P7 + 8 - Disorders of growth and neoplasia 4/5 Flashcards
what can be said for most tumours?
Most tumours are monoclonal ie all the cells in a tumour appear to arise from one parent cell which has undergone a genetic change. This is then passed on to all the progeny
What do tumour cells lack?
normal control mechanisms thus the clone expands due to uncontrolled proliferation
where can further genetic changes occur and what does it become?
- develop in the progeny
- tumour becomes heterogeneous
Name some way cells are transformed.
- Altered nuclear/cytoplasmic ratio
- Altered and variable nuclear morphology (pleomorphism)
- Altered nuclear staining (hyperchromasia)
- Altered DNA content (aneuploidy)
What happens for cells go to from normal tissue to neoplastic tissue?
carcinogenesis
Describe the aetiology of cancer.
- Cancer is not a single disease -Different cancers –different causes
- Often multiple factors involved
Name environmental factors of carcinogenesis.
- Chemicals
- radiation
- viruses
- Unknown
Describe chemical carcinogenesis.
- Many different chemicals have been implicated in
causing cancer - Often based on strong epidemiological evidence
- Animal studies
what is smoking linked to?
• Linked to many different types of cancer – particularly • Lung cancer • Oral Cancer • Smoke is not a pure chemical: – Polycyclic hydrocarbons – Nitrosodiethylamine – Ni and Cd
what sometimes acts directly?
chemicals
what do other chemicals require?
metabolic conversion to an active form
what is the multistep theory of carcinogenesis evolved from. animal studies of carcinogens ?
1- Initiation- DNA damage and mutation
2 -Promotion-clonal expansion of abnormal cells leading to cancer
what is the key issue with carcinogens?
able to recognise and identify carcinogens
Describe radiation.
• Much evidence that ionising radiation can induce cancers
• Radiotherapy can lead to later development of second cancer
-Ionising radiation damages DNA
-Breaks in single stranded and double strands of DNA
Breaks in a single strand can be repaired but this can be Inaccurate leading to single base mutations
-Double-strand damage leads to chromosomal breakage Repair can lead to major chromosomal rearrangements
what is UV irradiation is strongly implicated in?
Development of skin cancers :
- basal cell carcinoma
- squamous cell carcinoma
- malignant melanoma
Why is UV light damage limited to the skin?
UV light does not penetrate deeply
what does induced formation of pyrimidine dimers lead to?
base-pair substitution during replication
Describe viruses.
- Long recognised that some viruses can cause cancer
- Different viruses can contribute to the development of cancers in different ways
- Some RNA tumour viruses (retroviruses) contain genes (viral oncogenes) that are directly responsible for malignant transformation in cells
- Viral RNA genome is copied into DNA by the enzyme reverse transcriptase and this is then inserted into host genome
- Viral genes can then influence the expression of adjacent genes
How do viruses act indirectly?
Other viruses act indirectly by causing tissue damage, leading to increased cell proliferation and an increased risk of mutations eg Hepatitis C virus
what are the human papilloma virus (HPV) high risk subtypes?
- Cervical carcinoma, anal carcinoma, penile carcinoma,
- Subset of oropharngeal carcinoma
what is a hepatocellular carcinoma?
Hepatitis B and C
what are other parameters?
Patients: -general health -age -stage at presentation -immunosuppreion Other diseases: -further debility -lower tolerance to treatment Tumour : -factoprs implicit in grading and staging -molecular and biochemical features
Name the host factors .
- Chronic infection
- Hormonal stimulation
- Immunosuppression
- Risk factors
- Genetic predisposition
Describe immune surveillance.
- Cells of the immune system may target tumour cells for destruction.
- Lymphoid infiltrates common in cancer.
- Regression of some cancers, such as melanoma.
- Immunodeficiency states associated with increased risk of some types of cancer.
what type of disease is neoplasia?
genetic disease
what does tumour cells breeding true mean?
the progeny of tumour cells are tumour cells indicating inheritance of properties
what are nearly all carcinogens?
mutagens
what do tumour cells usually show?
nucelar abnormalities
what is also common in tumour cells?
altered DNA content (aneuploidy)
What does examination of chromosomes from tumour cells show?
many structural abnormalities, some being characteristic of specific tumour types
Can tumour be inherited?
Some tumours are clearly inherited and tumours can run in families
what do molecular studies indicate?
mutations exist in genes that regulate cell behaviour
What is cancer due to?
excessive and uncontrolled cell proliferation or insufficient cell loss i.e due to defects in normal control mechanisms for cell poopulation (Replication, Escape from senescence, Evasion of apoptosis, Limitless replicative potential)
what 2 genes are involved in cancer?
- oncogenes
- tumour-suppressed genes
What are oncogenes?
Normal genes switched on when cell division is needed and promote cell division when expressed are “proto- oncogenes”
what happens if oncogenes are inappropriately switched on?
the cell will divide at the wrong time
what is the abnormal gene?
oncogene
what is the abnormal protein expressed?
oncoprotein
how do oncogenes act?
in dominant manner therefore only 1 out of 2 cellular copies needed
How many categories can proto-oncogenes be separated into?
