Leopold Koss Lectureship Cellular Mechanisms in Hereditary Cancer

Cellular Mechanismsin Hereditary CancerAlfred Knudson, MD, PhDFox Chase Cancer CenterPhiladelphia, PABoston 2010

OncodemesCategories of Cancer CausationEnvironment–+Heredity–+BackgroundHeredityEnvironmentInteraction

A Dominantly Inherited Cancer

Mutational EquilibriumDominantly Inherited Conditionp 2 + 2pq + q 2 = 1normal Heterozygote MutantHomozygoteNew mutations = 2 p 2Mutations lost by selection = 2pq • sAt Equilibrium2 p 2 = 2pq • sp=sqFor example: = 10 -5 , s = 0.5, 2pq = 4x10 -5

Retinoblastoma

Retinoblastoma: The Riska Dominant Gene ImpartsTumor ProbabilityNormal childGene carrierRelative riskAbout 3 per 100,0003 tumors per child3________=10 53X 10 -5

Two Hits in Retinoblastoma

RetinoblastomaTwo MutationsHereditaryNon-hereditary

Germline Deletion in RB Patient

Loss of HeterozygosityDuring Carcinogenesis

G1pRb PathwaypRbppRbSCdk4/D1p16Cdk4 + cyclin D1

RB1 is the first clonedhereditary cancer gene andfirst tumor suppressor gene

Hereditary CancerMultiple TumorsHereditaryRetinoblastomaRetinoblastomaSarcomasLung CancerLi-FraumeniSyndromeBreast CancerSarcomasLung Cancer

TP53 AlarmsONCOGENE(e.g., MYC)DNADAMAGEp14 ARFInactiveATM, CHK2mdm2p53ApoptosisCell Cycle Arrest

CancerIncreased cell birth rate-RB-1Decreased cell death rate-TP53

TP 53 and CancerApoptosisDNA RepairOxidative PhosphorylationInhibition of Angiogenesis

Smart DNA VirusesDNAVirusAdSV40HPVViralProteinE1AE1BTE6E7InactivatepRb p53+ –– ++ +– ++ –

Phakomatosesand their cloned genesNeurofibromatosesTuberous SclerosisVon-Hippel-Lindau S.Gorlin’s S.Cowden’s Dis.Peutz Jeghers Dis.Juvenile PolyposisAdenomatous PolyposisNF1, NF2TSC1, TSC2VHLPTCHPTENLKB1/STK11SMAD4/DPC4APC

Neurofibromatosis Type 1

Familial Polyposis Coli

Multiple Gene Mutations inColorectal CancerNormal Early adenoma Intermediate Late adenoma CancerAPC K-RAS SMAD2, 4 TP53Adapted from Ilyas et al. Eur. J. Cancer 1999; 35:335-351 and Kelloff et al. Oncology 1996; 10:1471-1484

Two-Hit LesionsAnd Renewal Tissue Growth

Phakomatoses Network

Hereditary Predispositionto Genomic InstabilityBRCA 1 and 2Bloom Syndrome(Recessive)

Human Chromosomes

Genomic Instability inOvarian Cancer

Breakage-Fusion-Bridge Cycle

Double Strand Breaks(DSBs) in DNAOccur spontaneously (approx. 50) per cell cycleAlso inducible by IR, ROS, and some chemicalsIf not repaired cell diesRepair can lead to:Recombination (with LOH)Deletion (with LOH)TranslocationGenomic instability (via BFB cycle)

DSBs and Mutationsby Radiation1 Gy 30 DSBsDoubling dose for mutationsApproximately 1.7 Gyabout 50 DSBs

DNA Double-Strand BreaksRepair by a Multi-protein ComplexMsh2AtmBrca1/2Mlh1BlmFanc-D2Courtesy: Dr. Hong Yan

BLOOM SYNDROMETwin SpotsCourtesy: Dr. Anna Meadows

Bloom SyndromeSister Chromatid ExchangesNormal Bloom S.

Bloom SyndromeHomologous RecombinationCourtesy: Dr. James German

Mutational ConsequencesIn the Carcinomas• Growth of renewal tissue• Failure of differentiation/apoptosis• Genomic instability