Year 1 revision Flashcards
What is meant by multi-hit process?
number of mutations are required to generate a cancer
What are the hallmarks of cancer?
- Growth signals not required (uncontrolled growth and differentiation)
- Unresponsive to growth suppressors
- Evade apoptosis
- Defects in DNA repair mechanisms
- Cells become immortal
- Invade cells and metastasise
- Angiogenesis is sustained and increased
What is carcinogenesis?
multistep process of the transformation of a normal cell to a cancer cell
What is meant by transformation?
conversion of one cell phenotype to another
What is a carcinogen?
an agent (chemical, radiation, microbial) that induces changes in a cell population that can lead to cancer
Give examples of microbial carcinogens
Epstein-Barr virus - gastric adenocarcinoma
Human Herpes virus 8 - kaposi’s sarcoma
What is meant by differentiation?
Process by which a cell develops/matures which allows it to perform a specific function
What are the 3 main genes implicated in sporadic cell mutations?
Oncogenes
Tumour suppressor genes
DNA repair genes
What is an oncogene?
A gene that encodes a protein that is capable of inducing cancer
What is the effect of mutations in a proto-oncogene?
These mutations inappropriately enhance/activate cell signalling pathways, leading to uncontrolled growth and a lack of diversity/differentiation
What are the five classes of proto-oncogenes?
Growth factors Growth factor receptors Signal-transduction proteins Transcription factors Pro- or anti-apoptotic proteins
What growth factor is over expressed in:
- Benign Prostatic Hyperplasia
- Oesophageal Cancer
- Glioblastoma
- Vascular Endothelial Growth Factor (VEGF)
- Transforming Growth Factor alpha (TGF-a)
- Platelet Derived Growth Factor (PDGF)
What is Ras?
A GTP-binding molecule and a signal transduction protein
What occurs when Ras is mutated? (K-Ras)
Ras is permanently switched to the active state. Inappropriate activation results in unintended and uncontrolled signalling for cell division and differentiation in cells, causing cancer.
What types of cancer is EGFR over expressed in?
Colorectal cancer
Pancreatic cancer
Lung cancer
NSCLC
What types of cancer is Ras mutated in?
Pancreatic cancer
Papillary Thyroid cancer
Colon cancer
NSCLC
What types of cancer is B-Raf mutated in?
Melanoma
Papillary thyroid cancer
Colon cancer
What types of cancer is EGFR mutated in?
NSCLC
Glioblastoma
What types of mutations in proto-oncogene c-MYC occur in cancer, and are the effects of these mutations?
Translocations - promotes transcription of cyclin genes, which promotes cell cycle progression, e.g. in Burkitt’s Lymphoma.
In breast, colon and lung cancer c-MYC is overexpressed.
How does MYC induce tumourigenesis?
It evades multiple tumour-suppressing check point mechanisms, including:
apoptosis
proliferative arrest
senescence
What is apoptosis?
Physiological process that removes damaged or infected cells in order to maintain tissue homeostasis
How do cancer cells avoid apoptosis?
Upregulate anti-apoptotic proteins (e.g. BCL-2)
Downregulate pro-apoptotic proteins (e.g. Bax)
What are the cell cycle checkpoints?
G1 = entrance into S-phase is stopped if genome is damaged S = DNA replication is stopped if genome is damaged G2 = entrance into mitosis is stopped if DNA replication is not completed
When is p53 activated and what are the effects of mutations to p53?
P53 is activated in hypoxia, DNA damage or cell injury.
Mutations allow cells to progress through the cell cycle with DNA damage.
What is the effect of mutated pRB?
Prevents cell cycle progression past G1 phase by inhibiting the expression of S-phase genes.
What are the mechanisms of gene alteration?
Point mutations
Chromosomal rearrangements
Gene amplification
What are point mutations?
single base changes in DNA
What is the point mutation in Ras - KRas
Glycine to Valine (GGC to GTC)
What is chromosomal rearrangement?
