2. â˘Cancer is a genetic disease and is mostly caused by somatic
mutations.
â˘The characteristic properties of cancer cells - consequences of
genetic changes in the tumor cells - Genomic instability
â˘Self-sufficient proliferation of growth
â˘Refractory to inhibitory signals
â˘Survival without survival signals
â˘Unlimited replicative potential
â˘Recruitment of blood supply
â˘Invasion and metastasis
â˘Cancer cells contain multiple alterations in the number and structure
of genes and chromosomes, mainly acquired by mutations in somatic
cells.
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College
3. Individual genes display point mutations such as base changes,
insertions and deletions, or can be affected by chromosomal
translocations or inversions.
These changes lead to the
expression of altered gene products,
decreased or increased gene expression
novel gene products like fusion proteins.
Two classes of genes affected by genetic and epigenetic alterations in
cancer cells are oncogenes and tumor suppressor genes.
Oncogenes contribute to tumor development by increased or
misdirected activity.
Tumor suppressors - insufficient or lost function supports tumor
development.
Typically, in human cancers activation of oncogenes and inactivation
of tumor suppressor genes - both are observed.
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College
5. Oncogenes are cellular or viral (i.e., inserted into the cell by a virus)
genes; their expression can cause the development of cancer.
Proto-oncogenes are normal cellular genes - conversion to oncogenes
occur via several mechanisms. Gain-of-function mutations of proto-
oncogenes stimulate cells to multiply.
Tumor suppressors (anti-oncogenes) are cellular genes; their
inactivation increases the probability of tumor formation. Loss-of-
function mutations - relieve cells of control in replication.
About one hundred potential oncogenes (cellular and viral) and thirty
tumor suppressors have been recognized.
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College
8. Tumor suppressors are guardians against DNA damage.
â˘Slows or inhibits cell proliferation and prevents damaged or
abnormal cells from becoming malignant.
â˘Monitor DNA damage and help repair the damage before cells divide.
â˘Induce growth arrest at two DNA damage checkpoints: the first gap
phase (G1) and the second gap phase (G2) of the cell cycle. This enables
cells to check the integrity of the chromosomes before proceeding into
DNA replication (S phase) or division (M phase).
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College
9. Functions of tumor-suppressor proteins
Repression of genes that are essential for the continuing of the cell
cycle, effectively inhibiting cell division.
Coupling the cell cycle to DNA damage. Cell should not divide with
damaged DNA - the cell cycle continue once it is repaired.
If the damage cannot be repaired, the cell should
initiate apoptosis (programmed cell death) to remove the threat it
poses for the greater good of the organism.
Metastasis suppressors prevent tumor cells from dispersing, block
loss of contact inhibition, and inhibit metastasis.
DNA repair proteins are usually classified as tumor suppressors.
HNPCC, MEN1 and BRCA.
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College
10. The functional inactivation of tumor suppressors by Genetic (gene
mutation or deletion, mutations in the promoter of genes) or epigenetic
alterations (promoter methylation, mutations in the promoter of
genes) â creates imbalance between proliferation, cell death, and
differentiation programs that facilitates tumorigenesis.
Individuals born with mutations in tumor-suppressor genes are
predisposed to cancer.
Tumor suppressors represent about 0.001% of the total number of
genes (around 30,000) that make up the entire mammalian genome.
About 30 tumor suppressors are known.
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College
11. THE âTWO HITâ HYPOTHESIS: LOSS OF
HETEROZYGOSITY
The Knudson hypothesis - cancer is the result of
accumulated mutations to a cell's DNA.
Two mutations are required for the development of retinoblastoma
Familial retinoblastoma
Mutated allele from one parent (the first hit) in retinoblastoma (RB)
gene - Heterozygosity - not sufficient to cause tumor - child is initially
asymptomatic.
A second mutation or deletion on the other RB allele (second hit) - loss
of function of both alleles âloss of heterozygosity (LOH) âdevelopment
of tumor.
Nonfamilial or âsporadicâ retinoblastoma
Somatic mutations on both alleles (two hits) in retinal cells - disease is
not transmitted to the next generation.
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College
13. HAPLOINSUFFICIENCY IN CANCER
Appearance of a phenotype in cells or an organism when only
one of the two gene copies (alleles) is inactivated.
