Autosomal dominant

Gain of function mutation: RET

Familial cancer syndrome

(loss of function mutations --> Hirschprung disease)

Sporadic (acquired) t(8;14)

Translocates proto-oncogene MYC distal to the Ig heavy chain; MYC is placed under control of a strong Ig promoter, leading to overexpression of MYC --> high levels of cyclin D --> progression thorugh G1 --> S.

Small accessory chromosome of unknown origin is referred to as a marker (mar) chromosome.

Presents at extranodal sites or as acute leukaemia; African BL: often presents in mandible; Epstein bar virus (EBV).

Sporadic (acquired)

t(9;22)

Philadelphia chromosome has BCR-ABL fusion protein. Results in constitutively active tyrosine kinase activity --> activation of RAS-MAPK, PI3K-PKB/AKT (cell survival) pathways!

BCR-ABL: increases cell growth and decreases apoptosis.

Gleevec: new trug that targets & blocks Bcr-Abl (also Kit, and PDGF receptor).

*Turns OFF tyrosine kinase!!
Clinical presentation: anaemia, massive splenomegaly, bruising & bleeding, tiredness, decreased weight, fever, sweats. Treat to return to chronic phase, or if unresponsive then only a few months survival.

Treatment: imatinib/Gleevec (BCR-ABL tyrosine kinase inhibitor).

Inherited cancer syndrome

Loss of function of Rb1

All inherited cancer syndromes = autosomal dominant inheritance pattern via "2nd hit" mechanism.

1 inherited mutated Rb + then 1 somatic mutation that occurred --> retinoblastoma bilaterally. In normally-functioning Rb proteins, when Rb is HYPOPHOSPHORYLATED: inhibits the G1-->S transition in the cell cycle because it stays bound to E2F. However, when normal Rb is phosphorylated, it breaks off of E2F, and we get G1 --> S phase progression!

Inherited cancer syndrome

Inherited p53 mutation

Autosomal dominant; two 'hits' required for disease phenotype.

Soft-tissue sarcoma, breast cancer, leukemia, osteosarcoma (increased risk for developing multiple primary cancers).

Inherited cancer syndrome Mutation in BRCA1 (17q21) & BRCA2 (13q12)

Familial, autosomal dominant breast cancer = 5% cases

BRCA is involved in DNA repair. When not present, any damage (e.g. dsDNA breaks (as in normal homologous recombination or DNA damage) will go unfixed --> increase in p53 + induction of p21 + cell cycle arrest + apoptosis (cell death) OR proliferation of cells with damaged DNA.

Inherited cancer syndrome

Mutation in DNA MMR genes (tumour suppressor) MLH1, MLH3, MSG2, MSH6, PMS1, PMS2 are all DNA repair genes that are mutated in HNPCC. Replication slippage (not fixed due to faulty DNA repair genes) --> microsatellite instability/replication error positive (RER+) phenotype.

Differs from FAP in that patients do NOT present with polyps!

INITIATING mutation for HNPCC is the loss of function of DNA MMR genes, TGFβR II is mutated 70% of the time (10 adenines causes replication slippage --> deletion --> frameshift --> loss of function (of both alleles)!

Autosomal recessive

Defect in nucleotide excision repair (NER)

Most common defect = excision endonuclease deficiency.

Autosomal recessive Mutation of ATM

ATM (when normal) will sense DNA damage and activate p53 --> stop cell cycle/DNA repair.

Oculocutaneous telangiectasia (dilated vessels; eye, ears and face). Progressive ataxia (loss of movement).

Immunodeficiency, predisposition to lymphoma

Autosomal recessive

Loss of function of BLM (DNA helicase) --> high frequency of chromosome breaks & rearrangements.

Hypersensitivity to ionising radiation; high risk for many cancers.

Hundreds of sister chromatid exchanges per mitosis.

Autosomal recessive

Mutation in WRN (DNA helicase & exonuclease)

WRN is important in maintaining DNA @ ends of chromosomes.

Patients have shorter telomeres (no maintenance) & impaired DNA replication (lacking DNA helicase).

Premature aging!

Autosomal recessive

Mutation in DNA repair machinery

Upper limb abnormalities. Bone marrow failure (pancytopenia); risk of AML

Overexpression (100x) of miRNA.

*Most common & aggressive brain tumour!

1 mutated telomerase allele --> prematurely shortened telomeres.

Bone marrow failure --> pancytopenia (reduction in RBC, WBCs, and platelets) & immunosuppression.

Malignancy (from chromosome instability): shortening of the telomeric repeats may become fused together, forming dicentric and tricentric chromosomes.

Autosomal Dominant

Loss of function mutation in RAS-GAP gene leads to "long acting" Ras!! Ras-GAP gene NF1: encodes neurofibromin. Too much will cause benign tumours around peripheral nerves & bones, skin.

Autosomal deficiency in vWF Circulating in blood --> deficiency in factor VIII.

*Most common congenital bleeding disorder!! Deficiency in vWF results in defective platelet adhesion (and thus platelet plug formation)! In type 3, severe vWF deficiency (inclds. Deletions): heterozygotes essentially normal - affecteds are homozygous or compound heterozygous! Can be intracellular retention of vWF, missense mutations (processing of vWF), gain of function (abnormal binding of GPIb: thrombocytopaenia), deletions (severe).