Theme 5 - Neoplasia: Part 3 Flashcards
1
Q
What is parthenogenesis?
A
Diploid embryo is produced without the occurrence of fertilisation. Second polar body is not extruded after the second meiotic division - produces 46, XX
(asexual reproduction when an embryo grows without fertilisation by sperm)
2
Q
What is androgenesis?
A
- Female genetic material is extruded from developing egg
- male genetic material is doubled up
- karyotype is 46, XX as if the sperm brought in a Y chromosome there would be no X so the embryo would not be viable
- could also have 46 XY
- male is sole source of genetic information
3
Q
Why would a hydatidiform mole form?
A
- from androgenetic conceptions
- complete hydatidiform moles
- mostly homozygous 46, XX
- proliferation of abnormal trophoblast tissue
- can develop into malignant trophoblastic tumour
- no embryo
4
Q
Why would an ovarian teratoma form?
A
- parthenogenetic conceptions
- benign tumour
- derived from oocytes which have completed first or both meiotic divisions
- diploid
- wide spectrum of tissues: predominantly epithelial, no skeletal muscle, no membranes/ placenta
5
Q
Why do uniparental conceptions fail?
A
- Different roles of maternal vs paternal genes in determining developmental fate
- genomic imprinting
- mothers and fathers somehow “imprint” their genes with a memory of whether they are paternal or maternal
- maternal and paternal chromosomes are not identical and cannot be substituted
6
Q
what is genomic imprinting?
A
A mechanism that ensures the functional non-equivalence of maternal and paternal genomes
- not encoded in the DNA nucleotide sequence i.e epigenetic - no difference in DNA sequence of maternal and paternal genes
- depends on modifications of the genome laid down during gametogenesis e.g spermatogenesis vs oogenesis
7
Q
In genomic imprinting, what does the ability of a gene to be expressed depends on?
A
the sex of the parent who passed on the gene
8
Q
What are the clinical features of angel man syndrome?
A
- facial dysmorphism
- prognathism (protrusion of lower jaw), wide mouth, drooling
- smiling, laughing appearance
- mental handicap
- microcephaly, absent speech
- seizure disorder
- ataxic, jerky movements
9
Q
What are the clinical features of Prader-Willi syndrome?
A
- infantile hypotonia -floppyness
- feeding problems, motor delay
- mental handicap
- male hypogenitalism
- small hands and feet
- hyperphagia
- obesity
10
Q
What is the cytogenic abnormalities in angel man and prader-willi syndrome?
A
deletion of chromosome 15
always de novo, recurrence risk is v low
11
Q
Angelman is caused by the loss of contribution to a region of chromosome 15 from which parent?
A
maternal
12
Q
Prader-Willi is caused by the loss of contribution to a region of chromosome 15 from which parent?
A
paternal
(this tells us there must be genes in chromosome 15 that behave differently when they’re inherited on a male and female chromosome)
13
Q
What is the molecular mechanism in Prader-Willi syndrome?
A
lack of paternal 15q11-13 contribution
14
Q
What is the molecular mechanism in Angelman syndrome?
A
lack of 15q maternal contribution
point mutation of UBE3A
15
Q
What is DNA methylation?
A
- epigenetic modification to genome (does not normally alter DNA sequence)
- DNA methyltransferases add methyl groups
- reversible because its epigenetic
- occurs at CG dinucleotides (CpG islands)
- causes gene silencing
16
Q
How can you distinguish maternal and paternal genes?
A
they show differences in their methylation status
17
Q
Explain one hypothesis about why imprinted genes are different?
A
The fetal-maternal growth conflict:
- evolution favours genes that promote foetal growth
- growth genes are more likely to be passed on by father even if its at the expense of maternal health because the mother must survive pregnancy and delivery herself
- so paternal genes act to promote foetal growth but maternal genes act to repress
18
Q
What is the cytogenic abnormality that causes Beckwith-Wiedemann syndrome?
A
- 11p15
- sporadic occurence
- IGF2 is found on chromosome 11
- too much IGF2 production causing fetal overgrowth
19
Q
What are the clinical features of Beckwith-Wiedemann syndrome?
A
- fetal overgrowth
- high birthweight (>5kg)
- organomegaly
- exomphalos
- hypoglycaemia
- asymmetry
- tumour risk
20
Q
What are the clinical features of Russel-Silver syndrome?
A
- 11p15.5
- too little IGF2 production
- growth retardation
- persistent post natal growth failure
- triangular face
- brain size more preserved
21
Q
What happens to the methylation of IGF2 in BWS and RSS?
A
- usually, IGF2 is imprinted and expressed from the paternal allele
- in normal state, IGF2 gene on maternal allele is methylated but on IGF2 gene on paternal allele it is unmethylated
- this methylation changes in BWS and RSS
22
Q
What is imprint “switching”
A
- erasure of grandparental imprint
- establishment of new parental imprint during gametogenesis
- correct imprinting is required for normal growth development
23
Q
What is a pseudoautosomal region?
A
regions of X and Y chromosomes that share the same genes
24
Q
How can male and female cells ensure equivalent dosage of genes located on chromosome.X?
