Transcript 5-Year Cancer Mortality Rates in the US

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