Causes of cancer Flashcards

Question

Describe cell immortalization

Answer 1

Mutations in critical genes and maintainence of telomeres via telomerase or ALT pathways

Answer 2

Alternative lengthening of telomeres Strand invasion of the template molecule and formation of HR intermediate Copying Dissolution of HR intermediate Possible filling of complementary strands

Answer 3

Oligonucleotides complementary to the TERC template Telomerase targeted immunotherapy Targeting telomerase- expressing cells with suicide gene or oncolytic viruses

Answer 4

Receptor tyrosine kinase➡ PI3-kinase➡ PI(3,4,5)P3➡ PDK1➡ Akt➡ mTOR Cell survival and proliferation

Answer 5

Phosphorylates a variety of targets like Bad Upon phosphorylation Bad releases active apoptosis-inhibitory protein which promotes cell survival mTOR complex 1 (complex two helps to activate Akt)- contains the protein raptor, sensitive to rapamycin Stimulates cell growth by promoting ribosome production and protein synthesis and inhibiting protein degradation Akt inhibits the action of Tsc2 a GAP that inactivates the molecular switch Rheb, so Rheb remains GTP bound and can activate mTOR

Answer 6

Removal of receptor ligand Switching the activated RTK off using protein tyrosine phosphatases (PTPs- SHP1, SHP2) Dephosphorylation of target proteins by serine/threonine phosphatatases PTEN- inositol lipid phosphatase- removes s phosphate from PI(3,4,5)P3 spo jit is no longer a docking site for PDK1 or Akt

Answer 7

EGFR1 activated by ligands such as EGF and TGFalpha HER2 heterodimerises with EGFR1 Over expression and amplification of EGFR family members are implicated in 30% cancers

Answer 8

Cetuximab- humanised anti-EGFR1 antibody Only approved is patients with wildtype Ras Used to treat colon, lung, head, neck and pancreas cancer Trastuzumab (herceptin)- humanised anti-HER2 antibody Used in patients over expressing HET2 Used in breast cancer Imatinib- blocks the ATP binding site in the tyrosine kinase domain in the BCR-ABL fusion protein so it cannot phosphorylate target proteins and stimulate proliferation

Answer 9

Sarcomna in chickens can be transfered to previously undiseased chickens Caused by a virus Virus contains homologous genes to those found in the target species that cause the cancer- one must have been derived from the other- viral oncogene is a 'pirated copy' of the cellular gene (Using a radioactively labeled ssDNA copy of the v-src from Rous Sarcoma- annealed to melted chicken DNA)

Answer 10

Infection can lead to bursal lymphomas Lag in tumour development as the virus needs to be randomly inserted in to the genome close to the c-myc gene Provirus integration allows the strong enhancer in the LTR to induce deregulated transcription of the c-myc gene

Answer 11

Chromosomal translocation eg. 8:14/2/22 in Burkitts lymphoma The c-myc gene is placed near the immunoglobulin genes which are highly expressed in B cells and the expression of the c-myc gene is then constitutively increased Gene replication Double minute chromosomes

Answer 12

A transcription factor Heterodimerises with max to activate transcription of S phase genes Max homodimerises to suppress gene transcription in the absense of myc

Answer 13

Amino acid changes or over expression can lead to contituative activation or constant phosphorylation and cell growth cascades Eg. Pp60c-src a non-receptor tyrosine kinase- often over expressed in colon, liver, lung, breast and pancreas tumours binds to phosphorylkated receptors and the kinase domain becomes active leading to survival and proliferation

Answer 14

Commonest oncogene mutated in human tumours Common cancer causeoing mutations at codons 12,13 or 61 Is a molecular switch-inactive Ras-GDP➡ active ras-GTP (GEF) Ras-GTP➡ ras-GDP (GAP- Ra's has intrinsic GTPase) Reduced GTPase activity results in a constant 'on' leading to constitutive signalling ➡raf➡ mek➡ erk

Answer 15

Classical example for a genetic predisposition to cancer Recessive at the cellular level Almost inevitable that after all the necessary cell divisions that one retinal cell with acquire the mutation to inactivate the remaining RB1 gene in the heterozygote- therefore the cancer shows dominant inheritance Also shows increased incidence in other cancers- loss of heterozygosity RB is a master controller of the cell cycle controlling S-phase entry- when hyper-phosphorylated dissociates from E2F at R-point allowing the transcription of genes for S-phase

Answer 16

Deletion of chromosome region Whole chromosome loss Transcriptional silencing- aberrant methylation of promoter region Virus targeting

Answer 17

NF1- Ras-GAP- associated with Neurofibromatosis type 1 and colon carcinoma, astrocytoma, AML APC- beta-catenin degradation- associated with familial adenomatous polyposis coli and colorectal, pancreatic, gastric and prostate carcinoma PTEN- PIP3 phosphatase- associated with Cowden's disease, breast and GI tumours and glioblastomas, breast, prostate, thyroid carcinomas

Answer 18

It is the 'Guardian of the Genome' Regulates cell cycle arrest, DNA repair, block of angiogenesis and apoptosis in response to lack of nucleotides, UV, IR, oncogenic signalling, hypoxia, blockage of transcription Unlike most tumour suppressor a p53 mutations are predominately Mis-sense and a single allelic loss confers predisposition to cancer alone DNA damage stabilises p53 via phosphorylation so it is not ubiquitinated by MDM2 Mutations in the DNA binding domains prevent the transcription of cell cycle arrest proteins like p21

Answer 19

BRCA 1+2- DSB repair- associated with familial breast and ovarian cancers and breast, ovarian, prostate and pancreas ATM- DSB repair- associated with ataxia Telangiectasia, leukaemias, lymphomas and breast cancers