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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

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general principles
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
slide3
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
Strong familial link
  • Retinoblastoma - age<4
  • Bilateral cancers familial – unilateral somatic
  • Onl;y affects eye and bone
  • Chr 13q14 deletions common
wilm s tumour
Wilm’s tumour
  • Gene on Chr 11p13
  • Renal cancers – one hit only needed
  • WT-1 inhibits IGF2 EGF PDGF
li frameini syndrome
Li-Frameini syndrome
  • P53 mutations
  • Breast, sarcoma, lymphoma, brain
  • Development of cancer is a late event
breast cancer
Breast Cancer
  • Familial Breast Cancer
  • BRCA1 and BRCA2
  • Mutations affect both males and females
  • Expression of BRCA1 increased at G1 – increased by oestrogens
slide9

BRCA1

BRCA2

slide12

BRCA function in DNA repair

Single

Strand

Annealing

Recombination

Non-homologous

End-joining

slide16
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
slide17
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
slide18
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
slide20

E-cadherin

b-catenin

a-Cat

b-catenin

b-catenin

APC

Actin

MTs

Transcription

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