Familial Cancer

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Familial Cancer
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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

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• 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

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Strong familial link

• Retinoblastoma - agelt4
• Bilateral cancers familial unilateral somatic
• Only affects eye and bone
• Chr 13q14 deletions common

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Wilms tumour

• Gene on Chr 11p13
• Renal cancers one hit only needed
• WT-1 inhibits IGF2 EGF PDGF

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Li-Frameini syndrome

• P53 mutations
• Breast, sarcoma, lymphoma, brain
• Development of cancer is a late event

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Breast Cancer

• Familial Breast Cancer
• BRCA1 and BRCA2
• Mutations affect both males and females
• Expression of BRCA1 increased at G1 increased
  by oestrogens

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BRCA1
BRCA2
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BRCA function in DNA repair
Single Strand Annealing
Recombination
Non-homologous End-joining
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APC

• Adenomatous Polyposis Coli mutated in
• Familial Adenomatous Polyposis (FAP)
• Incidence 17,000.
• Colon cancer -gt 50 US population / age 70
• Inherited forms 15 of total
• FAP patients develop many adenomas outside colon
• Skin, eye, brain, osteomas

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APC

• 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

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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

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E-cadherin
b-catenin
a-Cat
b-catenin
b-catenin
APC
Actin
MTs
Transcription
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b-catenin APC pathway
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Cadherins and Catenins in Cancer
Colon
gastric
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