Download Familial Cancer

Familial Cancer
General Principles
• Mutations inherited through germ cells
contribute to a minority of tumours
• Two hits usually needed germline/somatic
• Germline mutations in repressor genes may
act in a recessive or dominant negative way
• Sporadic tumours may acquire mutations in
a similar way to genetic tumours
• Different germ-line mutations may have a
common end-point
• Germline mutations tend to affect specific
cell types
• Defective DNA repair results in increased
CA risk
Strong familial link
• Retinoblastoma - age<4
• Bilateral cancers familial – unilateral
somatic
• Onl;y affects eye and bone
• Chr 13q14 deletions common
Wilm’s tumour
• Gene on Chr 11p13
• Renal cancers – one
hit only needed
• WT-1 inhibits IGF2
EGF PDGF
Li-Frameini syndrome
• P53 mutations
• Breast, sarcoma,
lymphoma, brain
• Development of
cancer is a late event
Breast Cancer
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Familial Breast Cancer
BRCA1 and BRCA2
Mutations affect both males and females
Expression of BRCA1 increased at G1 –
increased by oestrogens
BRCA1
BRCA2
BRCA function in DNA repair
Non-homologous
End-joining
Single
Strand
Annealing
Recombination
APC
• Adenomatous Polyposis Coli mutated in
– Familial Adenomatous Polyposis (FAP)
• Incidence 1:7,000.
• Colon cancer -> 50% US population / age 70
• Inherited forms 15% of total
• FAP patients develop many adenomas outside
colon
– Skin, eye, brain, osteomas
APC
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APC 5q21; Ubiquitously expressed, 2843 AA
Functions as oligomer
Binds  -catenin, cytoskeleton
Can induce apoptosis
Mutation site influences phenotype
– Attenuated polyposis 1-157
– Classic polyposis
169-1600
– CHRPE
463-1387
– Gardeners syndrome 1403-1578
• 80% sporadic colon cancers have mutant APC
• Loss of APC C-terminal usual
APC
• Binds  -catenin (armadillo)
  -catenin binds cadherin (cell adhesion molecule)
  -catenin binds & activates Tcf/Lef transcription factors
– APC may inhibit -catenin signalling
  -catenin similar to plakoglobin
• May function in Wingless / Wnt signalling pathway
– Signal promotes APC/ -catenin binding
• inhibits Tcf/Lef activation
– Wnt involved in breast cancer in mice
E-cadherin
a-Cat
-catenin
-catenin
-catenin
APC
Actin
Transcription
MTs
-catenin {APC pathway}
Cadherins and Catenins in Cancer