopy:
– mass in colon
– biopsy taken
• Histology of mass
– Glandular neoplasm
– Pleomorphism
– Invasion
• Surgery planned
– Resection of colon
31. 31
Why epidemiology is useful
• It allows you to gauge what is common and
what is rare
• It can provide clues to aetiology
• Can guide the provision of scarce resources
• Can facilitate planning of preventative
measures
• It underpins the development of screening
methods for early diagnosis
32. 32
A range of factors can influence the
epidemiology of a disease
• Age variation
• Gender differences
• Historical variation
• Geographic variation
• Social and economic factors
• Occupational factors
• Dietary factors
• Genetic factors
etc . . . . . . . .
33. 33
EPIDEMIOLOGY examples
• Ultraviolet light and skin cancer
• Asbestos and mesothelioma
• Smoking and lung cancer
• HPV, sexual activity and cervix cancer
• Malaria and Burkitt’s lymphoma
• Meat consumption and colon cancer
• Radiation and thyroid cancer
• Aniline dyes and bladder cancer
• Family history and many cancers
• Alcohol and cancer
• Hepatitis virus, aflatoxins and liver cancer
34. 34
Colorectal cancer as an example
Age Incidence increases rapidly with increasing age
Gender Affects both men and women
Historical variation Is becoming more common
Geographic variation
Associated with developed nations rather than
developing nations
Social and economic
factors
Can occur in all groups
Occupational factors None known
Dietary factors
Associated with a low fibre, high fat, high red meat
diet
Genetic factors
Familial forms well described including:-
1. Familial Adenomatous Polyposis or FAP (APC gene)
2. Hereditary non polyposis cancer (HNPCC) DNA
repair genes
BUT ALSO
3. Genes whose products are involved in metabolism of
carcinogens can increase the risk of neoplasia
38. 38
Why tumours cause problems
• grow
• press on structures
• ulcerate
• bleed
• cause loss of organ function
• invade locally
• spread to distant sites (metastasise)
• produce substances
– appropriate for the site
– inappropriate for the site
39. 39
• It is implicit from our definition of neoplasia
that neoplastic (or tumour) cells have lost
normal regulation of cell number control
• Tumours are usually clonal in origin
• From this single transformed cell tumours
grow
• 1 cm3 of tumour = ~ 1 gram = ~ 109 cells
40. 40
Clonality
• Tumours are usually clonal in origin (that is they arise
from neoplastic change in a single initial cell),
• But there are exceptions
• BUT NOTE not all cell populations that are clonal are
tumours!
42. 42
How tumours present
• A consequence of local disease
– (eg. grow, compression, ulcerate, bleed, destroy adjacent
structures)
• A consequence of distant spread
– (eg. grow, compression, ulcerate, bleed, destroy adjacent
structures)
• A non-metastatic manifestations of malignancy
– (paraneoplastic effects) including anaemia, skin changes,
neurological effects, inappropriate hormone production,
weight loss and fatigue.
- CACHEXIA or severe weight loss and debility.
• An incidental finding
– (eg. on screening or on routine medical examination)
43. 43
When thinking about a tumour
at a given anatomical site, it might be
A primary tumour that can be either
benign or malignant
or be a
a secondary deposit (a metastasis)
from another site
44. 44
Spread of tumours
• Metastasis is the process whereby malignant
tumour cells spread from
• their site of origin
– (known as the PRIMARY SITE or PRIMARY
TUMOUR)
• to some other distant site in the body
– (known as the SECONDARY SITE or
SECONDARY TUMOUR or SECONDARY
DEPOSIT or METASTASIS or METASTATIC
DEPOSIT)
45. 45
INVASION and METASTASIS
• The two properties that accounts for
most of the serious (and lethal)
consequences of neoplasia.
• Associated with
– increased cellular motility,
– the production of enzymes with proteolytic
activity and
– alterations in cell adhesion
48. 48
The process of metastasis . . . .
• Local growth
• Angiogenesis
• Further local growth
• Alteration in cell-cell and cell-matrix
adhesion and altered cell motility
• Remodelling and alteration of extra-cellular
matrix
• Leading to invasion and detachment
• Entry into lymphatic and/or blood vessels
• Survival in the lymph and/or blood
• Arrest at some distant site
• Survival at the distant site
. . . then repeat the whole sequence
• THE SPREAD OF
TUMOURS IS NOT
RANDOM
• DEPENDS ON FACTORS
RELATING TO BOTH
• SEED
(THE TUMOUR CELLS)
AND
• SOIL
(THE SITE OF SPREAD)
49. 49
STAGE
Stage refers to the extent of spread
of a tumour.
