carcinogensis and tumour markers Flashcards
- —- is fundamental to development, maintenance of steady state
homeostasis and replacement of dead or damaged cells - Cellular proliferation is normally a — process
- Uncontrolled cellular proliferation leads to —
cell proliferation
controlled
neoplasia
cell types are:
* — cells (rapid turnover- continuously dividing)
– e.g., — cells ( –/ –)
* — (low turnover)
– —- , — cells
* — (no turnover)
– —
– —
labile
epithelial (skin/GIT)
stable
hepatocyte , renal tubular cells
permanent
nerueons
cardiomyocyte
cell cycle :
- The cell cycle has four phases:
– G1 (gap 1, a preparation phase)
– S (synthesis of DNA)
– G2 (gap 2, assembly of the apparatus of the
chromosome distribution)
– M (mitosis) - Quiescent cells in resting phase G0 (gap 0)
can re-enter the cell cycle - Permanent cells cannot re-enter the cell cycle
1- control of the cell cycle:
* The cell cycle is under tight –
* Cell cycle progression is controlled by —
* If no genetic defects detected, cyclins and CDKs form complexes which activate — factors necessary for the next step of the cell cycle
* If the cell detects DNA damage, progression through the — is halted
2- the 2 main checkpoints:
* Two main checkpoints
– G1-S checkpoint which senses — and prevents – of the cell cycle
( – protein)
– G2-M restriction point to ensure that accurate — before the cell divides
regulation
cyclins and cyclin-dependent kinases
(CDKs)
transcription factors
cell cycle
DAN damage
cell cycle
Rb proteins
accurate genetic replication
abnormalities of cell proliferation:
1- Controlled:
– –
– —
2- Uncontrolled
– —
– –
hyperplasia
hypoplasia
dysplasia
neoplasia
1- hyperplasia:
* – of the number of the – (and usually the – of the organ)
* It can only occur in – or – cells as permanent cells cannot divide
2- is an increase in the size of cells. It occurs in cells incapable of cell
division as left ventricle hypertrophy
- examples of hyperplasia:
* Breast:
– Physiological during —
– Pathological- excessive – stimulation
* Endometrium:
– Physiological during —
– Pathological excessive — stimulation
* Thyroid:
– Due to increased —
* — increases the risk of acquiring genetic aberrations
*Pathologic hyperplasia is a fertile soil in which cancerous proliferations may eventually arise
hyperplasia
increase
number
siz
labile and stable
hypertrophy
lactation
stimulation
pregnancy
hormone
TSH
hyperplasia
3- atrophy: — in – or the – of the cells resulting in a — in the – of the organ
Examples:
– — (loss of endocrine stimulation)
– – development (atrophy of thyroglossal duct)
– Atrophy of the brain
4- —-
* Failure of organ to reach expected size
5- —-
* Failure of organ to develop
reduction of size and number
decrease in the size
breast
foetal
hypoplasia
agenesis
6- —- change from one adult type another adult type which is a protective mechanism
* —- of stem cells
* e.g., squamous metaplasia of the bronchus ( — )
* Barrett’s oesophagus- change from – epithelium to – epithelium
7- — disordered growth of neoplastic epithelial cells without invasion of the basement membrane
* It precedes —
* The term carcinoma in situ is used when dysplastic cells replace the — of the epithelium
metaplaisa
genetic reprogramming
smoking
squamous to grandular
dysplasia
carcinoma
full thickness
- Sequence of events caused by uncontrolled cell proliferation leading to the development of malignant neoplasm refers to —
- Cancer formation is initiated by – of the stem cells
- The damage overcomes DNA repair mechanism, but is not lethal
- Results from accumulation of mutations in genes critical to the control of cell growth and division
- epidemiology of cancer:
1- — - Most cancers occur in adults older than — years of age
– Exposure to carcinogens with sufficient time to cause multiple – alterations
– — - – people have mild immunosuppression - Paediatric cancers are more likely to be caused by — mutations
( — genes)
2- — factors and — (substances that may cause cancer)
– Chemicals
– Radiation
– Infectious agent
– Smoking
– Alcohol
– Diet
– Obesity
3- high levels of — for example:
– Breast carcinoma- — (e.g. – )
– Endometrial carcinoma- — , –
– Prostatic carcinoma- –
carcinogenesis
dna damage
age
55
genetic
immunosprssion and elderly
inherited mutation as in tumour suppressor
environmental factors and carcinogens
hormones
osterogen ( HRT )
osteorgen and tamoxifen
androgens
Carcinogenic agents may work at a variety of levels:
— : .An event that alters the genome.