A
In females, mono allelic expression is needed to ensure balance with Y chromosome. This is achieved by epigenetic silencing (X inactivation)
25
When does X inactivation occur?
- randomly in cells of the early blastocyst
- after fertilisation, we start with 2 X chromosomes - one maternal and one paternal. each cell decides to shut one of these down
26
What are the differences in imprinting and X inactivation?
In X-inactivation:
- whole X chromosome is silenced - as oppose to a single gene
- random choice of parental chromosome
- different in different cells
- occurs early in embryogenesis
27
What is uniparental disomy?
both copies of a chromosome from one parent
28
What are the consequences of X-inactivation?
- females are "epigenetic mosaics"
- carrier of X-linked mutations have some cells that are functionally defective and some normal cells
- this may bring physical manifestations of the disease
29
What is hypohidriotic ectodermal dysplasia?
- genetic skin disease
- patches of skin with or without sweat glands
- in males, inability to sweat
30
What is the two-hit hypothesis?
Knudsons hypothesis: most genes require two mutations to cause a phenotypic change
familial cancer - has one mutation since conception - already one step closer towards cells becoming malignant
-if first hit is a gremlin mutation, second somatic mutation is more likely to enable cancer
31
Explain how Knudsons two hit hypothesis can explain retinoblastoma?
- two hits required in a single cell
| - one additional hit required in a single cell
32
What is the difference between sporadic and familial cancer?
Sporadic - both alleles in cell must acquire mutation to become cancerous as there is then no functioning copy of gene
Familial - all cells already have this gene affected by mutation so there only needs to be one more allele with this mutation
This explains why familial cancer is more likely, and why cancer is earlier in onset if there is a genetic predisposition
33
What are 3 important cancer genes and what are there functions?
1. gatekeepers - directly regulate tumour growth: monitor and control cell division and death, preventing accumulation of mutations
2. caretakers - improve genomic stability e.g repair of mutations
3. landscapers - control the surrounding stromal environment
34
What is the linklihood of developing cancer related too?
depends on the important of the gene function that contains the mutation e.g a mutation in a gatekeeper gene will make risk of developing cancer high
35
What are 4 examples of TSGs?
APC, BRCA1/2, TP53
36
How can you work out if cancer is familial or sporadic?
sporadic:
- onset at older age
- one cancer in individual
- unaffected family members
- cancers that are rarely genetic e.g lung
familial:
- onset at younger age
- multiple primary malignancies in individual
- other family members affected
37
How are BRCA1/2 genes associated to increased risk of cancer?
- involved in DNA repair
- autosomal dominant inheritance
- risk of breast cancer if mutation - 80%
- risk of ovarian: BRCA1-40%, BRCA2- 10/20%
- some increased risk of other cancers e.g prostate, melanoma, male breast cancer
38
What is Lynch syndrome?
- aka HNPCC
- most common cause of hereditary colorectal cancer
- mismatch repair genes: 50% MLH1, 40% MLH2
- polyps are common - removal of these improves survival
- role of aspirin in prevention
39
What criteria is used to assess risk of HNPCC?
Amsterdam criteria
40
What is FAP?
Familial Adenomatous polyposis:
- hundreds of bowel polyps (adenomas) from teens onwards
- high risk of bowel cancer if untreated
- autosomal dominant inheritance
- APC TSG
41
What is Li Fraumeni syndrome?
- autosomal dominant
- P53 mutations
- 50% risk of cancer by age 40, close to 100% lifetime
- breast, sarcoma, brain, leukaemia
- poor prognosis
42
If a 36 year old mother was diagnosed with colorectal cancer, are the children eligible for a colonoscopy?
yes because bowel cancer in 30s is extremely uncommon - likely familial
43
What are condyloma acuminatum?
genital warts
44
What is LSIL?
Low grade squamous intraepithelial lesion - warts
45
What are warts caused by?
HPV
46
What are the risk factors for developing CIN for women? (cervical intra-epithelial neoplasia)
- HPV infection (main risk factor)
- first coitus (sexual experience) < 17 years of age
- multiple sexual partners
- long term OCP use
- early first pregnancy
- high parity (multiple pregnancies)
- STDs
- smoking
- immunosuppression including HIV
47
What are the risk factors for developing CIN for men? (cervical intra-epithelial neoplasia)
- HPV infection
- penile warts
- multiple sexual partners
- cervical cancer in a previous partner
48
Is HPV a necessary cause of cervical cancer?
Yes - 99.7%
49
What are the two main types of HPV?
Low risk (non cancer causing):
HPV6 and HPV11
High risk (cancer causing):
HPV 16 and HPV 18
50
what is the objective of NHS SCP (cervical screening programme)?
- primary human papilliomavirus screening
- screening done by liquid based cytology to detect abnormalities of cervix
- if abnormal, referred to colposcopy to diagnose intraepithelial neoplasia (CIN) and to differentiate high-grade lesions from low grade abnormalities
51
What is Gardasil?
HPV vaccination in England used since 2012 - for HPV types 6/11/16/18
52
What is the significance of the transformation zone in the cervix?