TNM System
• T How big the primary tumour is
• N Whether nodes are involved
• M Whether distant sites are involved
(eg. Liver or bone marrow)
50. 50
WHY IS STAGE SO IMPORTANT?
• Key determinant
of prognosis
• Key factor in determining type of treatment
options available
– Surgery
– Radiotherapy
– Chemotherapy
55. 55
Properties of tumour cells
1. Self-sufficiency in growth signals
2. Insensitivity to anti-growth signals
3. Evasion of apoptosis
4. Unrestricted replicative potential
5. Sustained angiogenesis
6. Tissue invasion and metastasis
7. Genetic instability
56. 56
Self-sufficiency in growth signals
• Normal cells depend on exogenous growth factors to
stimulate growth and cell proliferation.
• Tumour cells grow and divide without these signals.
• Why?
– because of mutations in genes that encode components of
the signalling pathways that normally regulate these
processes.
– Such mutations lead to constitutively active signalling
57. 57
Insensitivity to anti-growth signals
• Usually the growth and proliferation of cells is
controlled by a balance of growth promoting signals
and growth inhibitory (or anti-growth) signals.
• The loss of growth inhibitory signals or the loss of
the ability to respond to these signals is typical of
tumour cells.
58. 58
Evasion of apoptosis
• A critical component of normal cell number control is
apoptosis (programmed cell death).
• Apoptosis is also a mechanisms for the removal of
unwanted cells, for example those with significant
damage, including genetic damage.
• Tumour cells have often developed mutations in key
genes whose products are involved in apoptosis such
that cell death is blocked.
59. 59
Unrestricted replicative potential
• Normal cells can only divide a finite number of times.
• This was first shown by Hayflick in the 1960s
– normal human fibroblasts will divide about 70 times if taken
from a neonate,
– but 40 times from a middle aged person,
– and barely divide at all from an elderly person.
• Normal cells thus have a restricted replicative potential as a
consequence of a number of mechanisms.
• Tumour cells have an unrestricted replicative potential and just
carry on dividing!
• The role of telomerase
61. 61
Sustained angiogenesis
• Tumours will stop growing when they outgrow their
blood supply - without this they will have insufficient
nutrients and oxygen to sustain themselves – and
undergo ischaemia and infarction.
• Tumours overcome this problem by the production of
various factors that stimulate the formation of new
blood vessels.
62. 62
Tissue invasion & metastasis
• Normal cells remain where they are supposed to be
and normal tissue boundaries are maintained.
• Tumours are characterised by invasion into nearby
tissues and structures (ie. normal boundaries are not
maintained) and may spread to distant sites
(metastasis).
• These properties are the main reason why tumours
are such a significant clinical problem.
63. 63
Genetic instability
• Normal cells maintain the integrity of their genomes
• Mutation is a key feature of neoplasia
• Genetic instability is common in neoplasms.
• A characteristic feature of tumours, particularly
aggressive tumours, is the unstable nature of their
genomes.
– They often develop aneuploidy (abnormal DNA content) with
abnormal chromosomes and mutation is also common
– Hyperchromasia (densely staining)
– Pleomorphism (variable size & shape)
64. 64
Evidence that neoplasia is a genetic disease
1 Nuclear abnormalities are
common in tumours
– Hyperchromasia
– pleomorphism
2 Often see abnormal mitoses
3 Abnormal DNA content is
common in tumours
4 Chromosomal abnormalities are
common in tumours
– Some are specific to particular
tumour types
– Some are non-specific
65. 65
5 Nearly all carcinogens are
mutagens
6 Specific mutations in
growth control genes are
common in tumours
7 Genetic instability is a
characteristic feature of
tumours
8 Tumour cells breed true
Evidence that neoplasia is a genetic disease
M FISH – GMP lecture 10
66. 66
9 SOME CANCERS RUN IN FAMILIES
There are a number of familial forms of neoplasia.
That is genetic abnormalities in genes that
predispose to neoplasia that can be inherited.
