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School of Medicine, Health Sciences and Engineering Susquehanna Township High School Lecture Series Week 9, September 2013 Clinical Relevance of This Week’s Topic Gene Expression and Retinoblastoma “Cancer of the Eye” Wen Jie Zhang, MD, PhD Eyes that look at the world Eyes that guard our homes Eyes that work at night Eyes that look at us on Halloween Eyes that can talk Eyes that look at the future Eyes that may lose vision Retinoblastoma, Rb Anatomy of the Eye 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 age the remaining within the 6 years of age Very rare after 6 years of age • Incidence of 18,000 to 30,000 live births worldwide Retinoblastoma (Rb) Categories (Types) • Familial Rb Hereditary and bilateral (affects both eyes) Approx 10% • Sporadic Rb Non-hereditary and unilateral (affects one eye) Approx 70% Retinoblastoma (Rb) Signs • Leukocoria (white pupil, 60% of Rb) Retinoblastoma (Rb) Signs • Strabismus (squint, cross-eye, 20% of Rb) Retinoblastoma (Rb) Signs • Other signs (10% of Rb) – Eye swelling with pain and redness Funduscopic finding of a retinoblastoma Funduscopic finding of a retinoblastoma Migration of retinoblastoma “seeds“ onto the iris surface. A Drawing of Retinoblastoma J. Wardrop, 1809 A Surgically Removed Retinoblastoma Mechanism(s) of Retinoblastoma Carcinogenesis Environmental Factors (Carcinogens) Cancer Genetic Factors (Mutations) Substitutions Physical Deletions Chemical Insertions Biological Translocations Lifestyle Tumor Suppressor Genes Gene Human Disease APC DCC E-cadherin (CDH1) DPC4 BRCA1 Colon cancer Colon cancer Breast cancer BRCA2 ATM P53 Function Interacts with catenins CAM domains Intracellularly interacts with catenins Pancreatic cancer TGF--related signaling Mammary cancer/ DNA damage repair, Ovarian cancer checkpoint control, apoptosis Mammary cancer DNA damage repair, genomic stability Ataxia-telangiectasia DNA damage response mutated gene upstream in p53 pathway Mutated in >50% Transcription factor, tumors checkpoint control, apoptosis 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) Cell Division Cycle Under Control If not controlled, Cancer (tumor) Formation RB1 Gene Location RB1 gene 13q14.1-q14.2 Crystal Structure of Retinoblastoma Protein (pRb) Crystal Structure of the Retinoblastoma Tumor Suppressor Protein Bound to E2F Retinoblastoma Protein is colored blue, E2F is violet Carcinogenesis – “Two-hit” Hypothesis (Knudson, 1971) First hit Outcome Second hit Multi-step process Germline Mutation (Insertion/ Deletion) First Mutation (Insertion/Deletion) Inherited Before birth Second Mutation (Insertion/Deletion) Acquired After birth Genetic Somatic Cancer develops “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) Common Mutations Substitutions (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. 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 Treatment • Simple enucleation (removal of the eye) • Eye-sparing radiotherapy • Chemotherapy-based multi-modality therapy – Laser therapy – Cryotherapy (freezing therapy at −196ºC or −321ºF) Images of Retinoblastoma (Rb) tumors by Retino-scan before and during chemotherapy Outcomes • Rb has one of the best cure rates (95-98%) among all childhood cancers • 9 out of every 10 patients survive into adulthood Eyes that look at the future The Coda