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Lecture 21
Cancer Genetics I
Stephen B. Gruber, MD, PhD
November 18, 2002
“Cancer is, in essence, a genetic disease. Although
cancer is complex, and environmental and other
nongenetic factors clearly play a role in many
stages of the neoplastic process, the tremendous
progress made in understanding tumorigenesis in
large part is owing to the discovery of the genes,
that when mutated, lead to cancer.”
Bert Vogelstein (1988) NEJM 1988; 319:525-532.
Cancer Genetics: I
Lecture Goals
- Types of Genetic Alterations in Cancer
- Evidence that Mutations Cause Cancer
- Multistage Model of Carcinogenesis
- Oncogenes, Tumor Suppressor Genes,
DNA Repair Genes
Cancer Arises From Gene Mutations
Germline mutations Somatic mutations
Somatic mutation (eg, breast)
Mutation in egg or sperm
All cells affected in offspring
Parent Child
l Present in egg or sperm l Are heritable l Cause cancer family syndromes
l Occur in nongermline tissues l Are nonheritable
THE BIG RED DOG RAN OUT.
THE BIG RAD DOG RAN OUT.
THE BIG RED.
THE BRE DDO GRA.
THE BIG RED ZDO GRA.
Point Mutations
Normal
Missense Nonsense Frameshift (deletion)
Frameshift (insertion)
Point mutation: a change in a single base pair
Chromosome Number Changes
- Aneuploidy
- Whole chromosome losses often are associated with a duplication of the remaining chromosome.
- LOH
Chromosome Translocations
- Random translocations
- breast, colon, prostate (common epithelial tumors)
- Non-random translocations
FISH
- Certain chromosomal translocations are easily detected by FISH
- Fluorescent in Situ Hybridization - probes on different chromosomes fluoresce
Review: Types of Genetic
Alterations in Cancer
- Subtle alterations
- Chromosome number changes
- Chromosomal translocation
- Amplifications
- Exogenous sequences
Each type represents one of the mutations a cell can accumulate during its progression to malignancy
Evidence that
Mutations Cause Cancer
- Most carcinogens are mutagens
- Not all mutagens are human carcinogens
- Some cancers segregate in families
- Genes cloned, mutations lead to cancer in animals
- Oncogenes and Tumor Suppressor Genes
- found in human tumors, enhance growth
- Chromosomal instability
- Defects in DNA repair increase prob of cancer
- Malignant tumors are clonal
Multi-Step Carcinogenesis
(eg, Colon Cancer)
Normal epithelium
Hyper- proliferative epithelium
Early adenoma
Late adenoma Carcinoma^ Metastasis
Loss of APC
Activation of K-ras
Loss of 18q
Loss of TP
Other alterations
Adapted from Fearon ER. Cell 61:759, 1990
Inter- mediate adenoma
ASCO
Tumors Are Clonal Expansions
Normal Tumor
Oncogenes, Tumor Suppressor
Genes, and DNA Repair Genes
- Oncogenes
- Tumor Suppressor Genes
- Retinoblastoma and the “2-hit Hypothesis”
- DNA Repair Genes
Oncogenes
Normal genes (regulate cell growth)
1st mutation (leads to accelerated cell division)
1 mutation sufficient for role in cancer development
Oncogenes Activated in Non-viral
Human Cancers
- Gene fusions / translocations
- Point mutations
Effects of Oncogenes are Dominant
- Positive effect on growth
- even in the presence of a normal (inactivated) version of the gene
- Example
- Oncogenes derived from growth factor receptors confer the ability to bypass the growth factor requirement…independent growth.
Tumor Suppressor Genes
Key Attributes
- Familial Cancer Syndromes
- Inactivation in Common Human Cancers
- “Recessive” at a cellular level
- Two-hit hypothesis
Tumor Suppressor Genes
Familial Cancer Syndromes
- Most familial cancer syndromes are related to
Tumor Suppressor Genes
- Retinoblastoma, FAP, Li-Fraumeni, Familial Breast- Ovarian, VHL, Melanoma, Tuberous Sclerosis...
- Only 3 known syndromes related to Oncogenes
- RET, MET, CDK
- Few DNA repair syndromes
- XP, AT, Bloom, Fanconi, Werner, HNPCC
Tumor Suppressor Genes
- Loss of Heterozygosity (LOH)
- 2 copies of each gene
- 1 is lost or inactived
- Only 1 remains…
- no longer heterozygous
- one copy of a defective gene, same as no gene
Mechanisms Leading to
Loss of Heterozygosity
Normal allele Mutant allele
Chromosome loss
Deletion Unbalanced translocation
Loss and reduplication
Mitotic recombination
Point mutation
Loss of normal allele
Features of Retinoblastoma
- 1 in 20,000 children
- Most common eye tumor in children
- Occurs in heritable and nonheritable forms
- Identifying at-risk infants substantially reduces morbidity and mortality
Genetic Features of
Heritable Retinoblastoma
- Autosomal dominant transmission
- RB1 gene on chr 13 (first tumor suppressor gene discovered)
- Penetrance >90%
- Prototype for Knudson’s “two-hit” hypothesis
Bilateral RB, 1 yr d. 78
Bilateral RB, 1 yr osteosarcoma, 16
Bilateral RB, 6 mo
Bilateral RB, 1 mo
Nonheritable vs Heritable
Retinoblastoma
Feature
Tumor Family history Average age at dx Increased risk of second primaries
Nonheritable
Unilateral None ~2 years No
Heritable
Usually bilateral 20% of cases <1 year Osteosarcoma, other sarcomas, melanoma, others
Presentations of Retinoblastoma
Nonheritable ~60%
Heritable ~40%
All Retinoblastoma
Heritable Retinoblastoma
Bilateral ~80% Trilateral (rare)
Unilateral ~20%
The RB1 Gene
- Large gene spanning 27 exons, with more
than 100 known mutations
- Gene encodes Rb protein which is involved in
cell cycle regulation
1 2 3 4 5 6 7 8 9 10 12 14 17 18 19 20 21 22 23 25 27
Nonsense Missense Splice Site Adapted from Sellers W et al. J Clin Onc 15:3301, 1997
Long-Term Survival of Children
With Heritable Retinoblastoma
35 30 25 20 15 10 5 0
Mortality (%)
Radiotherapy
No Radiotherapy
1 10 20 30 40 Years after diagnosis Eng C et al. J Natl Can Instit 85:1121, 1993
DNA Repair Genes
- DNA repair genes
- targeted by loss of function mutations
- Differ from tumor suppressor genes:
- TSG directly involved in growth inhibition or differentiation
- DNA repair genes are indirectly involved in growth inhibition or differentiation
DNA Repair Genes
- Inactivation of DNA repair genes
- increased rate of mutation in other cellular genes
- proto-oncogenes
- tumor suppressor genes
- Accumulation of mutations in the other
cellular genes is rate limiting…
- tumor progression is accelerated