Provide insights into the molecular events in
neoplasia
Evidence that neoplasia is a genetic disease
67. 67
TUMOUR PROGRESSION
• Clinical and experimental phenomenon
• With time tumours grow and successive
populations become increasingly abnormal,
accumulating more genetic abnormalities
(mutations)
• Associated with increasingly abnormal
appearance and behaviour
• Increasingly insensitive to growth inhibitory
signals, more resistant to apoptosis,
increasingly unstable etc.
71. 71
Molecular events in neoplasia
Exactly what genes are involved in neoplasia?
several hundred genes mutated in tumours have been identified
usually encode proteins involved in the kinds of process as being typical
of tumours.
• Self-sufficiency in growth signals
• Insensitivity to anti-growth signals
• Evasion of apoptosis
• Unrestricted replicative potential
• Sustained angiogenesis
• Tissue invasion and metastasis
We can call such genes 'CANCER CRITICAL GENES' :
meaning all genes whose mutation contributes to the causation and
progression of cancer.
73. 73
Cancer critical genes
There are two broad
categories of cancer
critical gene
• Oncogenes
• Tumour suppressor
genes
ONCOGENES
+
Cell number [or other
key cellular control]
-
TUMOUR SUPPRESSOR
GENES
74. 74
Cancer critical genes
Cancer critical genes
generally are involved
in cell cycle or cell
death processes
[Some are involved in
DNA repair]
ONCOGENES
Stimulate cell division OR inhibit cell death
+
Cell number [or other
Key cellular control]
-
Inhibit cell division or stimulate cell death
TUMOUR SUPPRESSOR GENES
75. 75
Oncogenes
Involved in cancer by an increased activity of the (proto)oncogene
stimulating an increase in cell number
Genetically dominant
Function like an accelerator
The gain of function of an oncogene product as a consequence
• of more of the gene product being expressed,
• or a mutation in the gene such that the resultant protein has increased
function,
• or expression occurring in the wrong cell type,
• or at the wrong time
leads to the stimulation of a critical cell process (such as the
cell cycle).
Examples include is the ras oncogene, myc oncogene, bcr-abl oncogene
76. 76
Tumour suppressor genes
Involved in cancer by a decreased activity of the tumour
suppressor gene leading to an increase in cell number
Genetically recessive
Functions like a brake
The loss of function of a tumour suppressor gene product as a consequence
• of less of the gene product being expressed,
• or a mutation in the gene such that the resultant protein has reduced
or loss of function,
• It is a genetically recessive event and requires the loss of both copies
of the tumour suppressor gene (as first proposed by Knudson in his 'two
hit hypothesis').
• Examples include the p53 gene, the APC gene and the Rb gene
77. 77
Understanding cancer critical genes:
an analogy
One Accelerator Two brakes
A foot on the accelerator can make you
go faster!
Oncogenes encode potential
accelerators of growth.
A single event is enough - it is
genetically dominant –
and involves GAIN OF FUNCTION
You have two brakes
If one stops working you can use the other.
If both stop working you cannot stop and will
accelerate.
Tumour suppressor genes usually encode the
brakes on cell growth –
loss of their function can lead to accelerated
growth - but it requires 2 events - loss of both
brakes.
You need LOSS OF FUNCTION of both alleles of a
tumour suppressor gene (genetically recessive)!
80. 80
erbB2 in breast and
ovarian cancer
(Neoplasia 6)
1. GENE AMPLIFICATION
Positive growth
signal
Receptor amplification
HSR=homogeneously staining region
81. 81
2. POINT MUTATIONS IN CODING SEQUENCE
Positive growth
signal
Receptor mutation
Mutations in oncogenes are
termed ‘gain of function or
activating mutations’
inappropriate expression of the
pathway eg. ras signalling
84. 84
Altered regulation: myc
gene over-expressed in
lymphoma
New gene formed: bcr-abl
with altered/new
properties
3. CHROMOSOMAL
REARRANGEMENTS
85. 85
Tumour suppressor genes
The Knudson Hypothesis
Knudson studies children
with an eye tumour called
retinoblastoma
2 groups of patients:-
• those with a family
history
• and those without (the
majority)
Familial form
• present earlier in
childhood
• often had bilateral
disease
• within an eye could be
multi-focal.
Sporadic
• presented later
• only had a single eye
involved.
