Download Tumor suppressor genes

Genetics and molecular
biology in breast cancer
Mahfoudh Wijden , Hassen Elham and Chouchane
Lotfi.
Laboratoire d’Immuno-Oncologie Moléculaire,
Faculté de Medecine de Monastir, Université du
Centre, Tunisia
Introduction
• Breast cancer is a common malignancy
affecting women around the world.
• It occurs in sporadic and hereditary
forms.
RISK FACTORS
• Uncontrollable risk factors : being
female, age, early menarche, benign breast
disease and family history.
• Controllable risk factors : obesity, use
of oral contraceptives and having 1st
child after 30.
Cancers are Genetics Disease
• Cancer is a collection of diseases that
result from loss of control over cell
division.
• Because the cell cycle is controlled by
proteins, and proteins are encoded by
genes, cancers are genetic diseases.
Gene
• A unit of
heredity
• A portion of
DNA molecule
• A DNA blueprint
for a protein
Base
Nucleotide
(base+sugar+phosphate)
DNA (Deoxyribonucleic acid)
Polymer of nucleotides
Chromosome
Human Genome
Human Genome
Gene
Functional protein
Disease-Associated Mutations
A DNA mutation is a change in the normal base pair
sequence
Single Mutation can result in nonfunctional protein
Functional protein
Nonfunctional protein
Germline and Somatic changes
Germline mutations
Parent
Mutation
in egg or
sperm


Somatic mutations
Child
All cells
affected in
offspring
Present in egg or sperm
Are heritable


Somatic
mutation (eg,
lung cancer)
Occur in cells during the woman's
lifetime
Are nonheritable
Genes That Regulate Cell Division
•Oncogenes: genes
whose protein product
functions to promote
cell division
• Tumor suppressor
genes: genes whose
protein product
functions to block cell
division.
Oncogenes
= gas pedal
Tumor Suppressor
Genes = brakes
Dr Griend. 2004
How Does a Cell Lose Control?
• Mutations in genes controlling cell division may change
the proteins that control cell division.
• Changes in oncogenes result in abnormal over-stimulation (i.e.
gas pedal stuck down) of cell division.
• Changes in tumor suppressor genes result in an inability to stop
cell division (i.e. breaks disabled).
Oncogenes
Always
On
Tumor
Suppressor
Genes
Disabled
Dr Griend. 2004
Breast cancer occurs in sporadic and
hereditary forms.
About 5-10% of all breast cancer is inherited as the
result of highly penetrant germline mutation in cancer
predisposing genes which leads to an autosomal
dominant predisposition to the disease.

Germline Mutations
All cells
affected in
offspring
Major Susceptibility genes to breast cancer:
BRCA1/2.
2
20
Mutations in either of these genes confer a
high lifetime risk, of up to 87%, of developing
breast cancer.
Genetic Risk Factors for Breast Cancer
5 to
10%
(Balmain, Gray and Ponder, Nature Genetics, 2003)
A wide variety of genes is commonly mutated or
incorrectly regulated in sporadic breast cancers
• overexpression of the epidermal growth factor receptors
EGFR, HER-2/neu, ERBB3 and ERBB4
•
amplification of the MYC gene
•
mutation and overexpression of the intracellular signaling
molecules h-Ras and c-Src
•
mutation and inactivation of p53 and RB1
•
overexpression of cyclin D1 and reduced expression of the
adhesion molecule E-cadherin.
Large Genome-wide association study
(GWAS)
1500 breast cancers
1500 controls
Genome-wide association study (GWAS)
• Common SNPs in several genes have been shown to
be associated with breast cancer risk:
•
•
•
•
•
•
•
CASP8
TGFB1
FGFR2 (fibroblast growth factor receptor 2)
TNRC9
MAP3K1
LSP1
ECHDC1 (which encodes a protein involved in
mitochondrial fatty acid oxidation)
• RNF146 (which encodes a ubiquitin protein
ligase).
Conclusion
• These studies illustrate the power of GWA studies
in large sample sizes to identify gene variants that
may increase risk of breast cancer, although these
are not high-penetrance genes.
• Perhaps the greater ramifications for these
findings are that they identify pathways that have
not been previously explored, and they open new
doors for basic science and epidemiologic studies
to identify additional causes of breast cancer.