Download Tumor suppressor genes

Session
9
Medical Genetics
Cancer
Genetics
J a v a d
F a s a
J a m s h i d i
U n i v e r s i t y
o f
M e d i c a l
S c i e n c e s ,
N o v e m b e r
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What is Cancer?
Uncontrolled growth of cells
Not all tumors are cancerous
Six characteristics of cancer cells:
Self-sufficiency in growth signaling
Insensitivity to anti-growth signals
Evasion of apoptosis
Enabling of a limitless replicative potential
Induction and sustainment of angiogenesis
Metastasis and invasion of tissue
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Cancer Classification
Carcinoma
Originate in epithelial origin, Most common ,80-90 percent of all cancer
Sarcoma
Originates in supportive and connective tissues
Myeloma
Originates in the plasma cells of bone marrow
Leukemia
Cancers of the bone marrow (the site of blood cell production)
Lymphoma
Originate in glands or nodes of the lymphatic system
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Is it due to Genetic Factors?
Small proportion is predisposed by inherited germline
mutations behaving as mendelian traits
For many cancers, environmental factors are etiologically
more important than heredity
Cancer is a genetic disease of somatic cells
End result of an accumulation of both inherited and somatic
mutations in cell growth related genes
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Cancer Genes Network
The detail in cancer genetics can be overwhelming
Every tumor is individual
There are so many different genes that acquire
mutations in one or another tumor, and they interact
in complex ways
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Classes of Cancer Genes
Oncogenes
Their normal activity promotes cell proliferation.
Act as the accelerator
Tumor suppressor genes
Products act to limit normal cell proliferation
Act as the break
DNA Repair Genes
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Oncogenes
Gain of function mutations - excessively or inappropriately
active.
A single mutant allele may affect the behavior of a cell.
The nonmutant versions are properly called proto-oncogenes
The viral oncogenes are copies of normal cellular genes,
proto-oncogenes
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Five broad classes of Oncogenes:
Secreted growth factors (e.g. SIS )
Cell surface receptors (e.g. ERBB and FMS)
Components of intracellular signal transduction systems (e.g. the
RAS family and ABLl )
DNA-binding nuclear proteins, including transcription factors
(e.g. MYC and JUN)
Components of the network of cyclins, cyclin-dependent kinases,
and their activators and inhibitors (e.g. CCNDl and MDM2 )
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Chronic Myeloid Leukemia
In 1960, in Philadelphia an abnormal chromosome in white
blood cells from patients with chronic myeloid leukemia
(CML) was described.
Philadelphia, or Phi, was chromosome 22 with
t(9;22)(q34;qll) translocation. seen in 90% of those with CML
Resulting in a chimeric transcript derived from both the cABL (70%) and the BCR genes
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Burkitt Lymphoma
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Burkitt Lymphoma
An unusual form of neoplasia seen in children in Africa is a
lymphoma that involves the jaw
90% of affected have a translocation of the c-MYC oncogene
from the long arm of chromosome 8 on to heavy (H) chain
immunoglobulin on chromosome 14.
MYC comes under the influence of the regulatory sequences
of the immunoglobulin gene and is overexpressed 10-fold or
more
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Tumor Suppressor Genes
These are genes whose function is to keep the behavior of cells
under control.
Restraining or suppressing inappropriate cell division
Maintaining the integrity of the genome
Ensuring that incorrigibly deviant cells are sentenced to death by
apoptosis
Loss of function mutations
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Retinoblastoma
The paradigm for our understanding of the biology of tumor
suppressor genes
Retinoblastoma (Rb) is a relatively rare, highly malignant,
childhood cancer of the developing retinal cells of the eye
Rb can occur either
Sporadically, the so-called nonhereditary form
Familial, the so-called hereditary form,
Inherited in an autosomal dominant manner.
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Retinoblastoma
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'Two-Hit' Hypothesis
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TP53
The TP53 gene is the most frequently mutated of all the
known cancer genes.
Seen in some 20% to 25% of breast and more than 50% of
bladder, colon, and lung cancers
It functions as a checkpoint control site in the cell cycle at G1
before the S phase
An inherited or germline mutation of TP53, Li-Fraumeni
syndrome, an autosomal dominant trait
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Telomere Length and Cancer
Some cancer cells express high levels of telomerase, so that
cell viability is maintained.
Most metastases contain telomerase-positive cells, suggesting
that telomerase is required to sustain such growth.
However, cancer cells generally have shorter telomeres than
the normal cells surrounding them
Telomere length is therefore almost certainly a key concept in
many cancers
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Multistage Process of Colorectal Cancer Development
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Cowden Disease
Cowden disease is autosomal dominant but very variable
Gastrointestinal polyps are found in about half of the cases and
are generally benign adenomas.
High incidence (50%) of breast cancer in females, and papillary
thyroid carcinoma in about 7% of the patients
Mutations in the tumor suppressor PTEN gene on chromosome
lOq23, encoding a tyrosine phosphatase
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Breast Cancer
Most common women cancer, 1/12 in west, between age of 40
and 55
1 in 3 develop metastatic disease. Some 15% to 20% have family
history
About 40% to 50% of families with early-onset autosomal
dominant breast cancer have a mutation in the BRCA1, 60% to
85% lifetime risk of breast cancer.
BRCA2 gene account for 30% to 40% of families with early-onset
autosomal dominant breast cancer
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Prostate Cancer
The most common cancer affecting men
lifetime risk of 10% of developing the disease and a 3%
chance of dying from
About 15% have a first-degree male relative with
prostate cancer
9% of all prostate cancers and up to 40% of early onset
prostate cancers, hereditary prostate cancer-l and -2
(HPCl and HPC2)
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