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
What are the most prominent breast cancer risk factors?
Most prominent breast cancer factors:
- age >50
- positive family history
- earlier menarche <12
- later menopause >55
- obesity
- alcohol
What are the genetic syndrome associated with breast cancer risk?
Breast cancer risk:
- BRCA1/BRCA2 mutation
- p53 mutation (ex Li-Fraumeni syndrome)
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 are the symptoms of breast cancer?
Breats cancer symptoms:
- new lump
- altered shape, size, pain
- skin changes
- nipple changes
- spread inflammation (rare)
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
What is a further diagnosis approach for classifying cancer?
Performing immunohistochemistry - ex: in breast cancer Abs for ERs / PRs / human epidermal growth factor (HER2) receptors
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
What are the risk factors for cervical cancer?
Cervical cancer risk factors:
- 45-49 age
- HPV infection
- multipel sexual partners
- non-barrier contraception
- immunosuppression
- smoking - reduces viral clearance
What are the approaches for diagnosing cervical cancer?
Diagnosing cervical cancer:
- vaginal and bi-manual examination
- pap smear - HPV testing
- colposcopy - observing cervical surface using a microscope loooking for neoplastic cells
- punch biopsy / large loop excision - -> excised out transformation zone from the cervix
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
Explain ovarian cancer
Ovarian cancer - 2nd most common gynaecological cancer after uterine - increased chance with age - silent killer because no specific, apparent symptoms - only when spread can be identified
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 spread routes for ovarian cancer?
Ovarian cancer spreads thorugh:
- direct extensions
exfoliation into peritoneal cavity - transcoelomic
- lymphatic invasion
What are the risk factors for ovarian cancer?
Ovarian cancer risk factors:
- age
- lifestyle factors
- oral contraceptives
- early menarche
- late menopause
What are the screening options for ovarian cancer?
No screenings - but diagnosis via:
- measuring US / CA125 levels - elevated in malignancies
- CT scan
What are the treatment options for ovarian cancer?
No specific treatment, usually not curative because of late diagnosis - surgery, chemotherapy, radiotherapy