Translocations/Transfer of genetic material from one chromosome to another
What is the most common translocation in Burkitt’s Lymphoma?
t(8:14) (q24;32)
What are examples of indirect acting carcinogens?
polycyclic aromatic hydrocarbons and alcohol
What are examples of direct acting carcinogens?
Radical oxygen species, chemical mutagens, UV radiation, X-rays
Name sources of spontaneous DNA damage.
Errors in proofreading Deamination Depurination Depyrimindination Oxidation
What is deamination?
Loss of NH2 - can change cytosine to uracil
What is depurination?
Spontaneous cleavage of bond between a purine base (A or G) and deoxyribose
What are DNA adducts?
Segment of DNA bound to a cancer-causing chemical - it is formed when a DNA base reacts with a carcinogen
How can tobacco smoke form DNA adducts?
BP (found in tobacco smoke) is oxidised by cytochrome p450, making it more soluble. This produces BPDE which is the ‘ultimate carcinogen’ and is able to form DNA adducts.
How are thymine dimers formed by radiation?
Bases are held together by hydrogen bonds which alpha, beta particles and x-rays are able to break. If two Thymine bases (pyrimidine bases) are beside each other and bonds holding bases together are broken, then these thymine bases can link together via covalent bonds forming thymine dimers which distort DNA.
What are the three critical determinants of tumour classification?
- Differentiation state
- epithelial
- non epithelia
- mixed - Embryonic origin
- ectoderm
- mesoderm
- endoderm - Biological behaviour
- benign
- malignant
What is an adenoma?
Tumour formed from glands
What is a papilloma?
Tumour with finger-like projections
occurs in epithelial tissues such as squamous epithelium or transitional epithelium
What is a cystadenoma?
Cystic tumour in ovary
What is a papillary cystadenoma?
Papillary pattern in cystic tumours forming glands
What is a polyp?
Tumour that projects above mucosal surface
What is the basic nomenclature for benign tumours?
What is the basic nomenclature for benign tumours?
Name of cell origin + morphological character + oma
e.g. Mesenchymal:
Fat = Lipoma
Fibrous/ connective = Fibroma
Bone = Osteoma
Cartilage = Chondroma
Epithelial/Endodermal:
Glandular = adenoma/papilloma/cystadenoma
Squamous epithelium = squamous cell papilloma
(look at table on benign tumour wiki page)
What is the basic nomenclature for malignant tumours?
Name of cell origin + morphological character + sarcoma/carcinoma
Epithelial = carcinoma Mesenchymal = sarcoma
What is a teratoma?
Tumour comprising of cells from more than one germ layer - it arises from totipotent cells. The most common teratoma = benign cystic teratoma of the ovary
What are the differences between benign and malignant tumours?
Benign:
- slow growing but progressive
- often encapsulated, oval or spherical
- low mitotic rate
- well differentiated
- non invasive/ basement membrane not breached
- non metastasising
Malignant:
- Fast growing
- Non-encapsulated, irregular shape
- high mitotic rate
- poorly differentiated
- invasive/basement membrane breached
- may be metastasising
Distinguish between well and poorly differentiated.
Well differentiated - resembles mature cells of tissue of origin
Poorly differentiated - primitive cells with little differentiation
Rate of growth is proportional to degree of differentiation
Aggressive growth pattern
Describe the process of metastasis
- vascularisation of tumour occurs - Upregulation of VEGF
- Cells detach from primary tumour
- Basement membrane is degraded and invasion into the ECM occurs
- Intravasation of nearby blood vessels
- Tumour cells circulate in the vascular system
- Some cells adhere to the walls of blood vessels
- Extravasation and migration to local tissue occurs
- Secondary tumour can then form after squeezing through blood vessels
What is the difference between the grading and staging of tumours?