86. 86
Tumour suppressor genes
The Knudson Hypothesis
For a tumour to develop Knudson proposed that:-
• a gene was involved
• mutations were needed in this gene (called the retinoblastoma
gene)
• normal people have two copies of this gene
• one inherited from the father and one from the mother
• Needed to have loss of function mutations in BOTH maternal
and paternal copies of the retinoblastoma gene
88. 88
Tumour suppressor genes
The Knudson Hypothesis
Sporadic form
• a mutation has to occur in both
copies of the retinoblastoma gene.
• If a single mutation could occur in
one in a 106 cells in a given period of
time then the probability of a
mutation occurring in both copies
would be one in 1012.
• ie. very rare.
• the longer the period of time that
elapses the more likely this is, but it
is unlikely to occur more than in one
cells. hence tumours occur late and
are unilateral.
Familial form
• the child inherits from one mutant
copy of the retinoblastoma gene.
• Since it still requires mutations in
both copies for a tumour to develop
then the probability of this is one in
a 106.
• This is a million times more likely
than in the sporadic form.
• the disease occurs earlier and also
there is a high probability of it
occurring in more than one cell, and
thus tumours may be multi-focal and
bilateral.
90. PEDIGREE OF THE FAMILIAL FORM OF RETINOBLASTOMA
• Disease status of 24 children & grandchildren descended from a
single male with retinoblastoma in childhood
• ~ 50% of his descendants developed disease (red)
• Proband did not develop disease but passed the susceptibility to 2 of
his children
• Proband is one of the small fraction (10%) with incomplete
penetrance 90
93. 93
p53 TSG
• Altered in more than 50% of human
cancers
• Involved in a pathway that responds to
DNA damage and allows repair or
apoptotic cell death:
– if it is not working damage accumulates and
tumours can arise.
• Is a transcription factor: regulates
other genes
97. The component cancers of Li-Fraumeni syndrome tend
to show up at different stages of life:
Age of Onset
1. Infancy
2. Under 5 years of age
3. Childhood and young
adulthood
4. Adolescence
5. Twenties to thirties
Type of Cancer
1. Development of
adrenocortical carcinoma
2. Development of soft-
tissue sarcomas
3. Acute leukaemias and brain
tumors
4. Osteosarcomas
5. Premenopausal breast
cancer is common
Those who survive the first cancer are at higher risk for a second cancer. These
second cancers often occur in areas of the body previously treated with radiation.
97
100. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
CHRPE rare CHRPE frequent
EXON
AAPC LESS PROFUSE
POLYPOSIS
PROFUSE POLYOSIS
EARLY ONSET
THE APC GENE- genotype/phenotype correlations
MUTATION CLUSTER
REGION
FAP
GARDNER’S
SYNDROME
AAPC
MULTIPLE
ADENOMAS
AS FOR FAP
VARIABLE NOS
OF ADENOMAS
DUODENAL POLYPOSIS,
GASTRIC ADENOMAS, CHRPE
AS FOR FAP + EPIDERMOID
CYSTS, DESMOID TUMOURS
GASTRIC POLYPS OF
FUNDAL GLANDS
100
101. FOUR GENERATION FAMILY PEDIGREE
WITH AN INHERITED PREDISPOSITION
TO BREAST & OVARIAN CANCER 101
102. BRCA1 Tumour Suppressor Gene
Isolated by positional cloning as one of the genes
predisposing to early onset breast and ovarian cancer
Germline mutations of BRCA1 found in
50% inherited breast cancers
81% inherited breast-ovarian cancer)
Penetrance varies based on age and population
56-85% by age 70 for inherited breast cancer
16-60% by age 70 for inherited ovarian cancer
Sporadic disease
- BRCA1 mutations detected in 10% of sporadic ovarian
cancer
- Reduced protein expression observed in the majority of
sporadic breast cancers 102
103. 22
(1) Regulation of transcription
(2) DNA damage
(3) Cell cycle
BRCA1 Function
103
104. XERODERMA PIGMENTOSUM
2 mutant copies of the same gene
inherited – one from each parent
Very rare condition
Susceptibility to skin cancer
Inherited defect in DNA repair
(excision repair)
Skin cancer rates 2000-fold > normal
Average age 8yrs cf 60yrs general
population
20-fold > brain, lung, stomach, breast
& leukaemias
Also a cancer critical gene!!
