BIOL 311 Human Genetics
Fall 2006
Cancer Genetics: Tumor Suppressor Genes
Reading: Chap. 17 and Chapters 7 and 9 Weinberg, R.A. (2007) The Biology of
Cancer. Garland Science, New York, NY.
Lecture Outline:
1. Tumor suppressor genes
2. Retinoblastoma gene
3. LOH
4. Familial cancers
5. p53
Lecture:
1. Tumor suppressor genes: Genes whose products suppress growth. Typically, both
copies of a tumor suppressor gene must be mutated to see the effect.
Henry Harris in the UK carried out experiments using cell fusions that first demonstrated
the existence in cells of genes that suppress tumor growth. When normal cells were fused
to cancer cells, the resulting phenotype was normal; this suggests that something in the
normal cells could restore the cells to their non-proliferative state.
2. Retinoblastoma gene
Retinoblastoma: Childhood tumor of the eye. There are sporadic and hereditary forms
of the cancer.
Sporadic form: No prior family history of the disease. Usually affects only one eye
(unilateral).
Hereditary form: Familial cancer, appears to be inherited as an autosomal dominant
trait. Often affects first one eye, then the other (bilateral). Also associated with increased
risk of osteosarcoma (bone cancer).
Knudsen's two hit model of carcinogenesis:
Two copies of tumor suppressor gene (Rb).
Individuals with hereditary form inherit one mutant form of the gene; a somatic mutation
in the other gene is associated with susceptibility to eye cancer.
Individuals with sporadic form need two somatic mutations to be susceptible to cancer.
3. Loss of heterozygosity (LOH)
1
Probability of two independent mutation events targeting each allele of a tumor
suppressor is very small (10-12 per cell generation); sporadic Rb occurs fairly readily
after just a single mutation has occurred.
Why? Due to loss of heterozygosity, or allelic deletion, which occurs due to mitotic
recombination or gene conversion. Typically neighboring genes are also lost when the
cell throws out the remaining allele of the tumor suppressor gene.
Loss of heterozygosity has been useful in helping to identify the chromosomal location of
tumor suppressor genes.
 Cloning of Rb gene: associated with loss of heterozygosity of region of 13q
 Region 17p12 is a common site for loss of heterozygosity; this is the
chromosomal location of p53, a master tumor suppressor gene.
4. Familial cancers
About 35 tumor suppressor genes have been cloned and their association with familial
cancers and some sporadic cancers have been identified.
Name of gene
TGFβR2
Chromosomal
location
3p2.2
VHL
3p25
APC
5p21
WT1
11p13
RB
13q14
TP53
17p13.1
NF1
17q11.2
Familial cancer
syndrome
HNPCC (colon
cancer)
von Hippel-Lindau
syndrome (kidney,
adrenal, blood
vessel tumors)
Adenomatous
polyposis coli
(colon cancer)
Wilms Tumor
(kidney cancer)
Retinoblastoma,
osteosarcoma
Li-Fraumeni
syndrome
Neurofibromatosis
type 1
Function of protein
TGF-β receptor
Ubiquitylation of
HIF
β-catenin
degradation
Transcription factor
Transcription factor;
cell cycle control
Transcription factor,
detect DNA damage
Ras-GTPase
activating protein
Another group of genes, originally designated as tumor suppressors, now found to be
important for DNA repair/maintaining genome integrity are listed below.
Name of gene
BRCA1
Chromosomal
location
17
Familial cancer
syndrome
Breast and ovarian
cancer
2
Function of protein
DNA repair
BRCA2
MSH2
Breast cancer
HNPCC
MLH1
HNPCC
DNA repair
Mismatch repair
repair
MismatchDNA
repair
5. p53
This tumor suppressor is often referred to as the "guardian of the genome". Originally
thought to be an oncogene, it was later found to be a tumor suppressor gene encoding a
transcription factor. It also is involved in monitoring the genome for DNA damage.
Presence of at least one wild type p53 allele is important for normal cell death (apoptosis)
pathways to be activated. Loss of p53 function is associated with the majority of human
cancers.
P53 gene codes for a 53 kilodalton protein, hence the name. Functions as a
homotetramer (4 identical 53 kdalton subunits).
Li Fraumeni syndrome is a hereditary cancer syndrome associated with increased
susceptibility to a variety of different tumors: Glioblastoma (brain tumors), leukemias,
breast cancer, lung cancer, pancreatic cancer, Wilms tumor and soft tissue sarcomas.
Li-Fraumeni syndrome appears to be an autosomal dominant trait. Susceptible
individuals are heterozygous.
Many mutations associated with Li Fraumeni syndrome are associated with alteration of
the DNA binding domain of the p53 transcription factor.
These would affect the expression of a number of p53 regulated genes
p53 regulated genes
Class of genes
p53 antagonist
Growth arrest genes
DNA repair genes
Regulators of apoptosis
Anti-angiogenic proteins
Example gene
MDM2
p21
GADD45, Xeroderma
Pigmentosum genes
BAX, Bcl-2 (represses
expression)
Thrombospondin
3
Function of gene product
p53 turnover pathway
Inhibitor of CDKs
Repair enzymes
Activate or repress cell
death
Antagonist of angiogenesis