Theme 5: Neoplasia - Part 1 Flashcards
What is Huntington’s disease?
progressive neurogenerative disorder with motor, cognitive and psychiatric disturbance
-mode of inheritance is autosomal dominant
What effect does Huntington’s have on your movement, memory and mood?
Movement:
- chorea (involuntary motor movement)
- dystonia (prolonged contraction in abnormal position)
- bradykineasia (slowing of movement)
- swallowing/choking
- dysarthria (difficulty speaking)
Mood:
- depression
- euphoria
- apathy
- anxiety
- aggression
- psychotic symptoms
Cognition:
- loss of executive functioning
- rigidity of thought
- memory loss
- dementia
What is the mean age of onset and the mean survival time?
Mean age of onset: 35 to 44 years
Mean survival time: 15 to 20 years after onset
Huntington’s has complete penetrance. What does this mean?
all individuals with the disease causing mutation will have clinical symptoms of the disease
Which gene is affected in Huntington’s?
HTT gene at 4q16.3
What is the HD mutation?
an expansion of CAG repeats with >40 triplet repeats
- few people will develop HD with 36-39 repeats = reduced penetrance alleles
- 27-35 repeats = will not develop HD but next generation might
What amino acid does CAG code for?
glutamine
what is the relationship between the HD triplet repeat size and age of onset?
as the size of the repeat increases, the age of onset gets younger
What is anticipation?
- the onset of a disorder occurs at an earlier age as it is passed from one generation to the next
- often associated with an increase in severity of symptoms
- phenomenon associated with triplet repeat disorders
Anticipation is often linked to a specific parental gender. Which parent provides a high anticipation risk with HD?
Paternal inheritance
-if HD is passed by the father, there is much higher chance of the triplet expanding than if it were passed on by mother
what are two other examples of triplet repeat disorders?
- myotonic dystrophy
- fragile X syndrome
high anticipation risk is associated to maternal inheritance (opposite of HD)
What is Juvenile HD?
- onset under 20 years
- rare
- usually paternally inherited (and repeats have expanded)
What is predictive testing?
The use of a genetic test in an asymptomatic, at risk person to predict the future of a disease
What are the reasons to undertake predictive testing?
- screening to detect early disease - cancer, arrhythmia
- initiate treatments early
- take prophylactic measures
- may offer prenatal testing options
- inform other relatives
- plan future care, careers
What are three other conditions where predictive gene testing is possible?
- BRCA (familial breast cancer genes)
- HNPCC (hereditary non-polyposis colon cancer)
- Myotonic dystrophy
What are the treatments for HD?
- symptomatic treatment only at present
- no prevention or cure
What is exclusion testing?
For parents who do not want predictive testing but want to ensure their children are not at risk - predicts whether the foetus is at risk
What is bioinformatics?
A combination of principles from computer science and IT, used to handle and interpret the large datasets generated by genomic analysis
What are the limitations of bioinformatics?
- computers simply follow a set of rules, they are not aware of what they’re doing
- variants are missed
Stats about rare diseases:
- What % of the population will be affected by a rare disease?
- What % of rare diseases have a genetic component?
- What % of rare diseases affect children?
- 7%
- 80%
- 75%
What is Cockayne Syndrome?
- A rare and fatal autosomal recessive neurodegenerative disorder charachterized by growth failure (dwarfism), impaired development of the nervous system, photosensitivity, eye disorders and premature ageing
- Most children with severe CS do not survive to 7
- no cure
- treatment of symptoms: hearing acids, protection of skin and eyes from sun, dental hygiene
What is FTT?
Failure to thrive - insufficient weight gain or inappropriate weight loss
Explain the genome analysis pipeline
- Collect DNA
- genomic DNA (e.g blood)
- tissue DNA (e.g tumour) - Capture DNA of interest
- clinical exome/ exome/ whole genome - Sequence captured DNA
- short/long read
- single-end/paired-end - Analyse sequence
- align data to human genome and call variants, SNVs, CNVs etc - Variant interpretation
- does the variant cause disease?
In what ways can cells adapt?