— : .An event that causes proliferation of the genetically altered cell.
—- :.The development of further genetic mutations.
initiation
promotion
progression
chemical carcinogens:
* Aflatoxins (Derived from Aspergillus which can contaminate stored rice and grains) causes — carcinoma
* Alkylating agents- (chemotherapy) causes — and —
* Alcohol- causes 000 cell carcinoma of the —
* Aniline dye- — carcinoma
* Arsenic (by-product of metal smelting)- causes — cell carcinoma of the — cancer
* Asbestos- causes — carcinoma and –
* Cigarette smoke- Carcinoma of the — and —
* Nitrosamines (found in smoked food)- — carcinoma
* Polycyclic hydrocarbons- — carcinoma
* Vinyl Chloride (occupational exposure)- causes — of the liver
* Silica, nickel (Occupational exposure)- causes – carcinoma
hepatocelluar
leukimia and lymphoma
squamous of the orphanryx
bladder
squamous of skin/lungs
lung and mesothelioma
lungs and oropharynx
stomach
lung
angiosacroma
lung
1- viruses that cause cancer:
* Epstein Barr
– — carcinoma
– — lymphoma
* HPV (16,18) - High risk
– — cell carcinoma of the vulva, vagina, anus, cervix and adenocarcinoma of the
cervix
– — carcinoma
* Hepatitis B&C Viruses
– — carcinoma
* Herpes type 8
– — sarcoma
2- ionising radiation :
– — reactor accidents: Hiroshima and Chernobyl
– —
– — and — carcinoma of the —
3- non ioznizing radiation can cause : —
Nasopharyngeal
burkitts
squamous
oropharyngeal
hepatocellualr
kaposi
nuclear
radiotherapy
leukaemia and papillary carcinoma of the thyroid
nonionzing can cause: Basal cell carcinoma, squamous cell carcinoma and melanoma
more epidemiology of cancer:
4- — predisposition conditions:
* — inflammation
– Helicobacter pylori chronic gastritis (gastric — and gastric – )
– Chronic inflammatory bowel disease- ulcerative colitis ( —)
– Cholelithiasis – (carcinoma of the — )
* Precursors —
- Hyperplasia: endometrial — –> endometrial —
- — : Barrett’s oesophagus oesophageal adenocarcinoma
- — : Colonic adenoma –>colonic adenoma
* —
- — transplant: carcinoma of the –
- — - carcinomas and lymphoma
acquired
chronic
gastric adenocarcinoma and gastric lymphoma
colonic adenocarcinoma
gallbladder
lesions
hyperplasia to adenocarcinoma
mateplasia
dysplasia
immunodeficiency
renal for carcinoma of the skin
AIDS
more of the epidemiology of cancer:
5- – predisposition and interactions between – and — factors
* Familial cancers are due to inherited – mutations in a — gene
-The risk of cancer development is influenced by — factors
* The risk of cancer in fameless with BRCA1 and BRCA2 mutations is threefold higher for females borne after 1940 than women born before that year –change in reproductive history
- – factors can alter the likelihood of cancers influenced by — carcinogens
* Genetic variation in enzymes responsible for conversion of — to active — (Polymorphism of— gens and smoking induced— cancer)
- for inherited gremlin mutation in tumour suppressor gene:
* Inherited germline mutations in a tumor suppressor gene
– Familial Adenomatous polyposis coli → – carcinoma
– – occur in families
– – carcinoma (5%)
genetic
environmental and inherited
germline mutation in tumour suppressor gene
nongentic factors
genetic
by evironmetal carcinogens
procarinogens to active carcinogen
P-450
lung cancer
colonic
retiboblastomas
breast
molecular basis of cancer:
* Nonlethal genetic damage (mutation) caused by — exposure, – or —
* Tumour is formed by the — of a – precursor cells that has
incurred — damage (i.e. tumours are–)
* Carcinogenesis results for the – of mutations over time
environmental , inherited , spontaneous
clonal expansion of a single
genetic damage
tumours are clonal
accumulation
gene abnormalities:
Germ line:
* An – germ line loss of – allele and subsequent loss of the second
allele is associated with some cancers e.g., –
* A germ line abnormality means – from that individual carry the gene abnormality
* A germ line genetic abnormality is found in some – cancer syndromes
Somatic:
* – gene loss is acquired, not through the germ line
inherited
one allele
retiboblastoma
all cells
familiar
somatic gene
molecular basis of cancer:
Three classes of genes are the principal targets of cancer-causing mutations:
– Growth-promoting —
– Growth-inhibiting —-
– Genes that regulate —
