genetics of cancer Flashcards
tumour suppressor genes: explain how tumour suppressor genes have been discovered through heritable malignancies, summarise the roles of p53
what are tumour suppressor genes
proteins whose function is to regulate cellular proliferation and maintain cell integrity
how many copies of each tumour suppressor gene does each cell have
2
what does mutation or loss of one, and then both, copies of tumour suppressor gene mean
mutation/deletion of one gene copy usually insufficient to promote cancer (although some patients have haploinsufficiency); mutation/loss of both copies means loss of control
describe Knudson’s 2 hit hypothesis: sporadic cancer
2 acquired mutations from environment leads to tumour
describe Knudson’s 2 hit hypothesis: hereditary cancer (predisposition for cancer)
1 inherited mutation, followed by 1 acquired mutation from environment, leads to tumour
6 features of inherited cancer susceptibility
family history of related cancers, unusually early age of onset, bilateral tumours in paired organs, synchronous or successive tumours, tumours in different organ systems in same individual, mutation inherited through germline
what is a retinoblastoma, and what was it used to learn more about
malignant cancer of developing retinal cells, which led to greater understanding of tumour suppressor genes
what does sporadic retinoblastoma usually involve, compared to hereditary retinoblastoma
sporadic retinoblastoma usually involves one eye, hereditary retinoblastoma can be unilateral or bilateral and multifocal
what is the inherited “hit” of hereditary retinoblastoma
RB1 tumour suppressor gene on chromosome 13q14
what does RB1 encode
nuclear protein involved with CDK4 and 6 (G1 -> S) in cell cycle regulation
4 functions of tumour suppressor genes to suppress neoplastic phenotype
regulate cell proliferation, maintain cellular integrity, regulate cell growth, regulate cell cycle
4 types of tumour suppressor genes
nuclear transcription factors, DNA repair proteins, cell adhesion molecules, cell death regulators
3 examples of cell cycle regulator tumour suppressor genes
p53, BRCA1, p16-INK4A
example of tyrosine and lipid phosphatase tumour suppressor gene
PTEN
example of cell signalling tumour suppressor gene
APC
example of mismatch repair tumour suppressor gene
MLH1
what 9 things does p53 (“guardian of genome”) respond to
oxidative stress, nitric oxide, hypoxia, ribonucleotide depletion, mitotic apparatus dysfunction, oncogene activation, DNA replication stress, double-strand breaks, telomere erosion
consequence of p53 responding to so many things
can’t respond to something individually (e.g. double-strand breaks) without affecting everything else
2 types of mutations affecting p53
driver (cause cancer) or passenger (have just developed)
what protein does p53 partner with, and what does it do
MDM2 (mitotic regulator which regulates p53)
in mild and physiological stress, what target genes does p53 regulate
metabolic homeostasis, antioxidant defence, DNA repair, growth arrest, senescence
in severe stress, what do protein-protein interactions of p53 cause
apoptosis
what do mutants of p53 act in (vs many other tumour suppressor genes)
dominant manner, and mutation of single copy is sufficient to get dysregulation of activity
what does APC tumour suppressor gene drive
familial adenomatous polyposis coli
what mutation causes loss of APC tumour suppressor gene
deletion in 5q21
what is APC tumour suppressor gene involved in
cell adhesion (stroma) and signalling (WNT signalling pathway)
presentation of loss of APC tumour suppressor gene
multiple benign adenomatous polyps of colon (90% risk of developing colorectal carcinoma)
what protein does APC tumour suppressor gene negatively regulate
B-catenin, preventing uncontrolled cell division and anchors cell to stroma
2 possible inherited “hits” (will have to be followed by acquired hit) to cancer via cell growth and proliferation, via proto-oncogenes and tumour suppressor genes
proto-oncogene mutates to oncogene but normal tumour suppressor gene, or normal proto-oncogene but defective tumour suppressor gene
development of colorectal cancer involving tumour suppressor genes and oncogene
normal epithelium -> APC tumour suppressor gene mutated and lost -> hyperproliferative epithelium (hyperplasia) -> DNA hypomethylation causing aberrant K-ras (proto-oncogene -> oncogene) -> (metaplasia -> dysplasia) adenoma -> p53 tumour suppressor gene mutated and lost -> carcinoma (carcinogenesis)
oncogene vs tumour suppressor gene: activity in tumours
oncogenes active, tumour suppressor genes inactive
oncogene vs tumour suppressor gene: mutation types
oncogenes have specific translocations/point mutations which are rarely hereditary, tumour suppressor genes have deletions or mutations which can be inherited
oncogene vs tumour suppressor gene: genotype at cell level
oncogenes dominant at cell level (1 mutated copy), tumour suppressor genes recessive at cell level (2 mutated copies)
oncogene vs tumour suppressor gene: specificity
oncogenes have broad tissue specificity, tumour suppressor genes have considerable tumour specificity
oncogene vs tumour suppressor gene: types of tumour
oncogenes responsible for leukaemia and lymphoma, tumour suppressor genes responsible for solid tumours
how many driver mutations required for cancer
2-11 depending on organ affected
what is COSMIC
catalogue of somatic mutations in cancer
why is COSMIC important
enables precision medicine to be administered
