question

difference between inherited germ line mutation and a somatic cell mutation

answer

inherited germ line mutation - mutated gene inherited and other members of family have disease, cancers tend to develop at relatively young age, e.g. retinoblastoma somatic cell mutation - due to replication errors in DNA which is compounded by carcinogens

question

describe the behaviours of a cancer cell

answer

uncontrolled proliferation - gain of function oncogenes, loss of function of tumour suppressor genes immortalisation - telomerase replacing TTAAG repeats so uncontrolled proliferation may occur. this is essential for cancer stem cells but not for others that differentiate from it altered gene expression - different genes/proteins invasion/metastasis - metalloproteinases degrade cellular membrane large tumour masses - has stroma for support but also undergoes necrosis due to hypoxia (hypoxia reduces sensitivity of radiation/chemo and drusg penetrate poorly into these area)

question

describe aberrant GF signalling

answer

normally, GF binds to extracellular domain, monomers dimers adn cross-phosphorylation occurs mutations can result in ligand-independent firing. EGFR is a proto-oncogene. mutation turns it into an oncogene

question

describe HER2 gene mutation and amplification

answer

HER2 is in family of epidermal growth factor receptors mutation can cause ligand-independent firing of receptor. amplification seen in cancers and can occur at DNA, mRNA or protein level

question

describe the regulation and control of EGFR

answer

normally EGFR internalised into vesicles and degraded into lysosomes. if degradation inhibited, more EGFR in cell surface and longer sustained signal of downstream markers, e.g. p38 also, positive feedback enhances effect if there is an increase in EGFR receptor - one of downstream genes involve mRNA for synthesis of EGFR

question

describe the use of mAb-drug conjugates

answer

antibody makes targeting of drug to cell specific, e.g. trastuzumab-emtansine - trastuzumab targets HER2 overexpression

question

describe the actions of anti-EGFR drugs

answer

these are small molecule inhibitors that inhibit tyrosine kinase activity useful against antibodies as antibodies can't penetrate solid tumours

question

describe the features of malignant tumour tissue

answer

loss of normal tissue architecture multinucleate cells invasion of surrounding tissue

question

outline how HER2 is a biomarker in breast cancer outline the grading

answer

increased gene copy identified using FISH ELZA used - anti-HER2 antibodies with enzyme-linked secondary antibody grading; 0-1; normal HER2 levels (negative) 2; moderate levels; anti-EGFR with herceptin (trastuzumab) recommended 3; high (positive)

question

outline how oestrogen receptor is a biomarker

answer

dimerises and translocates to nucleus, biomarker present in 70% of cancers

question

which drug blocks the translocation of the oestrogen receptor to the nucleus (seen in 70% of cancers)

answer

tamoxifen

question

describe dominant viral oncogenes

answer

viral genes able to induce a dominant phenotype - viral oncogenes can dictate cellular behaviour despite continued presence and expression of opposing cellular genes that would normally ensure normal proliferation

question

describe how proto-oncogenes can be activated to oncogenes through mutation

answer

can be through single nucleotide change, e.g. H-Ras oncogene activation through single DNA mutation from glycine to valine

question

describe how proto-oncogenes can be activated to oncogenes through oncogene amplification

answer

number of oncogenes may affect lower probability of event free survival over time seen with number of copues of N-myc determining neuroblastoma prognosis

question

describe how proto-oncogenes can be activated to oncogenes through translocation between chromosomes

answer

de-regulation of proto-cocogene regulation; philadelphia chromosome - abnormality in chromosome 22 of chronic myelogenous leukaemia (CML) where Abl1 of chrom. 9 juxtaposed onto BCR of chrom. 22 over-expression of BCR-Abl - this is a tyrosine kinase that inhibits DNA repair and drives cell division

question

describe the chromosomal translocation seen in burkitt's lymphoma

answer

promotor placed in front of oncogene (myc and bl-2)

question

describe the basis for familial retinoblastoma

answer

typically bilateral and due to mutated allele being inherited in an autosomal dominant fashion

question

describe the basis for sporadic retinoblastoma

answer

typically unilateral and two new mutations are required in the alleles

question

describe the two hit model that explains the development of retinoblastoma

answer

both alleles need to be affected case of familial tumour consistent of single random somatic mutation as first mutation has already been inherited case of sporadic tumour consistent with 2 random somatic mutation

question

what are the mechanisms proposed for the inactivation/loss of tumour suppressor gene

answer

mitotic recombination leading to loss of heterozygosity (LOH); gene conversion leading to LOH; chromosomal non-disjunction and LOH; lack of repair leading to LOH;

question

describe mitotic recombination leading to loss of heterozygosity (LOH)

answer

mitotic recombination leads to defect gene being in two chromatids in either homologous chromosome

question

describe gene conversion leading to LOH

answer

same area copied from template strands of both chromosomes so mutant allele may replace the wild-type allele on its homolog