For some tumor suppressor genes, the loss of a single allele is
sufficient to induce susceptibility to tumor formation - these are
haploinsufficient tumor-suppressor genes.
Inactivation of one allele can be achieved by genetic (i.e.
mutation or deletion) or epigenetic (transcriptional silencing by
methylation, repressor complexes, or mutations in the promoter
region) events.
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College
14. EPIGENETIC EVENTS
Epigenetic regulation of genes - methylation, repressor complexes,
or mutations of the promoter regions â reduce messenger RNA
transcription - reduction or loss of protein expression.
Methylation occurs on the cytosine nucleotide of CpG pairs usually
located in promoter regions, resulting in transcriptional silencing.
Mutations in the promoter region can affect binding of
transcription factors to specific DNA binding domains.
Repressor protein complexes bind to the promoter regions of
affected genes - Transcriptional repression .
Epigenetic events are linked to cancer development and are equally
important in the process of carcinogenesis.
Eg. tumor suppressor p16INK4A or p14ARF - silenced by
methylation of their promoters or by active transcriptional
repression by repressor protein complexes.
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College
15. RETINOBLASTOMA PROTEIN is important in the control of
proliferation and development of not only retinal cells, but also other
tissues.
Retinoblastoma - large deletions of coding exons or point mutations -
loss of the messenger RNA or the expression of a nonfunctional pRb
protein.
Children with germ-line RB mutations are at higher risk of developing
osteosarcomas later in adolescence.
Certain sporadic human tumors with RB mutations - carcinomas of
the bladder, breast, and in particular small-cell lung carcinomas.
The retinoblastoma protein plays a critical role in the control of
neoplasia in a variety of tissues.
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College
17. p53/TP53 âThe guardian of the genomeâ - a transcription factor â
its loss leads to genomic instability and increased mutagenesis.
Restrains uncontrolled cell growth â block cell cycle and induce
apoptosis.
Sense multiple cellular stresses (genotoxic stress e.g., UV, X-ray,
carcinogens, and cytotoxic drugs) or oncogenic stresses
(hyperproliferative signals from oncogenes ).
In response to stress, the p53 protein is stabilized and activated -
induce a set of genes involved in cell cycle arrest, DNA repair, or
apoptosis.
p53 is inactivated in most human cancers (50% of tumors) as a result
of mutations in the TP53 gene, or through binding to viral proteins.
Tumor suppressor activity of p53 is due to its ability to induce
apoptosis
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College
20. The phosphatase PTEN (phosphatase and tensin homolog)
negatively regulates cell proliferation.
Loss of PTEN function is common in several cancer types.
Somatic inactivating mutations in PTEN are frequently found in
glioblastoma, endometrial carcinoma, and prostate
adenocarcinoma, in sporadic cancers of the breast, thyroid, lung,
stomach, and blood.
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College
22. The GTPase NF-1
NF-1 is a GTPase - negatively regulates Ras signaling.
Ras - mediator of proliferative signals in response to receptor
activation - its unrestricted action induces hyperproliferative
signals.
Activated Ras-GTP is inactivated to Ras-GDP by NF-1
Mutated in neurofibromatosis and gliomas.
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College
24. BRCA1 and BRCA2 are tumor suppressor genes and are involved
in DNA repair of double-strand breaks.
Mutations in BRCA1 (chromosome 17) and/or BRCA2
(chromosome 13) cause decreased stability of the human
genome and result in dangerous gene rearrangements that can lead
to hematologic cancers.
A BRCA mutation is a mutation in either of the
genes, BRCA1 and BRCA2.
Heterozygous germline mutations in either the BRCA1 or BRCA2
genes - high risk for breast and ovarian cancer phenotypes -
exhibit loss of heterozygosity (LOH).
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College
27. REGRESSING TUMORS BY ACTIVATING
TUMOR SUPPRESSOR GENES â A
THERAPEUTIC TARGET
Preclinical studies both in vitro and in vivo have shown that
restoring p53 function can induce apoptosis in cancer cells.
P53 gene therapy for lung cancer, hepatocellular carcinoma using
viral delivery system.
However, resistance develops in many patients, suggesting that
combination of such gene-targeted therapies may be required.
Tumor Suppressor genes, Dr. Dhanya KC, St.Mary's College