1Proto-oncogenes are present in normal cells and code for proteins that promote –
* Oncogenes are mutated or over expressed genes that are abnormally activated
* These mutations cause – of function and can transform cells despite the presence of a normal copy of the same gene
– They work in a — manner
* — drive cellular proliferation. They cause excessive — even in the absence of – factors and other growth promoting external cues
proto oncogenes
tumour supressor gene
apoptosis
division
gain of function
dominant
oncogene
cell growth
growth factor
physiologic growth factor induced signilling:
* Binding of a growth factor to its –
* Transient and limited activation of the growth factor receptor, which in turn activates several — proteins
* Transmission of the signal to the –
* Activation of transcription factors that initiate —
* Expression of genes that promote entry and progression of the cell into the cell cycle resulting in —
receptor
cytoplasmic signal transducing
nucleas
dna transpcriton
cell division
classification of some proto oncogenes:
* — factors (HGF- over expression in — carcinoma)
* — factor receptors (HER2- amplification in – carcinoma)
* – transduction (KRAS- point mutation in — cancer, BRAF-point
mutation in – and – cancer)
* — regulation (MYC- translocation in — lymphoma)
* — regulators (cyclinD1- translocation in – lymphoma, CDK4
mutation in — )
growth
hepatocellualr
growth
breast
signal
colon
melanoma and colon cancer
nuclear
burkitts
cell clue
mantle cell
melanoma
- Normal genes which code for proteins that inhibit cellular proliferation (apply
breaks to cell proliferation) - Mutations that affect tumour suppressor genes cause loss of function (failure
of growth inhibition) - Both alleles (gene copies) must be damaged before transformation can occur
these are known as – - — genes which halt the proliferation:
– Rb (Retinoblastoma)
– P53
– APC - — genes responsible for repairing DNA damage
– BRCA1, BRCA2
– DNA mismatch repair genes (MSH2, MLH1, MLH6, PMS1, PMS2)
tumour supressor genes
gatekeeper
caretaker
- — is the governor of proliferation
- — regulator of G1/S transition
- In activation of – releases the break in the cell cycle
- Mutations can – or – mutations
- Sporadic mutations are found in many tumours
- – mutations are found in familial retinoblastoma
–> —
– >In familial cases children inherit one— copy of Rb (the first hit) and one – copy
– Retinoblastoma develops when normal copy is – in retinoblasts ( – hit)
rb
negative
rb
sporadic or gremlin
gremlin
autosomal dominant
defective and one normal
mutated
second hit
knudsons 2-hit hypothesis:
- In familial cases children inherit one defective copy of Rb (the first hit) and
one normal copy. The defective copy is present in all somatic cells
– Retinoblastoma develops when normal copy is mutated in retinoblasts (second hit)
– The disease can be bilateral - in sporadic cases, both hits occur within a single retinal cell (rare)
p53:
* Guardian of genome (molecular policeman).
* It detects — and stops cell progressing through the cell cycle to
give cell repair enzymes time to repair before they divide.
* Therefore, maintain the – of the DNA of the cell
* Normal P53 is called —
* Mutated P53 is found in a wide range of tumours
* Mutated P53 allows genetic damage to survive and accumulate
* Mutations can be sporadic or inherited (Li- Fraumeni syndrome)
* Li- Fraumeni syndrome is – as an – with risk of sarcomas, breast a carcinoma and other types
dna damage
integrity
wild type
inherited
autosomal dominant
1- ADENOMATOUS POLYPOSIS COLI GENE (APC)
* Sporadic or germline mutations
* Sporadic mutations are found in —
and other tumours
* Germline mutations are associated with —
– — which leads to formation of thousands of polyps in the GIT in patients in their teens – must be lost
2- BRCA1 AND BRCA2
* — genes
* Transmitted as — - (percentage of
carriers who develop breast cancer is 30-90%)
* Breast cancer at an early age (before 40)
* Carriers are susceptible to other cancers (colon, prostate and pancreas)
* BRCA 1: high risk for – ca (30%)
* BRCA 2: high risk for — ca
colon cancer
adenomatous polyposis coli syndrome
autosomal dominat
both copies must be lost
tumour supressor
autosomal dominant variable penetrance
ovarian
males breast
- — encode for proteins that proof read the DNA.
