Cancer: A Genetic Disease COPY Flashcards
- what type of mutations in proto-oncogenes give rise to oncogenes?
- what are the three main mechanism of gene alterations that activate oncogenes?
1. gain of function mutations in proto-oncogenes give rise to oncogenes
- mechanisms:
- point mutations: single base change in DNA (e.g. Ras oncogene)
- chromsomal rearrangements: translocation of chr activates oncogene by using regulatory elements from a highly transcribed gene to drive expression of oncogene
- gene amplification (e.g HER2)
how does a point mutation in H-ras result in oncogene activation?
- (ras is a GTPase (converts GTP into GDP)
- normally regulates cell proliferation and survival)
- single nucleotide exchange GGC TO GTC in bladder cancers (glycine -> valine)
- get different isoforms of ras gene resulting in different cancers (see photo)
where is c-myc normally encoded?
where is IgH normally encoded?
explain cancer that occurs when the above translocate
- c-myc:* found on chr 8
- on chromsome 14, there is a gene that codes of IgH - has a very strong promoter
- translocation of region of chr 8 and 14: myc gets translocated near to promoter of IgH
- results in strong promoter driving the expression of myc: Burkitt lymphoma
what are the disease characterisitics of Burkitt lymphoma?
disease involves jaw, distal ileum, cecum, ovaries kidney or breast
explain another translocation that occurs with chromsome 14 IgH promoter
- strong promoter of IgH on chromosome translocates to chromsome 18
- switches ON bcl-2 gene (anti-apoptotic protein) in active B-lymphocytes (is normally switched off)
- cells that harbour mutations do not go into apoptosis
- causes lymphoma
which cancers do we see activated bcl-2 being upregulated in?
- leukaemia
- Non-Hodgkin lymphoma
- solid tumours
whats an example of gene amplification of oncogene?
overexpression of HER-2 _(_growth factor receptor) in breast cancer cells
what type of mutations inactivate tumour suppressor genes?
what does a mutation in p53 cause? - how often seen in cancer?
- Loss of function mutations inactivate tumour suppressor genes. often point mutations or small deletions.
- (sometimes somatic recombination during normal gene copy is replaced with mutant copy)
- mutation in p53 causes in cell cycle carrying on and not to stop in G1 (DNA repair) to occur. REPORTED IN NEARLY EVERY TYPE OF CANCER - just different rates
how does p53 mutation often occur?
- point mutations - results in missense mutation - change in sequence in protein doesnt allow it conduct normal function
- majority of mutations result in loss of function of p53’s ability to bind to DNA in a sequence specific manner and activate transcription of p53 target genes
describe how DNA methylation can lead to tumour suppression (epigenetics)
- in promoter AND downstream regions
promoter region:
- mutated tumour suppressor genes often undergo hypermethylation in promoter region (where the CpG island is).
- methylation moves from lysine 4 of the histone 3 (H3) (normal function) to lysine 9 of H3
- leads to transcriptional repression
- loss of tumour suppressor gene expression
Downstream of gene:
- repeat sequences undego hypomethylation
- leads to mitotic recombination and genomic instability.
what does difference in DNMT3B (DNMT3B - DNA methyltransferase 3 Beta) expression show in colon carcinomas?
- how can we use methlylation regions of promoter regions to predict cancer?
- normal -> v aggressive colon carcinoma: little expression of DNMT3B to intense expression of DNMT3B in nuclei
(DNMT3B - DNA methyltransferase 3 Beta)
- increased promoter methylation correlates with grade and stage of cancers
what is penetrance?
which classses of genes may be inherited mutations?
penetrance: the proportion of individuals carrying a pathogenic variant who will manifest the disease
- oncogenes
- tumour suppressor genes
- DNA repair
- cell cycle control
how does inheritance of germ line mutations APC and BRAC1 / 2 influence survival compared to those who are havent inherinted these genes?
(i think more for awareness)
what is Knudson’s two hit hypothesis?
- suggested susceptibility - multiple hits necessary to cause cancer
- a mutation in both alleles of tumour suppressor gene is required in order for malignancy to occur. a single functional tumour suppressor gene is usually sufficient for normal function
- sporadic cancer: needs two acquired mutations. tumour occurs at later age
- hereditary cancer: inherit one mutation and only need one hit to have both hits. tumour occurs earlier age
how does DNA damage occur by formation of DNA adducts in lung cancer?
in lung epithelial cells:
- (benzopryene (BP) from smoke is oxidised (x2))- results in BPDE (ultimate carcinogen)
- BPDE forms adduct with guanosine residues in lung epithelial cells
- occurs often in tumour suppressor genes, such as p53
(mutations in p53 gene are more common in smkers than non smokers)
explain other an example of DNA adducts causing cancers
oral and oespophageal cancers - caused by excess alchohol intake
- reaction: ethanol –> acetaldeyde
- acetaldeyde reacts with deoxyguanosine = weak mutagen. further reaction -> stronger mutagen (DNA adduct)
how do some viruses cause cancer?
- integrating viral genes (often oncogenes) into chromosomal DNA of infected cell
(picture is for awareness)