4
what are the 4 categories of proto-oncogenes?
- Genes that produce growth factors eg sis gene encodes PDGF
- Genes that produce growth factor receptors eg erbB1 gene, encodes a receptor with tyrosine kinase activity for epidermal growth factor
- Genes that encode signal transducers ie proteins that transmit the growth signal to the nucleus. Mutataions may cause permanent “on” signal eg ras genes encode for GTP- binding proteins
- Genes that activate other genes to promote growth (transcription activators) eg fos and myc genes
How can oncogenes be activated?
- Point mutations
- Gene amplification- multiple copies formed leading to increased oncoprotein produced
- Translocation between chromosomes eg c-myc in Burkitt’s lymphoma
What are tumour-suppressor genes?
Genes that normally stop a cell growing, promote differentiation of a cell to a terminal end state, or trigger checkpoints that cause cell cycle arrest if DNA damage occurs. i.e cell cycle arrest genes or DNA -repair genes
when do problems problems arise with tumour-suppressor genes?
if normal tumour- suppressor function lost
How can normal tumour-suppressor function be lost by?
- Inactivating mutations
- Deletions
- Viral proteins causing complexes to form
what is needed to lose complete control of cell cycle with tumour-suppressor function?
loss of both copies of tumour suppressor gene
Give examples of tumour-suppressor genes.
APC- Familial adenomatous coli and colon cancer
BRCA-1- Breast cancer, ovarian cancer
TP53- Li-Fraumeni syndrome, sporadic cancers
what is lost in abnormal function?
p53 : guardian of the genome
what has tumour -suppressor genes been learned from?
inherited cancers
what are the 3 broad groups of familial cancer syndromes (predisposition to various tumours)?
- Familial cancer syndromes 2. Familial Cancers
3. Autosomal Recessive Disorders due to Defects in DNA repair
Describe familial cancer syndromes.
-Increased risk of cancer due to transmission of a single gene
Eg Li- Fraumeni- TP53
Describe familial cancers.
-In some families there is marked increase in incidence of common cancers
Eg breast, colon, ovary
(Responsible gene discovered in some cases e.g. BRCA1)
Describe autosomal recessive disorders due to defects in DNA repair.
- Eg Lynch syndrome
- Colorectal cancer in both sexes and Endometrial carcinoma in women
- Due to impaired DNA repair- failure of “mismatch repair genes”
Describe the presentation of cancer.
- Very variable
- May be incidental, screening test
- Maybe effect of primary OR metastatic lesions
- Depends on site
How can tumours present as a consequence to what?
- A consequence of local disease (eg. space occupying lesion, compression, ulceration)
- A consequence of distant spread (eg. space occupying lesion, compression, ulceration)
- Non metastatic manifestations of malignancy (also known as paraneoplastic effects) such as anaemia, skin changes, neurological effects, inappropriate hormone production etc.
- Incidental findings, eg. on screening or on routine medical examination
How is asymptomatic cancer found?
incidental finding
What are the vague symptoms of cancer?
– Tiredness
– Weight loss
– Anorexia
– Fever
What are specific symptoms of cancer?
– Related to primary or secondary lesions
– Skin rash, Itch
– Paraneoplastic syndromes
Describe how oral cancer presents in the mouth.
- Very variable
- Whitepatch
- Red/ Speckled Patch
- Lump
- Ulcer
- Often not painful
Name some common metastatic sites.
– Bone – Pain and pathological fracture
– Brain – Raised intracranial pressure, epilepsy, CVA
– Liver – Jaundice
– Adrenal glands – Addison’s disease
What may patients with advanced cancer have?
– other less specific symptoms or
– signs of a paraneoplastic syndrome
What are paraneoplastic syndromes?
Symptoms / syndromes in cancer patients that cannot be explained by the effects of local or distant spread of tumours
How often does paraneoplastic syndrome occur?
up to 10% of cancer patients
what is important to recognise in paraneoplastic syndromes?
– May be first sign of underlying cancer
– May be significant clinical problem in themselves : potentially lethal
– May mimic metastatic disease and affect staging, therapy and prognostic issues
Describe cancer screening.
• Breast, cervix, prostate, colo-rectal
• Based on understanding biology of the condition
• Define “at risk” groups – family history may be important
• Tests
– Standard clinical tests
– Cytology “Smear”
– New molecular tests
What does the patient want to know about their cancer?
- cancer prognosis
- treatment options
What is included in cancer prognosis?
• Tumour Type • Tumour Grade – Histology • Tumour Stage – Histology, Clinical, Radiological • Other Parameters – Patient – Tumour
Name some choices of therapy for cancer patients.
- Modality
- intensity
- combination
- nothing
- palliation ( relieve symptoms /shrink tumour)