- increase in size of cells (hypertrophy)
- increase in number of cells (hyperplasia)
- decrease in size and metabolic activity of cells (atrophy)
- increase in functional activity of cells
- change in the phenotype of cells (metaplasia)
Can fibroblasts adapt to environmental change?
they can survive severe metabolic stress without harm e.g absence of oxygen
-don’t need to adapt
Can epithelial cells adapt to environmental change?
- labile (flexible) cell population
- active stem cell compartment
- highly adaptive in number and function
- adapt easily
What are the 3 types of adaptive response?
- Increased cellular activity - increased size or number of cells
- Decreased cellular activity - decreased size or number of cells
- Change in cell function and/or morphology
What does hypertrophy result in? Examples
- increase in size of existing cells - resulting in increase in size of organ
- increase in function capacity
- seen in permanent cell populations e.g cardiac and skeletal muscle
- increased synthesis of structural components (explains why organ gets larger)
- increased metabolism
- growth of the uterus in pregnancy results from the hypertrophy of muscle fibres
Why does left ventricular hypertrophy occur?
- systemic hypertension is caused by increased peripheral vascular resistance
- so will increase the work required of the left ventricle
- hypertrophy will compensate for some time, but if hypertension is untreated, left ventricle will fail
What is sub cellular hyperplasia and hypertrophy?
-increase in size and number of sub cellular organelles
What is an example of hormone-driven hyperplasia?
proliferation of the glandular epithelium of the female breast at puberty and during pregnancy
What is compensatory hyperplasia?
Increases tissue mass after damage or partial resection
How does hyperplasia occur in Graves disease?
an autoantibody binds to and switches on the TSH receptor in the thyroid, leading to prolonged, uncontrolled hyperplasia of the thyroid ad hyperthyroidism (thyrotoxicosis)
What is the charachteristic sign of Grave’s disease?
eye signs (exophthalmos) - bulging of the eye anteriorly out of the orbit
What is atrophy?
reduction in size of organ or tissue by decrease in cell size and number
What are the common causes of atrophy?
- decreased workload (atrophy of disuse)
- loss of innervation (damage to nerve causing denervation atrophy)
- diminished blood supply (ischamia)
- inadequate nutrition e.g cachexia
- loss of endocrine stimulation
- pressure
What are the mechanisms of atrophy?
- reduced metabolic activity
- decreased protein synthesis
- increased protein degradation in cells
- reduction in volume of individual cells
What is metaplasia?
- transformation of one differentiated cell type into another
- may form the basis of which neoplasia develops
What is dysplasia?
- earliest morphological manifestation of multistage process of neoplasia
- in-situ disease; non invasive
- shows cytological features of malignancy
- recognition of dysplasia gives us the chance to treat a potentially fatal tumour before it arises
- basis of cervical screening programme
What is omeprazole?
proton pump inhibitor
medicine to reduce stomach acid
What s metformin?
drug for type 2 diabetes
What is GORD?
Gastro-oesophageal reflux disease
What is Baretts oesophagus?
- lining of oesophagus is damaged by acid reflux
- a metaplastic process in which the normal stratified squamous epithelial lining is replaced with columnar epithelium (gastric or intestinal) with goblet cells
- predisposes to dysplasia and invasive malignancy
What does bisoprolol, furosemide, ramipril treat?
high blood pressure
What is BPH?
- Benign prostatic hyperplasia
- common condition affecting males > 50 years resulting in enlargement of the prostate
- characterised by hyperplasia of glandular and stromal tissue
What is dyskaryosis?
Dyskaryosis means abnormal nucleus and refers to the abnormal epithelial cell which may be found in cervical sample
What is CIN?
Cervical intraepithelial neoplasia
- dysplastic condition caused by HPV
- carcinoma in situ is the presence of dysplastic cells that have not yet breached the basement membrane, but have a high risk of progressing to invasive malignancy
What is Beckwith Weidemann syndrome?
n overgrowth syndrome due to the dysregulation of IGF2 gene
What is a tumour?
A swelling or a mass of any kind
What is a neoplasia?
A new, uncontrolled growth of cells that is not under physiologic control. Usually forms a tumour. Can be benign or malignant
what is cancer?
- malignant neoplasia
- growth of abnormal cells that can invade and metastasise
What are the 8 hallmarks of cancer?
