Cancer Genetics Flashcards
Telomerase in many tumours
Proto-oncogene amplification
Increases telomerase activity –> immortalise cell
Chronic myeloid leukaemia
Proto-oncogene activated by translocation
Creates a novel chimaeric gene
9 (ABL) and 22 (BCR) translocation –> philapelphia chromosome
ABL-BCR fusion gene encodes activated tyrosine kinase that can transform white blood cell precursors in bone marrow
Burkitts lymphoma
Activation of proto-oncogene by relocation
Translation of 8 (CMYC protooncogene) to 2, 14 or 22 (immunoglobulins are actively transcribed)
CMYC is overexpressed
Initial step is malaria induced B-lymphocyte hyperplasia, which increases the target cell population for a translocation
Retinoblastoma
Sporadic or familial loss of the RB1 gene
RB1 protein level of phosphorylation –> checkpoint at G1-S
Causes tumour on retina of eye - both and very young if familial - lose red cone cells
HPV virus
Loss of function of tumour suppressor gene
Encodes an oncogenes protein that binds to the RB1-encoding protein and prevents gate keeping role in cell cycle at G1-S
Causes warts an urogenital cancer
Li Fraumeni
Germline mutation in tumour suppressor gene TP53
Predisposition to sarcomas, breast cancer, brain tumours, leukaemia and adrenocortical carcinoma
TP53 importance in cell cycle and triggering apoptosis
Type 1 neurofibromatosis
Germline deletion in NF1 tumour suppressor gene
Neurofibromin normally stimulates GTPase activity and therefore prevents over-expression of RAS signalling proteins
Loss of function increases RAS signalling and promotes cell proliferation –> tumour
Cafe-au-lair spots and small cutaneous tumours
Familial Adenomatous Polyposis
Germline mutation in APC tumour suppressor gene
APC-encoded protein regulates intracellular levels of B-catenin –> free state binds to intranuclear transcription factors –> activates transcription
Loss of APC protein increases free B-catenin
Causes polyps of intestines –> one will become malignant
Xeroderma pigmentosa
Impaired nucleotide excision
UV light causes thymine residues to dimerise
Distortion is not recognised, excised and repaired by DNA polymerase, exonuclease and ligase, so mutation accumulate causing skin cancer (exposed most to UV)
BRCA 1/2
Impaired double-strand breakage repair
BRCA1 (17) and BRCA2 (13) are integral components of the multiprotein complex which repairs double strands by homologous recombination and binding to the ends of DNA fragments
Cause hereditary breast and ovarian cancer
Double hit hypothesis
Ataxia telangiectasia
Impaired double-strand breaker repair
ATM protein arrests the cell cycle and activates the double strand repair complex
Hereditary non-Polyposis colon cancer (HNPCC)
Impaired mismatched base-pair repair
Germline mutation in gene causes marked increase in the number of microsatellites and their instability
Early onset of colon cancer
Multiple endocrine Adenomatosis type 2
Activation of proto-oncogene RET by point mutation
-MEN2A : medullary thyroid carcinoma, phaeocytochroma, hyperpadathyroidism
-MEN2B : spectrum of tumours, body similar to Marfans
Gain of function of tyrosine kinase in Neuro-endocrine tissues
Type 2 neurofibromatosis
Loss of function of tumour suprressor gene NF2
NF2 encodes cytoskeletal protein merlin influences cell adhesion to suppress tumours
Tumour on VIIIth cranial nerve, and cafe-au-lait and neurofibromas
Bladder cancer
Point mutation in a proto-oncogene
Reduced intrinsic activity of GTPase in RAS proteins, so RAS-GTP can’t be concerted to RAS-GDP –> increases cell signalling
