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Gene Expression and Retinoblastoma“Cancer of the Eye”
Wen Jie Zhang, MD, PhD
School of Medicine, Health Sciences and EngineeringSusquehanna Township High School
Lecture Series Week 9, September 2013
Clinical Relevance of This Week’s Topic
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Eyes that look at the world
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Eyes that guard our homes
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Eyes that work at night
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Eyes that look at us on Halloween
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Eyes that can talk
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Eyes that look at the future
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Eyes that may lose vision
Retinoblastoma, Rb
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Anatomy of the Eye
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Retinoblastoma (Rb)Cancer of the Eye
• Rapid developing cancer of the childhood– Outgrowth of immature cells of the Retina, the
light-detecting tissue in the eye• Diagnosed:
90% of Rb within the first 3 years of agethe remaining within the 6 years of age
Very rare after 6 years of age• Incidence of 18,000 to 30,000 live births worldwide
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Retinoblastoma (Rb)Categories (Types)
• Familial RbHereditary and bilateral (affects both eyes)Approx 10%
• Sporadic RbNon-hereditary and unilateral (affects one eye)Approx 70%
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Retinoblastoma (Rb)Signs
• Leukocoria (white pupil, 60% of Rb)
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Retinoblastoma (Rb) Signs
• Strabismus (squint, cross-eye, 20% of Rb)
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Retinoblastoma (Rb) Signs
• Other signs (10% of Rb)– Eye swelling with pain and redness
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Funduscopic finding of a retinoblastoma
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Funduscopic findingof a retinoblastoma
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Migration of retinoblastoma “seeds“ onto the iris surface.
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A Drawing of RetinoblastomaJ. Wardrop, 1809
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A Surgically Removed Retinoblastoma
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Mechanism(s) of Retinoblastoma
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CarcinogenesisEnvironmental Factors Genetic Factors
Physical
Chemical
Biological
(Mutations)
Substitutions
Deletions
Insertions
Lifestyle
Cancer(Carcinogens)
Translocations
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Tumor Suppressor GenesGene Human Disease Function
APC Colon cancer Interacts with cateninsDCC Colon cancer CAM domainsE-cadherin Breast cancer Intracellularly interacts(CDH1) with cateninsDPC4 Pancreatic cancer TGF--related signalingBRCA1 Mammary cancer/ DNA damage repair,
Ovarian cancer checkpoint control, apoptosisBRCA2 Mammary cancer DNA damage repair, genomic
stabilityATM Ataxia-telangiectasia DNA damage response
mutated gene upstream in p53 pathwayP53 Mutated in >50% Transcription factor,
tumors checkpoint control, apoptosis
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Mechanism(s) of Retinoblastoma
• RB1 gene encodes a protein (pRb) that serves as a tumor suppressor– Suppress cell (division) cycle
• Mutation of RB1 gene – Results a defective pRb protein, therefore,
unable to suppress cell cycle leading uncontrolled cell division (tumor formation)
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Cell Division Cycle Under Control
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If not controlled,Cancer (tumor)
Formation
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RB1 Gene Location
13q14.1-q14.2
RB1 gene
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Crystal Structureof Retinoblastoma Protein (pRb)
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Crystal Structure of the Retinoblastoma Tumor Suppressor Protein Bound to E2F
Retinoblastoma Protein iscolored blue, E2F is violet
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Carcinogenesis – “Two-hit” Hypothesis(Knudson, 1971)
First hit Second hit Outcome
GermlineMutation
(Insertion/Deletion)
First Mutation(Insertion/Deletion)
InheritedBefore birth
Cancerdevelops
Second Mutation(Insertion/Deletion)
AcquiredAfter birth
SomaticGenetic
Multi-stepprocess
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“Two-hit” Hypothesis
• Familial Rb fits the hypothesis
First hit: One mutated gene inherited (recessive)
Second hit: Another gene is also mutated due to different reason(s) (e.g., UV radiation, reported in New Zealand)
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Common MutationsSubstitutions (point mutation)
In a DNA sequence, a single nucleotide is exchanged for another (A G, C T), leading to missense or nonsense mutation.
Insertions (insertion mutation)The addition of one or more nucleotide base pairs into a DNA sequence.
Deletions (deletion mutation)Part of a chromosome or a sequence (base pairs) of DNA is missing from a DNA sequence.
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Genetic Testing
• Several methods for detecting the RB1 gene mutations have been developed
• A method that can detect large deletions in the RB1 gene that correlate with advanced stage retinoblastoma
“Well Baby Screening” for Signs for Early Diagnosis
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Treatment• Simple enucleation (removal of the eye)• Eye-sparing radiotherapy• Chemotherapy-based multi-modality therapy
– Laser therapy– Cryotherapy (freezing therapy at −196ºC or
−321ºF)
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Images of Retinoblastoma (Rb) tumorsby Retino-scan before and during chemotherapy
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Outcomes
• Rb has one of the best cure rates (95-98%) among all childhood cancers
• 9 out of every 10 patients survive into adulthood
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Eyes that look at the future
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The Coda