– During DNA replication, small errors in DNA copying are made in – regions which are repeated sequences of DNA
– — proteins recognise and repair erroneous insertion, deletion, and mis- incorporation of bases that can arise during DNA replication - Mismatch repair genes include:
– MSH2
– MLH1
– MLH6
– PMS1
– PMS2 - Defect in these genes lead to accumulations of genetic mutations
(— instability) - Hereditary nonpolyposis colorectal cancer (HNPCC = – syndrome)
– Autosomal dominant
– Lynch syndrome 1- Increased risk of– cancer
– Lynch syndrome 2- Increased risk – cancer and – cancers (endometrial)
DNA mismatch repair genes
microsatillite
mismatch repair proteins
microsatelite
Lynch
autosomal dominant
colon
colon and non gi cancer
- in anti apoptotic genes:
- Mutations causing less – and enhance –
- BCL2 (anti-apoptotic) over expression in — —> evasion of –
- limitless replicative potential - a stem cell like properties:
- Cancer cells are – and have – replicative potentials
- In normal cells progressive — of telomeres due to incomplete
replication of chromosome ends results in mitotic crisis and cell death - Cancer cells express – which prevent telomere shortening
cell death and enhances survival
follicular lymphoma
cell death
immortal and limitless
shortening
tolemerase
- Proteins produced by the tumour cells and can be found in the blood, urine, stool, or other bodily fluids known as —
- – tumour markers
– Hormones, Oncofoetal antigens, lineage specific proteins, mucin - – markers
tumour markers
circulating
tumour tissue
examples of circulating tumour markers:
1* Lineage specific proteins:
– — antigen (PSA)
* — carcinoma
* PSA may also be elevated in benign prostatic —
2* — antigens:
– — antigen (CEA)
* Colon, stomach, pancreas, breast
* Can be elevated in – conditions
– Alpha-fetoprotein (AFP) as in:
* – carcinoma
* — tumour (germ cell tumour)
* Can be elevated in – conditions
3* — :
– Human chorionic gonadotropin (HCG) as in —-
– Calcitonin
* Medullary carcinoma of —
4* —
– CA-125
* — cancer
– CA 19.9
* — cancer
lineage
prostatic specific
prostatic carcinoma
hyperplasia
oncofoetal
Carcinoembryonic antigen
non-neoplastic
hepatocelllular
yolk sac
non neoplastic
Choriocarcinoma
thyroid
mucins
ovarian
pancreatic
circulating tumour markers :
1- — when combined with other – such as biopsies and imaging but not on their own
- Lack specificity- non-cancerous conditions can cause an increase in the levels of certain
tumour markers. PSA is increased in benign prostatic hyperplasia
- Lack of sensitivity: not everyone with a particular type of cancer will have a high level of a
tumour marker associated with that cancer
2- Estimate — and tumour —
3- Determine the – of cancer
4- Detect cancer that remains after treatment ( — disease)
5- Detect cancer — after treatment
6- Monitor— to treatment
7- Monitor whether the treatment has —
tumour tissue markers ( cell markers):
* Markers found in the — , typically in a sample of the tumour that is removed during a —
* — are markers that indicate whether the patient is a candidate for a particular targeted therapy
* Examples
– — and — receptors in breast cancer tissue can determine response to hormone therapy
– HER2 receptors in breast cancer tissue can determine if — can be used
– — to determine if immunotherapy can be used
diagnosis
combined w other tests
prognosis
stage
residual
recurrence
response
stopped working
actual tumour
biopsy
biomarkers
oestrogen and progesterone
Herceptin
PD-L1
- A liquid biopsy is identification of biomarkers in body fluids is known as–
- It is performed by testing a sample of — for the presence of –
cancer cells and – tumour DNA (cfDNA), which are fragments of DNA
shed by – cells into a patient’s – - clinical application:
- Identify specific genetic mutations for – treatments
- –
- Can be performed when – biopsies cannot be obtained (tumours are
difficult to reach or patients can’t tolerate surgery) - Liquid biopsies have the – to detect cancer cells in a patient’s body at an — than many standard screening methods
liquid biopsies
blood
cicualtinf cancer cells or cell free tumour dna
cancer cells
bloodstream
targeted
non invasive
surgical
potential
earlier stage