104
105. XERODERMA PIGMENTOSUM PEDIGREE
Both parents are ‘carriers’ with no disease symptoms
Child has 50% chance of inheriting mutant allele from each parent
Overall probability of developing XP is 50%x50%=25%
1st generation 2/8 children developed the disease
All of their children inherit a mutant allele so are carriers
Some in the 1st generation may be carriers but not evident from
the pedigree
105
106. FOUR GENERATION FAMILY PEDIGREE
WITH AN INHERITED PREDISPOSITION
TO BREAST & OVARIAN CANCER 106
107. 30 50 70
AGE (YEARS)
PROBABILITYOFBREASTOROVARIANCANCER(%)
50
100
With BRCA1
mutation
With family
history
Without BRCA1
mutation
WHY BOTHER TO TEST FOR BRCA1
MUTATIONS?
107
108. RISKS/BENEFITS OF CANCER
GENETIC TESTING
• Ambiguous results
• Results cause
anxiety
• Lack of prevention
strategies
• Discrimination
• Strain on family
relationships
• Ends uncertainty
• Possible absence of
mutation
• Improved medical
care
• Clarifies risk for
relatives
• Informed
reproductive choices
RISKS BENEFITS
108
109. ETHICAL ISSUES
• Patient confidentiality
- insurance
- employment
• Commercialism – Myriad Genetics
• Prenatal testing
Harris, Winship & Spriggs Lancet Oncology 2005; 6:
301-10 ‘Controversies and ethical issues in cancer-
genetics clinics’.
To be continued PoDT year 2 – clinical genetics 109
110. A MULTIFACTORIAL DISEASE
• Having these mutant genes inherited
from a parent is not enough: need other
mutations
• Also the other genes in the genome
contribute to overall risk
– The deck of cards!
• Modifying loci
– Penetrance
– The exact mutation
110
111. The causes of neoplasia
Carcinogenesis is the process by which a
normal cell is converted into a neoplastic cell
A carcinogen is an agent that can cause neoplasia
• Most neoplasms occur as a consequence of environmental factors
• Epidemiological and experimental studies provide insight into
carcinogens
• It is rare for a carcinogen to act by itself - it usually requires
co-factors
• Genetic variability in the population and other host
factors contributes to carcinogenesis
• Carcinogens are almost invariably mutagens
112. The causes of neoplasia
• Toxins such as smoking
• Ionising radiation
• Non-ionising radiation
• Viruses
• Bacteria
• Fungi
• Parasites
• Hormones
• Diet
• Inherited genes
There is a
complex interplay
between
environmental
factors and host
factors, including
genetics
susceptibility
113. How do we find carcinogens?
• Epidemiology
– Geographical risk
– Historical changes
– Occupational risk
– Behavioural risk
• Experimental evidence
– Cell culture
– Animal models
114. Genetic damage is the key to neoplasia
Chemical carcinogenesis
• History
– Percival Pott 1776
• Identified skin cancer in chimney sweeps as
being due to soot
– Aniline dyes and bladder cancer
115. Genetic damage is the key to neoplasia
Chemical carcinogenesis
• Diverse compounds
– Direct acting
– Indirect acting: require metabolic
activation
• Examples
– Alkylating agents (direct)
– Polycyclin hyrdocarbons (indirect)
116. Genetic damage is the key to neoplasia
Chemical Carcinogenesis
– Ames test
• Use bacteria that can only grow on particular
media
– Treat with compound: do they mutate to grow on
other media?
