week 7 Flashcards
Driver mutations involved in cancer?
1) proto-oncogene (becoming oncogeene)
2) Tumour supressor gene
proto-oncogens when mutated become?
Oncogeenes
Burkitt Lymphoma mutation
dysregulated MYC expression on chromosome 8 and 14
* Excessive production of MYC proetein
Mutations involved in ‘Philadelphia’ chromosome in Chronic Myeloid Leukaemia (CML)
1) BCR –> chromosome 22
2) ALB1 -> chromosome 9
The translocation break point in BCR and ALB1 genes [involved in ‘Philadelphia’ chromosome in Chronic Myeloid Leukaemia(CML)] are located in gene ——–, which result in —-, ——- gene
The translocation break point in BCR and ALB1 genes [involved in ‘Philadelphia’ chromosome in Chronic Myeloid Leukaemia(CML)] are located in gene introns, which result in novel, chimeric gene
* chimeric gene –> BCR-ALB1 (increased gene activity)
[one/two] allele(s) of the proto-oncogene may need to be altered for tumour formation to be initiated
Only one
[1/2]alleles in Tumour supressor genes need to lose their function for tumour to develop
Both alleles
Inherited TSG loss-of-fx mutations increase significatnly the risk of cancer. how many hits are requried for cancer to develop?
Only second hit required
(these type of cancers are normally aquired at a younger age, may devlop in multiple, distinct sites. And may be bilateral like retinoblastoma)
Gene involved in Retinoblastoma?
RB1 gene
If inherited TSG loss of function is biallelic, phenotype is [milder/more sever]
More severe
Which gene cause Breast cancer in males
BRCA2
(Also includes prostatic cancer)
BRCA1 has higher risks in causing breast cancer, ovarien cancer etc in F
Surveillance management following diagnosis (BRCA1/2)
- SOS: Transvaginal ultrasound and serum CA-125
- MRI/ Mammograms (start at 30, or earlier for MRI)
- clinical surveillance (breast)
Faconi anaemia MoI and Mutation
MoI: AR
Mutation: BRCA2 ( 18 AR loci)
CM of Fanconi anaemia
1) microcephaly,
2) limb abnormalities (hypoplastic thumb/ radius),
3) abnormal skin pigmentation (hypo/hyper pigmentation),
4) ophthalmic,
5) genitourinary
6) Bone marrow failure with pancytopaenia
7) Increased risk for malignancy–Acute myeloid leukaemia, solid tumours
- Pancytopaenia –> deficiency of all three cellular components of the blood (red cells, white cells, and platelets)
Xerodema Pigmentosum MoI and Mutation
MoI: AR
mutation: XP gene
CM of Xeroderma Pigmentosum
1) Sun sensitivity (severe sunburn, blisters, freckling)
2) Ocular involvement (inflammation, keratitis, eyelid abnormalities)
3) Increase in skin cancer risk (sunlight-induced)
4) Neurological manifestations
Ataxia Telangiectasia MoI+ mutation
MoI: AR
Mutation: ATM gene
CM of Ataxia Telangiectasia
1) Cerebellar ataxia (1-4 years)
2) Telangiectasia
3) Immunodeficiency
4) Sensitivity to ionising radiation
5) Increased risk of malignancy (leukaemia and lymphoma)
Bloom Syndrome MoI and mutation
MoI: AR
Mutation: BLM
CM of Bloom Syndrome
Severe pre and postnatal growth retardation, sunsensitivity, increased cancer risk (wide variety)
Nijmegen breakage syndrome MoI and mutation
MoI: AR
mutation: NBS
CM of Nijmegen breakage syndrome
Progressive microcephaly, growth retardation, recurrent chest infections, increased risk of malignancy (lymphomas and solid tumours)
***
Lynch Syndrome MoI and mutation
* CANCER predisposition syndrome
MoI: AD
Mutation: MLH1, MSH2 (EPCAM*), MSH6, PMS2
* mutations in mismatch repaire genes
CF of Lynch Syndrome
1) Large number of polyps
2) Adenomatous polyps do develop in Lynch but they are in small numbers
***
Colorectal cancer is linked with a number of syndromes featuring ——
Colorectal cancer is linked with a number of syndromes featuring multiple polyps
***
Clinical management of Lynch syndrome (in individuals not diagnosed with cancer)
- Primary prevention:
–> Prophylactic removal of uterus and ovaries - Surveillance
-> Colonoscopy (from 20-25, every 1-2 years) and removal of adenomas is highly effective - Upper GI endoscopy and urinalysis
Peutz-Jegherssyndrome MoI + Mutation
MoI: AD
Mutation: STK11 tumour supressor gene
CF of Peutz-Jeghers syndrome
Characterised by:
1) Gastrointestinal polyps (hamartomas)
2) Mucocutaneous pigmentation
3) Cancer predisposition: includes Colorectal (39%), Breast (up to 54%), Gastric (29%), Small bowel (13%), Pancreas (up to 36%), ovarian tumours (21%, mainly sex cord)
Familial adenomatous polyposis (FAP) MoI and mutation
MoI: AD
mutation: APC gene tumour supressor gene
CM of Familial adenomatous polyposis (FAP)
1) Hundreds to thousands of adenomatous colonic polyps
2) By age of 35 most individuals with FAP have polyps
3) **Colorectal cancer develops if colectomy is not performed **
Extracolonic mifestations in FAP
1) polyps of duodenum/ stomach
2) desmoid tumours
3) Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE)
4) associated cancers (thyroid, small bowel, hepatoblastoma)
