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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
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
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
Cadherins and Catenins in Cancer
Colon gastric