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

BRCA1 BRCA2

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

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 APC 5q21; Ubiquitously expressed, 2843 AA Functions as oligomer Binds  -catenin, cytoskeleton Can induce apoptosis Mutation site influences phenotype –Attenuated polyposis1-157 –Classic polyposis –CHRPE –Gardeners syndrome % 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

 Cat  catenin APC  catenin Actin Transcription MTs E-cadherin

 -catenin {APC pathway}

Cadherins and Catenins in Cancer Colongastric