1. 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

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. Anatomy of 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. Funduscopic finding of a retinoblastoma

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

18. A Drawing of Retinoblastoma J. Wardrop, 1809

19. A Surgically Removed Retinoblastoma

20. Mechanism(s) of Retinoblastoma

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

22. Tumor Suppressor Genes
Gene Human Disease Function
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
BRCA2 Mammary 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

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. of Retinoblastoma Protein (pRb)
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. Carcinogenesis – “Two-hit” Hypothesis (Knudson, 1971)
First hit
Second hit
Outcome
Multi-step
process
Germline
Mutation
(Insertion/
Deletion)
First Mutation
(Insertion/Deletion)
Inherited
Before birth
Second Mutation
(Insertion/Deletion)
Acquired
After birth
Cancer
develops
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 “Well Baby Screening” for Signs for Early Diagnosis
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-based multi-modality therapy
Laser therapy
Cryotherapy (freezing therapy at −196ºC or −321ºF) 

34. Images of Retinoblastoma (Rb) tumors by 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