- TZ ; area between original and new SCJ where the columnar epithelium is being replaced by new metaplastic squamous epithelium
- TZ may be wide or narrow depending on age, parity, prior infections and exposure to hormones
- TZ is prone to oncogenic effects of HPV; hence is the site of CIN development
53
What are the 4 types of Pap smear appearances?
1. Normal
2. CIN1 - low grade
3. CIN2
4. CIN3 - high grade
5. Cervical cancer
54
What are the morphological features of CIN I?
- maturation is seen in upper 2/3 of epithelium
- some degree of nuclear abnormality
- normal mitotic figure's may be increased
55
What are the morphological features of CIN II?
- cytoplasmic maturation is seen in upper 1/3 of epithelium
- nuclear atypia more marked than CINI
- MF's increased; atypical mitosis common
56
What are the morphological features of CIN III?
- maturation may be absent or confined only to superficial layers
- nuclear atypia is severe, through full epithelial thickness
- MF's are seen at all levels of epithelium
57
What does p16 treatment do?
differentiate between CIN II and CIN III and immature squamous metaplasia
58
How do you treat CIN?
- colposcopy - wire loop through external opening of cervix
| - LLETZ slicing
59
What is stage 1 cervical squamous cancer?
- tumour confined to the cervix
- types: T1A, T1a1, T1a2, T1b, T1b1, T1b2
- 5 year survival is 85%
60
What is the extent of spread of disease in Stage 2, 3 4 cervical cancer?
2- disease beyond cervix but not to pelvic wall or lower 1/3 of vagina
3- disease to pelvic wall or lower 1/3 of vagina
4- invades bladder, rectum or metastasis
61
What are some names of different cervical tumours?
- adenosquamous carcinoma
- adenoid basal carcinoma
- adenoid cystic carcinoma
- neuroendocrine tumours
62
What are the two types of VIN? (Vulval intraepithelial neoplasia)
1. uVIN:
- usual type/ undifferentiated
- graded VIN 1-3
- HPV related
- younger women, <40
2. dVIN:
- differentiated type
- not graded
- not HPV related
- older women
63
Is uVIN or dVIN more likely to progress to squamous cell carcinoma?
- dVIN
| - recurrence correlated to smoking, multifocality (arising from many locations) and positive margins
64
Which cancer is VIN associated with?
Vulval squamous cell carcinoma
65
What is Paget's disease?
- 1% of vulval cancers
- mean age 7-s
- pruritus, burning, eczematous patch
- bones become fragile and misshapen
- commonly occurs in pelvis, spine, skull and legs
66
What do lobules in the breast do and what are they made of?
- make milk and can develop carcinomas
- look like bundles of grapes
- lobules are made up of lots of ringed structures called acini
67
What is your areola?
the small circular area pigmented around your nipple (brown area)
68
What is the lactiferous duct?
where milk comes out of - links up to lobules of breast
69
What is the NICE recommendation if a breast lump is found?
Refer using suspected cancer pathway (appointment within 2 weeks) if person 30 or older and has unexplained breast lump
70
What are the 6 causes of breast lumps?
1. Fibroadenoma - benign tumour composed of a proliferation of the glandular and stroma elements
2. Hamartoma - benign abnormal mixture of cells
3. Lipoma - tumour of the fat
4. Cyst
5. Fibrocystic change - constellation of benign changes in the stroma and glands
6. Carcinoma - malignant transformation of epithelial glandular parts of breast
71
What features of a breast lump are you looking for?
- mobile or fixed
- well-defined or not
- smooth or irregular
- firmness
- location
72
What are nipple symptoms of breast cancer?
- inversion
- rash
- discharge
73
What skin changes might you experience in breast cancer?
- tethering/retraction - skin pulled in by lump
- oedema - swollen
- "peau d'orange" - 'orange peel skin'
- ulcerating/ fungating lesion
74
What is the clinical P code?
```
P1 - normal lesion
P2 - benign lesion
P3 - atypical, probably benign lesion
P4 - atypical, probably malignant lesion
P5 - malignant
```
75
What colour is fat on an ultrasound?
white
76
What colour is fibroglandular breast tissue on an ultrasound?
black
77
What is a mammogram?
X-ray of breast from several angles
| -solid masses are shown as white (radio-opaque) and fat (black)
78
What is the difference between biopsy and cytology?
cytology just pulls out cells whereas biopsy takes tissues
79
What do BRCA genes do?
genes that encode TSGs
80
What is an example of targeted treatment in breast cancer?
- oestrogen plays a key role in the development of breast cancer and stimulates the growth of tumour that express oestrogen receptors (ER positive)
- endocrine therapy e.g tamoxifen used in these cases to block the effect of oestrogen on the tumour cells and improve prognosis
81
What is Her2 and how can it influence treatment?
- Her2 is one of the human epidermal growth factor receptors that sit on cell membrane
- the Her2 gene is amplified in 20-25% of breast cancers and predicts poorer prognosis
- Herceptin is an antibody that targets and blocks the receptors improving the prognosis in her2+ cases
82
What are the types of surgery available for breast tumour removal?
- wide local excision
- mastectomy
- sentinel lymph node biopsy
- axillary node clearance
