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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


Familial cancer


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


Familial cancer

BRCA1

BRCA2


Familial cancer

BRCA function in DNA repair

Single

Strand

Annealing

Recombination

Non-homologous

End-joining


Familial cancer
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


Familial cancer
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


Familial cancer
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


Familial cancer

E-cadherin

b-catenin

a-Cat

b-catenin

b-catenin

APC

Actin

MTs

Transcription


B catenin apc pathway
b-catenin {APC pathway}