question

describe chromosomal non-disjunction and LOH;

answer

missegregation of chromosomes during mitosis leading to daughter cell retaining both chromatids of chromosome (rather than single one) and extra chromosome which is shed to revert to homozygous diploid state

question

describe lack of repair leading to LOH

answer

chromosomal region breaks off and is not repaired. leads to hemizygosity of this region where all genes of the chromosomal arm is present in single copy rather than two copies of cell

question

describe epigenetic changes in cancer

answer

hypomethylation of DNA and loss of histone methylation means that chromatin becomes unwrapped and unsilenced

question

describe the importance of p53

answer

key cell cycle regulator - guardian of the galaxy, molecule of the year and has won various other awards can stop cell cycle, repair DNA, apoptose cell. cell loses ability to halt excessive proliferation if p53 is not working properly

question

how doe IFN-gamma affect tumour growth

answer

important for immunity so blocking IGN-gamma results in tumour growth

question

how can the immune system respond to a tumour

answer

antibodies against tumour antigens tumour specific T cells tymour infiltrating lymphocytes; infiltration of CD8 T cells improves prognosis

question

outline immunoediting in humans

answer

elimination phase - immune system destroys tumour formation equilibrium - tumour resists immune cells through genetic instability/immune selection escape - when tumour overpowers immune system

question

describe the control of CD8 T cells through co-inhibitory molecules through CTLA1 and PD-1

answer

CTLA1; normally CD28 binds to B7.1/2 (CD80/CD86) but CTLA1 binds to B7.1/2 with higher affinity than CD28 mutations in CTLA is lethal in utero as there is unregulated proliferation of T cells PD-1; expressed on T cell and binds to PD-L1 and PD-L2 on target cell to decrease T cell response

question

actions of ipilimumab

answer

anti-CTLA4 antibody that binds to t cell CTLA4 and prevents co-inhibitory response

question

actions of nivolumab

answer

anti-PD1 antibodies blocking interaction between PD1 on T cell and PD-L1 on tumour cell

question

outline the chemotherapy agents available

answer

alkylating agents anti-metabolites intercalating agents spindle cell poisons topoisomerase inhibitors

question

outline the different timing variability of chemotherapy

answer

neo-adjuvant; before surgery to shrink tumour mass adjuvant; after surgery to remove micro-metastases and reduce risk of recurrence curative; certain tumours respond extermely well, e.g. leukaemia/lymphoma with rapidly dividing cells so high response rates palliative; patient has metastatic disease but aim to control tumour for as long as possible

question

describe why the probability of cure is inversely porportional to the tumour burden

answer

large tumour burden presents; probability of metastasis resistant clones smaller growth fraction more cycles of treatment

question

importance of MDR-1/P-glycoprotein

answer

this is an efflux pump that is overexpressed in some cancer cells that pumps out most cytotoxic chemotherapy drugs

question

outline renal cell cancer targets and side effects of targeting these targets

answer

VEGF/VEGFR pathway activated use VEGF inhibitors/drugs that are active on tyrosine kinase downstream side effects; hypertension, rash, diarrhoea, hair colour changes (hair becomes white when you are on the drugs)

question

outline colorectal cancer targets

answer

EGFR signalling targetted - antibodies to this signalling pathway/inhibitors of tyrosine kinase downstream from EGFR, there may be a mutated KRAS. anti-EGFR treatment only works if there is no mutation in KRAS, otherwise cells will continue to proliferate as a result, colorectal cancer screened for KRAS mutation as this determines effectiveness of anti-EGFR treatment

question

what is the difference between a chimeric and a humanised antibody state their suffix

answer

chimeric antibody - graft mouse V regions onto human constant region chimeric antibodies end in -ximab humanised antibody - graft mouse CDR into human V region humanised antibodies end in -zumab

question

rituximab

answer

chimeric antibody used for non-hodgkin's lymphoma binds to CD20 on normal and malignant B cells but does not bind to immature B cells so B cell population can be re-establishde

question

bevacizumab

answer

also known as avastin anti-VEGF - prevents growth of tumour blood vessels by neutralising VEGF which is a potent cytokine for angiogenesis humanised with IgG1 C-regions

question

panitumumab

answer

anti-EGFR - binds to EGF and prevents activation used in colorectal cancer

question

describe how antitumour effects may be achieved

answer

antibody dependent cellular cytotoxicity - IgG on tumour and FcgammaR on NK cells activates lysis through perforin/granzymes. mAbs binding to antigen can also cause C1q binding leading to complement dependent cytotoxicity - formation of MAC and then cell lysis direct cytotoxicity - Fc dependent phagocytosis and lysosomal degradation antibody mediated signaling inhibition - mAbs can inhibit ligand binding/dimerisation/activation of signalling cascade