– Pre treat compound with metabolic enzymes (liver
microsaomes) and repeat
– Animal studies
• As good as it gets! . . . . but possibly not always
relevant to man
118. Genetic damage is the key to neoplasia
Chemical carcinogenesis
– Human studies
– Epidemiology
– Complex and difficult but lots of good
evidence for environmental chemical
carcinogens
• Asbestos
• Aflatoxins
• Aniline dyes
119. Genetic damage is the key to neoplasia
Chemical carcinogenesis
– Smoking
– Huge number of chemicals involved
– Clear evidence for carcinogenic role of smoking
– “If everyone smoked then lung cancer
would be a genetic disease”
– Emphasises the point that we are all genetically
different
• Xenobiotic metabolism
• DNA repair
• Other
121. Genetic damage is the key to neoplasia
Radiation carcinogenesis
• Non-ionising radiation
• UV causes skin cancer
– Low risk in Negroes, high risk in Caucasians,
high risk in albinos
– Families with defective DNA repair
(Xeroderma pigmentosa)
122. Genetic damage is the key to neoplasia
SOME EXCEPTIONS
• Hormones
– Act as promoters, stimulating cell proliferation
– Breast, endometrial and ovarian cancer are
hormone dependent (used in treatment)
• Bacteria, fungi and parasites
– Gastritis caused by Helicobacter pylori
– Aflatoxins (carcinogen) produced by Aspergillus
flavus and liver cancer
– Bladder inflammation caused by Schistosomes
(Eygpt) - bladder cancer
123. Genetic damage is the key to neoplasia
Viruses and cancer
• Good evidence in experimental models
• Good evidence that viruses cause human
cancer
– HPV and cervical cancer
– HBV and liver cancer
– EBV and lymphoma
• Viral genes functioning in human cells
124. Viral carcinogenesis I
• Viral genes can act as dominant
transforming oncogenes like ras
• Viral genes can encode proteins that can
inactivate cellular proteins
– HPV encodes 2 proteins called E6 and E7
that bind to and inactivate p53 and Rb thus
effectively inactivating these tumour
suppressor proteins (genes)
125. 125
Human papillomavirus and the pathogenesis of cervical carcinomas
This histological section of a human papillomavirus (HPV)-infected cervical epithelium
reveals, through immunostaining with an anti-HPV antibody stain (brown), clusters of
HPV-infected cells in dysplastic areas of the epithelium, termed high-grade squamous
intraepithelial lesions (HSILs). The dysplastic cells arise, in large part, from the ability
of the HPV E7 oncoprotein to inactivate pRb and thus block entrance into a postmitotic
state, and to suppress apoptosis, the latter being achieved through the
actions of the viral E6 oncoprotein, which targets the host cell’s p53 protein for
destruction. The resulting lesions progress with a low but significant frequency to
cervical carcinomas.
126. Viral carcinogenesis II
• Viruses can also integrate into the
genome of a cells and do one of two
things
Activate the expression of a cellular gene
(proto-oncogene)
OR
Inactivate a gene by disrupting it
(inactivate a TSG)
127. Viral carcinogenesis III
• Viruses can also function in neoplasia by
stimulating proliferation (HBV in liver;
EBV in lymphocytes) and thus acting as
a promoter
• Also some viruses can cause
immunosuppression (EBV and HIV) and
this may be associated with
development of tumours
128. Genetic damage is the key to neoplasia
Host factors
– Race,
– diet,
– gender,
– inherited factors, etc
• Familial cancers
129. Hereditary cancer
• Some tumours run in families
• We know the genes involved in some
cases
– Familial polyposis coli
• (APC)
– Hereditary non polyposis colon cancer
• (DNA repair enzymes)
– Breast cancer (+/- ovarian cancer)
• BRCA1 and BRCA2
– Li Fraumeni syndrome
• p53
130. Hereditary cancer
• Having these mutant genes inherited
from a parent is not enough: need other
mutations
• Also the other genes in the genome
contribute to overall risk
– The deck of cards!
• Modifying loci
– Penetrance
– The exact mutation
131. Genetic damage is the key to neoplasia
• Abnormalities of DNA repair genes are
common in cancer
• Can be inherited or be acquired
– Mismatch repair
– Double strand repair
– Nueclotide excsion repair
132. Genetic damage is the key to neoplasia
• Familial cancers are relatively rare
• Genes involved in familial forms of
cancer are (usually) also involved in the
sporadic forms of cancer
133.
134. Overview of treatment options
Accurate clinical diagnosis of patients with neoplastic
disease requires a logical and careful application of
history taking
clinical examination and
appropriate special tests & investigations.
Ultimately the diagnosis of neoplasia requires
histopathological assessment or a tissue diagnosis.
This involves
cytology (eg. fine needle aspiration)
needle or core biopsy
incision biopsy or
excision biopsy
135. Multi-disciplinary team approach
The diagnosis and treatment of cancer is increasingly complex
Requires a multi-disciplinary team (MDT) of professionals including
– Surgical oncologists
– Radiation oncologists
– Medical oncologists
– Pathologists
– Radiologists
– Geneticist
– General practitioners
– Palliative care specialists
– Psychologists
– Social workers
– Nurses
– Chaplains etc . . . . . . . . . .