Grading:
- Degree of anaplasia/ degree of differentiation
- Rate of growth
Staging:
- Size of tumour
- Extent of growth
What does GX mean?
The grade of the tumour cannot be assessed
What is TNM?
Tumour Nodal Metastasis
T - size of tumour and how far it has spread
N - Whether cancer has spread to lymph nodes (0-3)
M - Whether cancer has metastasised (0 or 1)
What is the Gleason Scale and how does it work?
This is the grading system specifically for prostate cancer.
Primary + secondary pattern = Gleason grade
What is a paraneoplastic syndrome?
Clinical syndromes not caused by direct invasion or metastasis of tumour which accompany malignant disease. Arise from tumour secretion of: - Hormones - Peptides - Cytokines
What is a neoplasm?
abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissues, and persists in the same excessive manner after cessation of the stimulus which evoked the change.
Neoplasms are irreversible.
What is hyperplasia?
proliferation of cells within an organ/tissue (excessive number of cells) - may result in formation of benign tumour
What is dysplasia?
abnormal growth and maturation of cells within a tissue (potentially early neoplastic process)
- some features of malignancy present
- transitional state between benign and malignancy
What features might be seen in dysplastic cells?
- Variability in nuclear size and shape
- increased nuclear : cytoplasmic ratio
- increased mitotic activity
- change in the relative numbers of specific cell types
What are the features of a normal prostate and a prostate with malignancies?
Normal:
- Columnar and some cuboidal cells
- Pale cytoplasm
- Inconspicuous nucleoli
- Basal cells are flattened/cuboidal
Malignant:
- Increased nuclear: cytoplasmic ratio
- Prominent nucleoli
- Absence of basal cell layer
- Hyperchromasia
What is seen in abnormal nuclear morphology?
Hyperchromasia Chromatin clumping Prominent nucleoli Little cytoplasm Increased nuclear: cytoplasmic ratio (>1:5 to 1:1) Frequent mitoses
Given an example of a translocation that results in over expression of Bcl-2? What cancer does this lead to?
(t14:18)(q32;21)
leads to follicular lymphoma
Overexpression of which growth factor can lead to breast cancer?
HER2/ErB2
Give an example of a point mutation that is seen in bladder cancer.
mutation in c-H-ras:
Glycine –> Valine
GGC –> CTG
Give examples of growth factors commonly associated with cancer.
EGF
HER2
Give examples of growth factors receptors commonly associated with cancer.
EGFR
VEGF
Give examples of signal transduction proteins commonly associated with cancer.
K-ras
B-raf
Give examples of transcription factors commonly associated with cancer.
c-myc
Give examples of anti-apoptotic proteins commonly associated with cancer.
Bcl-2
What do the following cancers have in common:
- Colorectal cancer
- Pancreatic cancer
- Lung cancer
- NSCLC
EGFR is over expressed
What do the following cancers have in common:
- NSCLC
- Glioblastoma
EGFR is mutated
What do the following cancers have in common:
- Pancreatic cancer
- Papillary thyroid cancer
- Colon cancer
- NSCLC
Ras mutation
What do the following cancers have in common:
- Melanoma
- Papillary thyroid cancer
- Colon cancer
B-raf mutation
Give examples of tumour suppressor genes that are ‘gatekeepers’.
p53
pRb
Give examples of tumour suppressor genes that are ‘caretakers’.
BRCA
MMR (mismatch repair)
Give examples of tumour suppressor genes that are pro-apoptotic.
Bax
In terms of histology, what is the difference between normal prostatic tissue and BPH?
Normal:
- tubuloalveolar glands
- basal cells
BPH:
- columnar arrangement near gland
- crowded tubules
- nucleoli not typically seen
What is the difference between low grade and high grade PIN, histologically?
Low grade:
- nucleoli are not prominent
- tissue appears almost normal
- intact basal layer
High grade:
- large nuclei
- hyperchromasia
- prominent nucleoli
- scattered basal cells along periphery
