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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

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Familial Cancer

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  1. Familial Cancer

  2. 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

  3. 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

  4. Strong familial link • Retinoblastoma - age<4 • Bilateral cancers familial – unilateral somatic • Onl;y affects eye and bone • Chr 13q14 deletions common

  5. Wilm’s tumour • Gene on Chr 11p13 • Renal cancers – one hit only needed • WT-1 inhibits IGF2 EGF PDGF

  6. Li-Frameini syndrome • P53 mutations • Breast, sarcoma, lymphoma, brain • Development of cancer is a late event

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

  8. BRCA1 BRCA2

  9. BRCA function in DNA repair Single Strand Annealing Recombination Non-homologous End-joining

  10. 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

  11. 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

  12. 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

  13. E-cadherin b-catenin a-Cat b-catenin b-catenin APC Actin MTs Transcription

  14. b-catenin {APC pathway}

  15. Cadherins and Catenins in Cancer Colon gastric

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