136. New information helps diagnosis
• Molecular profiles
• Expression arrays
• Antibodies
• More robust and reproducible diagnoses
and classification
• Identification of subgroups that need
specific therapies
• Tailored treatments
137. Identifying prognostic factors
Things that predict survival
• Tumour type
• Stage and Grade
• Karnovsky status
• Tumour factors
– Gene expression
– Proliferation
138. Identifying predictive factors
Things that predict response to therapy
• Sub types of tumour
• Expression of various genes
• Expression of p53
• Expression of other genes
143. Treatment goals
The goals of patient management:
• Cure
• Palliation
– with the aim of improving lifespan and
quality of life
144. Treatment principles I
Are based upon:
• Biological behaviour of the tumour
• Extent and bulk of disease
• Mortality and morbidity of any therapies
• The efficacy of the therapies
• The general well being of the patient including co-
existent (co-morbid) diseases
145. • Screening
– Early Diagnosis is preferable (eg. Breast cancer)
– Diagnosis at a pre-malignant stage (eg. Cervical
cytology)
• Prevention
– Behaviour modification (eg. smoking, sun exposure)
– Risk avoidance (eg. occupational risks, dietary
factors)
Treatment principles II
146. Cancer cure: difficult but not hopeless!
• SURGERY is very effective
• For some tumours chemotherapy and radiotherapy
are very effective
• Over the last decade all sorts of new approaches and
new drugs coming into the clinic.
• Lots of hope for the future . . . . . . .
147. How do current therapies work?
• Exploit properties of tumour cells
– Proliferation & loss of cell cycle control
– Genetic instability
• Most drugs and radiation cause massive
DNA damage and induce cell cycle
arrest and cell death
150. Cancers can evolve resistance to
treatment
• Just like bacteria and antibiotics!
• Mutation and natural selection for resistant
clones
• If the apoptotic pathway is not working then
drugs will not work.
– Therefore, Increased resistance when there is
mutant p53
• Increased expression of MDR1 in tumours: an
efflux pump that exports exogenous
compounds out of cells
151. Monitoring treatment I
• Clinical examination
• Radiology
• Tumour markers
– Measure something produced by the tumour
cells as an index of tumour burden
• AFP (alpha feto protein in liver cancer)
• AFP & HCG (human chorionic ganadotrophin in
testicular cancer)
157. New treatments are based on new
understanding of cancer biology: p53
• Drugs that reactivate mutant p53: restoring
sensitivity to current drugs.
• Viruses that will only grow in cells with mutant
p53 as biological therapy
• Side effects of current therapy include cell
death in bone marrow due to p53 function in
normal cells: use drugs that inactivate p53 in
normal cells to reduce side effects of current
therapies and increase therapeutic ratio
158. What about blocking blood vessels?
• Angiogenesis is key to tumour growth so
is an obvious target
• Angiogenesis is induced by various
factors such as VEGF: this acts on a
receptor VEGF-R to induce new blood
vessels to grow. Design drugs that
block the receptor so that the tumour
derived VEGF does not work?
159. Small molecules can be designed to
target specific oncogenic proteins
• The example of HERCEPTIN
– An antibody that blocks the erbB2
receptor (also called HER2) now used in
breast cancer
• The example of GLEEVEC
– A small molecule that blocks the active site
of the abnormal bcr-abl protein, now used
in CML (chronic myeloid leukaemia)
160. INTRACELLULAR SIGNALLING VIA THE ERBB2 RECEPTOR
LIGAND
RECEPTOR
mRNA
NUCLEUS
INTRACELLULAR
TRANSDUCER
ERBB2 RECEPTOR
INTRACELLULAR SIGNALLING VIA THE ERBB2 RECEPTOR
LIGAND
161. AMPLIFICATION OF THE ERBB2 PROTO-ONCOGENE
LIGAND
INTRACELLULAR
TRANSDUCER
NUCLEUS
ERB B2
RECEPTOR
162. THERAPY VIA RECEPTOR BLOCKING BY ANTIBODY
LIGAND
INTRACELLULAR
TRANSDUCER
NUCLEUS
RECEPTOR
ANTIBODY
Herceptin
163.
164. Understanding cancer biology leads
to rationale tailored treatments
• Next generation of treatments will be
based on our new understanding
PLUS
• Specific treatments for specific
patients based on genetic and molecular
knowledge . . . . . .
Grounds for optimism
