22. Reproductive cancers Flashcards
What are the types of reproductive cancers?
Reproductive cancers:
- breast
- cervical
- ovarian
- endometrial
- prostate
- vulval
- vaginal
- penile
- testicular
What is a tumour?
Tumour - a tissue formed from excessive, uncontrolled proliferation of cells of irreversible genetic change - passed from one tumour cell to its progeny -> can be benign / malignant (cancer)
What is neoplasia?
Neoplasia - new growth
What are neoplasms?
Neoplasms - newly grown tissues - tumours - benign or malignant (cancer)
How are tumours classified?
Tumours can be:
- benign - stay localised at their site of origin
- malignant - able to invade and spread to different sites = cancer
- primary - tumours arise at primary site from cells normally present there
- secondary - metastatic tumours
What is the sequence of events in cancer development?
Development events:
1) mutation
2) hyperplasia (abnormal change in number)
3) dysplasia (abnormal change in cell morphology, organisation)
4) in situ cancer
5) invasive cancer (neoplasia - new growth)
What causes cancer to develop?
Mutation -> inactives tumour supressor mechanism -> cells overproliferate -> mutation inactivates DNA repair -> mutation of a proto-oncogene - oncogene -> mutation inactivates more other tumour supressor mechanisms => cancer
What are the main origins of cancer?
Genetics + epigenetics
What are the types of genetics aberrations which can cause mutations which cause cancer?
Genetic aberrations which cause mutations usually occur in S phase:
- duplication
- inversion
- deletion
- insertion
- translocation
Why are oncogenes usually called dominant acting?
Only one allele of oncogene needed to cause cancer - dominant acting oncogene
What are oncogenes?
Oncogenes - converted mutated proto-oncogenes - undergo activating mutations - cause cancer
What are proto-oncogenes?
Proto-oncogenes - normal oncogene version which does not cause cancer - but if aqcuires specific activating mutation - convert into cancer-causing
What genes cause cancer?
Cancer caused by:
- mutated proto-oncogenes
- mutated tumous supressor genes - ex: p53
What do oncogenes code for?
Oncogenes code for:
- a hyperactive version of a protein
or
normal protein but:
- in abnormal quantities
- at the wrong time
- in wrong cell type
Depends on the mutation and where it happens in the gene
Explain how does p53 work?
p53 - tumour supressor gene - inhibits cell cycle progression - arrests for DNA repair - depending on the damage -> apoptosis / metabolic homeostasis / DNA repair / growth arrest
Mutant p53 - dominant negative effect - prevents WT p53 from binding to target genes
Explain Li-Fraumeni syndrome
Li-Fraumeni syndrome:
- p53 mutation in the germline - predisposes the child to many cancers
What processes do cancer cells perform?
Cancer cells:
- proliferate - limitless replicative potential
- matastate
- invade tissues
- create inflammatory microenvironment
- insensitive to growth inhibitors - self-sufficient in growth signals
- sustain angiogenesis
- evade apoptosis
=> form tumours
What is angiogenesis?
Angiogenesis - growth of blood vessels from the existing vasculature
Explain how cancer performs metastasis
1) mutation
2) primary tumour formation
3) vascularization (angiogenesis)
4) detachment
5) EMT
6) intrainvasion
7) extrainvasion
8) invasion
9) secondary tumour
10) vascularization (angiogenesis)
repeat cycle
What are the routes of metastasis?
Metastasis can take several routes to spread:
- local invasion
- lymphatic spread (breast cancer)
- blood spread
- transcoelomic - spread in peritoneal cavity - lined by peritoneum membrane
Why is metastatic cancer not curable?
Metastatic cancer not curable because has spread - multiple locations + acquired different mutations - same therapy might not work for all cancer cells in the body
What is the most common female cancer?
Breast cancer - but survival increasing because of routine scans - can catch in early stages and prevent spread - usually in mid 60s
Explain how BRCA1/BRCA2 cause breast cancer
BRCA1/BRCA2 - tumour supressor genes - produce proteins involved in dsDNA repair -> in mutated BRCA1/BRCA2 - DNA not repaired efficiently -> increase in p53, cell cycle arrest, apopotosis or proliferation of cells - cancer
What is the typical diagnosis routine for breast cancer?
Explain between cancer stage vs grade
Stage = how advanced cancer is - stage I (local) - stage IV (metastatic)
Grade = how tissue looks under a microscope (histology) - higher grade - poorer prognosis
Why is immunohistochemistry performed in cancer diagnosis?
To figure out which receptors in cancer cells are present which could be ‘feeding’ them - ex: in breast cancer Abs for ER / PR / HER2 receptors
Explain how steroid can be driving cancer?
Estrogen in pre-menopausal women - from ovaries, in post-menopausal - from fat cells - in breasts -> higher estrogen levels signal for growth: binds ER - 2 bound ERs dimerize - move into the nucleus => gene activation
Explain how endocrine therapy can be used to treat breast cancer?
Endocrine therapy - affecting estrogen:
- aromatase inhibitors (AIs) - inhibit testosterone conversion into estrogen - no ER binding
- tamoxifen - synthetic estrogen analogue - prevents ER from dimerizing, moving into the nucleus and activating genes cells no longer ‘fed’ - can’t survive
Why is adjuvant tamoxifen beneficial?
Adjuvant tamoxifen taken 10 years after sugery - for all estrogen driven cancer cells to die off => lower rates of recurrence
Explain HER2 driven breast cancer
HER2 gene amplification - abnormal cancer cells with overexpressed HER2 levels - respond more to growth factor signals - initiate overproliferation
Treatment - Her2-targeted monoclonal Ab Trastuzumab
What is the test for exact HER2+ diagnosis in breast cancer?
1) Immunohistochemistry - Ab for HER2 - see if stained
2) FISH - if inconclusive (some stained) - perform FISH - see # gene copies of HER2 gene in cells
What are the therapies used to treat HER2 cancers?
Monoclonal Ab therapies which inhibit signaling:
- ligand-indep signaling
- ligand-dep signaling
- ligand dep+indep signaling
What are the stages of breast cancer?
What are the approaches for breast cancer management?
Approaches for breast cancer management:
- surgery
- radiotherapy
- chemotherapy
- immunotherapy
- targeted therapy
- hormone (endocrine) therapy
Explain cervical cancer
Cervical cancer - 4th most common maliganncy in women - mainly caused by HPV infection - from skin-to-skin sexual contact - if infection resolves - no cancer - return to baseline - but if not resolved => cancer
Explain cervical cancer physiopathology
HPV infection -> usally cleared in 3 years - if not -> persistance - genomic integration - latency incubation - invasion = carcinoma
Explain pap smear
Taking tissue swab - looking for abnormal cells which could indicate HPV
Explain colposcopy
Colposcopy - observing cervical surface using a microscope loooking for neoplastic cells
What is CIN and how is it assessed?
Cervical intra-epithelial neoplasia (CIN) - use histology to observe abnormal changes to squamous cells in cervix
Explain what is punch biopsy / large loop excision
Cervical cancer management strategies
What are the two origins of ovarian cancer?
Ovarian cancer can arise from:
- high grade serous - debated if arises from ovarian or oviduct cells - p53 mutation
- ovarian surface epithelium (OSE) and mullerian inclusion cysts
What are the screening options for ovarian cancer?
No screenings - but diagnosis via:
- measuring US / CA125 levels - elevated in malignancies
- CT scan