question

describe ADCs and how they work

answer

antibody-drug conjugates - antibody linked to cytotoxic agent. ADC bind to antigen, ADC-antigen internalised, cytotoxic component disassociates in lysosome most cytotoxic components bind to minor DNA groove (strand breakage) or tubulin (microtubule disruption) leading to apoptosis

question

describe pretargeting

answer

antibody linked to non-toxic molecule given, concentrates in tumour and cleared from circulaiton. then therapeutic component given which is activated by binding to first component gives high concentration of therapeutic agent in tumour with lower levels in normal tissues

question

outline some uses of antibodies in cancer treatment

answer

recruiting natural effectors - ADCC, CDC, phagocytes neutralise growth factors, e.g. VGEF block receptors stimulate apoptotic signalling deliver cytotoxic drugs

question

use of imatinib in treating CML

answer

almost all CML patients have balanced translocation between chromosome 9 and 22 causing Bcr-Abl fusion gene which activates kinase inhibitor. kinase inhibitor important to maintain tumour imatinib blocks signalling pathway

question

use of BRAF inhibitors in melanoma

answer

half of melanoma patients have mutation in C600 codon in BRAF which is a part of MAPK pathway. when MAPK pathway activated, allows cell to proliferate without growth factors BRAF inhibitors can inhibit this pathway

question

describe clinical resistance mechanisms in tumours

answer

primary (intrinsic) - disease progression despite therapy secondary (acquired) - shrinks/becomes stable but then progresses

question

describe molecular resistance mechanisms in tumours

answer

intrinsic drug resistance - resistance-mediating factors pre-exist acquired drug resistance - develops during therapy so tumour initially sensitive then becomes resistant

question

why do 20% of patients with mutant melanoma do not respond to BRAF inhibitors

answer

shows primary resistance mechanisms - mutations in other pathways can cause same activation in proliferation, bypassing BRAF mutation inhibition secondary resistance may show mutation in MEk which is more downstream

question

general rules surrounding viruses and neoplasia

answer

inverse relationship between viral replication and cell transformation. apart from burkitt's lymphoma, virus either replicating or inducing neoplasia. viral infection not sufficient alone - needs accummulation of gnetic errors cancers caused by viruses are a biological accident

question

describe an abortive infection

answer

when viral infection no longer productive and virus transforms to produce neoplasia, known as abortive infection

question

describe the core genes in papillomavirus genome

answer

E1/E2 for packaging L1/L2 for replication most of HPV associated cancers due to HPV 16 - due to way in which E6 and E7 is expressed. can act as oncogenes when dysregulated

question

describe how HPV can cause cervical cancer

answer

site is infected epithelium. cervical cancer mostly arises from transformation zone - infects reserve (stem cells) and junctional cells virus infects cells at bottom of epidermis that are mitotically dividing - prolonged infection as basal cells give rise to one differentiating cell and one that remains in layer in certain sites, e.g. cervical transition zone, more E6 and E7 so higher grades of neoplasia. eventually cancer develops

question

low risk HPV infect in same way but why do they not cause cancer

answer

they do not drive neoplasia as their E6/E7 expression differs

question

actions of E7 on HPV causing cervical cancer

answer

drives cell cycle entry in absence of growth factors. normally, cyclin D controls cell cycle entry and is controlled by p16 but p16 can't contribute as a negative feedback system as E7 is controlling cycle and not cyclin D neoplasia

question

actions of E6 on HPV causing cervical cancer

answer

affects growth suppressive functions of p14 p14 prevents breakdown of p53 and stimulates apoptosis. E6 is an oncolytic gene that leads to degredation of p53

question

describe cervical screening in preventing cervical cancer

answer

cervical cancer due to papillomavirus takes deades to develop so smear testing can look at abnormalities at surface of epithelium does not impact on women younger than 30

question

describe vaccination in preventing cervical cancer

answer

gardasil for HPV 6, 11, 16, 18 given to females before sexual activity - around 11/12 years of age. not given to men as not cost effective but offered to men who have sex with other men

question

describe how beta papoillomavirus can lead to skin cancer

answer

low risk skin viruses which may be dysregulated in immunocompromised leading to skin cancer beta papillomavirus E6 prevents repair of genetic damage. if immunocompromised, excessive UV may cause mutations. beta papillomavirus associated with accummulation of errors rather than viral cell maintenance so may bot be present in final cancer 'hit and run' mechanism predisposes to cancer beta E7 protein not a potent driver of cell proliferation

question

describe the pathogenesis behind merkel cell polyomavirus

answer

immunosuppression causes re-emergence T antigens in MCV genome bind to and inhibit Rb and p53

question

describe how epstein barr virus can lead to burkitt's lymphoma

answer

transmission in kissing - glandular fever, musocal epithelium of nasopharynx and salivary glands infected and virus establishes latent B cell infection predisposes to genetic errors, including recripocal c-myc translocation

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