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

RecombinationSingle Strand Annealing

Non-homologousEnd-joining

BRCA function in DNA repair

APCAPC

• 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

APCAPC

• 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

APCAPC

• 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

catenin

ActinTranscription MTs

E-cadherin

-catenin {APC pathway}-catenin {APC pathway}

Cadherins and Catenins in Cancer

Colon gastric