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Gene Expression and Retinoblastoma “ Cancer of the Eye”

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.

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Gene Expression and Retinoblastoma “ Cancer of the Eye”

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  1. 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

  2. Eyes that look at the world

  3. Eyes that guard our homes

  4. Eyes that work at night

  5. Eyes that look at us on Halloween

  6. Eyes that can talk

  7. Eyes that look at the future

  8. Eyes that may lose vision Retinoblastoma, Rb

  9. Anatomyof the Eye

  10. 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

  11. 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%

  12. Retinoblastoma (Rb)Signs • Leukocoria (white pupil, 60% of Rb)

  13. Retinoblastoma (Rb)Signs • Strabismus (squint, cross-eye, 20% of Rb)

  14. Retinoblastoma (Rb)Signs • Other signs (10% of Rb) • Eye swelling with pain and redness

  15. Funduscopic finding of a retinoblastoma

  16. Funduscopicfindingof a retinoblastoma

  17. Migration of retinoblastoma “seeds“ onto the iris surface.

  18. A Drawing of RetinoblastomaJ. Wardrop, 1809

  19. A Surgically Removed Retinoblastoma

  20. Mechanism(s) of Retinoblastoma

  21. Environmental Factors Genetic Factors (Carcinogens) (Mutations) Cancer Substitutions Physical Deletions Chemical Insertions Biological Translocations Lifestyle Carcinogenesis

  22. GeneHuman DiseaseFunction APC Colon cancer Interacts with catenins DCC Colon cancer CAM domains E-cadherin Breast cancer Intracellularly interacts (CDH1) with catenins DPC4 Pancreatic cancer TGF--related signaling BRCA1 Mammary cancer/ DNA damage repair, Ovarian cancer checkpoint control, apoptosis BRCA2Mammary cancer DNA damage repair, genomic stability ATM Ataxia-telangiectasia DNA damage response mutated gene upstream in p53 pathway P53 Mutated in >50% Transcription factor, tumors checkpoint control, apoptosis Tumor Suppressor Genes

  23. 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)

  24. Cell Division Cycle Under Control

  25. If not controlled,Cancer (tumor)Formation

  26. RB1 Gene Location RB1 gene 13q14.1-q14.2

  27. Crystal Structure of Retinoblastoma Protein (pRb)

  28. Crystal Structure of the Retinoblastoma Tumor Suppressor Protein Bound to E2F Retinoblastoma Protein is colored blue, E2F is violet

  29. Multi-step process Carcinogenesis – “Two-hit” Hypothesis (Knudson, 1971) First hit Outcome Second hit Cancer develops Germline Mutation (Insertion/ Deletion) First Mutation (Insertion/Deletion) Inherited Before birth Second Mutation (Insertion/Deletion) Acquired After birth Genetic Somatic

  30. “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)

  31. 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.

  32. 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

  33. Treatment • Simple enucleation (removal of the eye) • Eye-sparing radiotherapy • Chemotherapy-basedmulti-modality therapy • Laser therapy • Cryotherapy (freezing therapy at −196ºCor −321ºF) 

  34. Images of Retinoblastoma (Rb) tumorsby Retino-scan before and during chemotherapy

  35. Outcomes • Rb has one of the best cure rates (95-98%) among all childhood cancers • 9 out of every 10 patients survive into adulthood

  36. Eyes that look at the future

  37. The Coda

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