Part 3

Tp53

A tumour suppresor that has active DNA repair processes

Arrests cell division if damage is severe 

Over half of human cancers have this mutation 

Also detects metabolic stress, hypoxia, dysregulated growth

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Li-Fraumeni syndrome

Congenital TP53 mutation 

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Lynch Syndrome

AKA Hereditary non-polyposis colorectal cancer 

Makes patients prone to many cancers: 

Colorectal

Endometrial 

Small bowel 

Ureter 

Renal 

Pelvis 

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Cachexia

Weakness and wasting of the body 

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Protooncogene

Promote cell growth and proliferation 

Regulation of apoptosis 

Regulation of differentiation 

Regulation of cellular life span

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Protooncogene

These are examples of? 

Ras(G12V)

Bcl-2 (over expression of anti-apoptitic Bcl-2) 

BCR-ABL (reciprocal translocation between C9 and C22 - CML) 

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Lung and Breast

Elevated expression of EGFR is commonly seen in what cancers? (2)

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TSGs

Requires loss of both alleles to result in dysregulation

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Chemotherapy

Targets the M phase of the cell cycle to prevent it 

Therefore preventing rapid growth of cells 

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Retinoblastoma (Rb)

A major cell cycle regulator 

Blocking transcription of E2F responsive genes, preventing the cell entering S phase 

Loss of this will therefore lead to loss of growth suppression 

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Choristoma

Tumour composed of normal cells / tissues, present in an abnormal place 

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Hamartoma

Tumour composed of disorganised growth of different cell types normally present in that organ

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Teratoma

Tumour composed of derivatives of all three embryological layers 

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EBV

Virus that can cause:

Hodgkins lymphoma 

Nasopharyngeal carcinoma 

Kaposi's sarcoma 

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Protooncogenes, TSGs, genes that regulate apoptosi

4 classes of normal genes that are damaged in carcinogenesis 

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Breast

Her2-neu (oncogene)

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Colorectal cancer

Kras (oncogene)

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Melanoma

BRAF (oncogene)

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DNA repair genes

Examples of what types of genes: 

BRCA 1 and 2 (double strand repair)

MMR genes (single nucleotide changes, very important pathway in Lynch syndrome) 

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BRCA 1 / 2

What gene mutation are these treatment methods targeting: 

Platinum based chemotherapies (carboplatin) - induces DNA cross links, cannot be repaired by gene deficient tumours due to defective homologous recombination - results in cell death 

PARP inhibition:

Accumulation of single strand DNA breaks - subsequently converted to ds DNA breaks - lethal to gene deficient cells 

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Lynch Syndrome

MMR genes: 

MLH1 

MSH2 AND 6

PMS 2 

Dominantley inherited 

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PD-L1

Blocks the immune systems response to High-microsatellite instability (MSI-H) 

Instability in short tandem repear sequences (microsatellite) is in mutated mismatch repair genes 

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PD1 inhibition of the T cell

Pembrolizumab 

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Hypercalcaemia

30% of patients with NSCLC will develop? 

Symptoms: 

Thirst, constipation, depressed and then confused 

Due to PTHrP release, stimulated resorption of bone 

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SIADH

15% of patients with SCLC develop? 

Incresaed H20 absorption at distal tubule and hence hyponatraemia 

F < 130 and M < 125 = confused state and seizures 

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BRCA1

Breast cancer = 70% 

Second primary breast cancer = 65% 

Ovarian cancer = 45% 

Prostate cancer (M) = 15% 

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BRCA2

Breast cancer = 70% 

Contralateral breast = 65% 

Ovarian cancer = 20% 

Male: 

Breast = 8% 

Prostate = 25% 

Pancreatic = 3% 

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BRCA 1 /2, PALB2, CHEK2del1100C, TP53

Breast cancer gene panel 

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Familial adenomatous polyposis

Caused by a mutation in the APC gene 

Rare <1%, cause of CRC 

95% will have polyps by the age of 35 

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Lifetime population risks

Breast = 11% 

Colorectal = 4% 

Prostate = 2% 

Ovarian = 1% 

Stomach = 1% 

Pancreatic = 1% 

Male breast cancer = 1% 

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Breast, cervical, colorectal

Current cancers screened in the UK 

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Sensitivity

Ability of the test to correctly identifty those who have the disease 

True positive 

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Specificity

Ability of test to correctly identify those who do not have the disease 

True negative 

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Cervical cancer screening

Females aged 25-64 

25-49 every 3 years 

50-64 every 5 years 

Both preventative and early detection

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HPV 16 and 18

Virus associate with 70% of cervical cancer cases 

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Bowel screening

FOBT every 2 years from 60-74 

Flexible sigmoidscopy from 55y/o 

High risk - risk intervention = full colonscopy 

Both preventative and early detection 

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Breast cancer

50-70 every 3 years 

2 view mammogram 

Not preventative but reduction in mortality 

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Patients who are BRCA1/2 +ve or other high risk ge

30-40 annual MRI 

40-50 annual MRI and mammogram 

50+ annual mammogram 

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