- Enabling replicative immortality
- Activating invasion and metastasis
- Inducing angiogenesis
- Resisting cell death
- Deregulating cellular energetics
- Sustaining proliferative signalling
- Evading growth suppressors
- Avoiding immune destruction
What are lung cells, thyroid cells and digestive cells formed from?
undifferentiated endoderm (internal layer)
What are cardiac muscle cells, skeletal muscle cells, tubule cells of the kidney, red blood cells, smooth muscle cells?
undifferentiated mesoderm (middle layer)
What are skin cells of epidermis, neuron on brain and pigment cells?
undifferentiated ectoderm (external layer)
What cells are carcinomas derived from?
Digestive cells
What cells are sarcomas derived from?
smooth muscle cells
What cells are melanomas derived from?
Pigment cells
What is differentiation?
The extent to which a neoplasm resembles its tissue of origin
Well-differentiated - neoplasm closely resembles tissue of origin
Poorly differentiated - neoplasm does not resemble the tissue the tissue of origin/ can’t tell where its come from
What does pleomorphic mean?
When a large number of cells show lots of variability in cell size and cell shape
What is anaplasia?
A neoplasm that is poorly differentiated and highly pleomorphic
What are the 3 most common types of cancer in females?
- Breast - 31%
- Lung - 13%
- Bowel - 10%
Which cancer has the highest mortality?
lung
What are the 3 most common types of cancer in males?
- Prostate - 26%
- Lung - 14%
- Bowel - 13%
Cancer in which organ has the highest percentage mortality?
pancreas (then brain, lung, oesophagus etc)
Benign Vs Malignant neoplasm:
- Invasion?
- Mets?
- Rate of growth?
- Differentiation?
- Prognosis?
- Benign - neoplasm does NOT invade surrounding tissues
Malignant - neoplasm DOES invade surrounding tissues - Benign - does NOT metastasise
Malignant - may metastasise - Benign - slow rate of growth
Malignant - fast rate of growth - Benign - usually well-differentiated
Malignant - well –> moderate –> poorly differentiated –> anaplastic - Benign - rarely fatal
Malignant - often fatal
Malignant tumours grow through the basal lamina/ basement membrane
What are the 3 potential routes that malignant neoplasms can metastasise?
- lymphatic
- haematogenous (blood vessels)
- direct seeding
What is seeding?
Malignant neoplasm penetrates into a natural body cavity
What complications can arise as effects of the primary tumour?
- invasion into and replacement of normal tissue–> failure of that organ to function
- pressure on normal tissue
- invasion into blood vessels –> bleeding
- pressure on blood vessels —> ischaemia
- pressure/invasion into nerves –> loss of nerve function /pain
- grow into lumen –> obstruction
What other complications can arise as a result of tumours?
- Effect of distant metastases (same effect as primary tumour, just in different location)
- Paraneoplastic syndromes
What are paraneoplastic syndromes and why do they develop?
Signs and symptoms that are NOT related to local effects of the primary or metastatic tumours
Develop as a result of:
-proteins/hormones secreted by tumour cells e.g cancer cachexia
-immune cross reactivity between tumour cells and normal tissues e.g Lambert eaton myasthenia syndrome
What is cancer cachexia?
Proteins affect metabolism causing cancer patients to have muscle wasting and become very thin
What is parenchyma?
Cells that perform actual function of an organ e.g cells that do gas exchange (pneumocytes) in the lungs, cells that contract the heart (myocytes)
What is stroma?
Cells that support the parenchyma (all other cells except parenchyma) including:
- blood vessels
- fibroblasts
- immune cells
What is an organ made up of?
Parenchyma + stroma
What is tumour stroma?
- everything around the tumour
- required for a cell to acquire the ‘hallmarks of cancer’ and become malignant
What is a common symptom of bladder cancer and why?
blood in urine - local effect because all the new blood vessels from the tumour are eroding into existing blood vessels
What is a common symptom of bowel cancer?
diarrhoea - local effect due to local inflammation and cell turnover which will irritate the lining of the bowel and lead to more water in stool
What is Lambert Eaton Mysthenic Syndrome?
a rare autoimmune disorder where the immune system mistakenly attacks the body’s own tissues
-paraneoplastic syndrome
