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Cancer

Uncontrolled cellular proliferation leading to a mass or a tumor (neoplasm)

For a mass to be a tumor, the mass needs to be malignant

Malignancy means that the mass has uncontrolled growth and has the ability
to invade neighboring tissues or spreading to distant sites

Tumors that do not metastasize are not cancerous but are called benign
tumors

Occurs because of an imbalance between cellular proliferation and cellular


attrition

cancer can be caused by:

1. Activation (gain of function) of oncogenes


2. Loss of function of tumor suppressors

Oncogenes

Mutant activated alleles of a class of normal genes known as protooncogene

Can also be genes that encode telomerase, or that block apoptosis

The function of the oncogenes is in supplying the blood to the tumor, or


blocking apoptosis

Mutations in oncogenes

The activating mutation could be:

1. In the oncogene itself


2. In its regulatory element
3. Genomic copy number

Oncogenes have a dominant effect at the cellular level

A single mutant allele is sufficient to change the phenotype

Examples of oncogenes :
1. Ras GTPase

Ras is a small monomeric GTP binding regulatory protein

About 30% of all tumors have mutations in Ras GTPase

They could be functionally coupled to G protein coupled receptor, in this


case they exist as trimers

They could exist as functionally distinct monomeric proteins

They have GTPase activity which allows them to function as molecular


switches

Exchange of GDP with GTP activates the proteins


1- Active conformation: binds to the GTP.
2- Inactive conformation that binds GDP
Any mutation that prevents the GTP
binding protein from losing the GTP, will
cause the signaling downstream to
continue infinitely, which will lead to
cancer.

Ras GTPase is a component of a cell signaling pathway activated by receptor


tyrosine kinases

Receptor tyrosine kinases (RTKs)

A group of cell surface receptors that are involved in mediating cellular


growth

RTKs are activated by growth factors; epidermal growth factor (EGF) or


platelet derived growth factor (PDGF)

binding of the ligand to the receptor that is


found as a monomer, allows the receptor
dimerization which leads to the activation of the
catalytic domain
the catalytic domain is called tyrosine kinase
because it has the ability to phosphorylate
certain proteins
in this case, it has the ability to
autophosphorylate itself on the tyrosine
residues

Mechanism of Receptor tyrosine kinases signaling

Ligand binding induces receptor dimerization and activates catalytic domain

Catalytic domain auto-phosphorylates receptor (receptor also functions as an


effector protein)

Phosphorylated tyrosine residues become anchoring point for adaptor


proteins

Adaptor proteins have special protein-protein interaction domains called (SH2


=SRC Homology 2 = aid in the signal transduction of receptor tyrosine
kinase pathways)

RTKs allow accumulation of many types of tyrosine phosphorylated proteins


(secondary effector proteins)

Role of Ras GTPase in RTK signaling

Adaptor proteins (following receptor dimerization) can directly bind to


phosphorylated RTKs and recruit Ras activating proteins

Ras activating proteins enhance GDP exchange with GTP

Ras protein can then activate downstream signaling pathways involved in


proliferation (MAP kinase cascade)

Mutations that increase GTPase activities of Ras proteins will lead to


cancer

Most common mutation is to lose the GTPase activity, and Ras will remain
bound with GTP, which will cause a tumor.
Loss of extracellular domain, which will allow it to dimerize without any
ligand, which will also cause a tumor.

Activation of Oncogenes by Chromosome Translocation

Oncogenes are not always the result of a DNA mutation

A proto-oncogene is activated by a chromosome mutation, usually through


translocation

Mostly seen in leukemias and lymphomas but sometimes seen in connective


tissue sarcoma

1-Translocation leading to chimeric oncogenic proteins

Translocation breakpoints are within the introns of two genes, thereby fusing
two genes into one abnormal gene

The oncogene encodes a chimeric (from 2 genes) protein with novel (new)
oncogenic properties

An example is the translocation between chromosomes 9 and 22 that is seen


in chronic myelogenous leukemia (CML)

This results in what is called the Philadelphia chromosome

Philadelphia chromosome

Translocation between chromosomes 9 and 22

The translocation moves the proto-oncogene ABL, from chromosome 9q to


the gene (BCR), on chromosome 22q

Abl is a tyrosine kinase while BCR has no known function

The juxtaposition of BCR sequences and ABL sequences allows the synthesis
of a chimeric protein that is longer than the normal Abl protein and has
increased tyrosine kinase activity.

The enhanced tyrosine kinase activity is what leads to leukemia

A new drug Imatinib has been developed that inhibits enhanced tyrosine
kinase activity monoclonal antibodies that bind to the receptor, and
prevents the binding of GF, and locks the receptor in an inactive
conformation, which will inhibit the signaling pathway.

Resistance to imatinib By having a mutation in the receptor, or a mutation


GTP that will cause the loss of the GTPase activity, because there will cause a
signaling independent from the upstream signal from the ligand

2- Translocation placing an oncogene downstream of a stronger


promoter

Translocation activates an oncogene by placing it downstream of a strong,


constitutive promoter belonging to another gene.

Two well-known examples are:

1. Translocation between chromosomes 8 and 14 in Burkitt lymphoma


2.

Translocation involving chromosome 18 in B-cell lymphoma

Burkitt lymphoma

B-cell tumor of the jaw commonly seen in equatorial Africa but rare elsewhere

MYC proto-oncogene is translocated from its chromosomal position at 8q to a


position distal to the immunoglobulin heavy-chain locus at 14q

The translocation brings enhancer sequences, associated with the


immunoglobulin genes, near to the MYC gene.

Could also involve translocating immunoglobulin light-chain enhancer on


chromosomes 22 and 2 near to the MYC gene

Function of MYC not completely understood.

It appears to be a transcription factor with powerful effects on the expression


of a number of genes involved in cellular proliferation as well as on
telomerase expression

Follicular B cell lymphoma

Apoptosis (programmed cell death), is a normal process in which cells


undergo suicide

Apoptosis is characterized by fragmentation of cellular DNA and activation of


a family of cysteine proteases known as caspases

Prominent in lymphocytes in which cells need to die to prevent them from


reacting against their own antigen

Overexpression of an antiapoptotic protein in lymphocyte lineages could


result in vast expansion of lymphocyte populations

In B-cell lymphomas of the follicular type, BCL2 located at 18q21 is activated


by a t(14;18) chromosomal translocation

Translocation places the gene under the strong enhancer of the


immunoglobulin heavy-chain gene located at 14q32

The protein encoded by BCL2 is a mitochondrial inner membrane protein with


antiapoptotic effects in B cells.

Telomerase as an oncogene

A reverse transcriptase required to synthesize hexamer repeat (TTTAGG) as a


component of telomeres at the ends of chromosomes

During DNA replication, DNA polymerase, cannot complete the synthesis of


lagging strand all the way out to the very 3 end of the template

In human germline cells and embryonic cells, telomeres contain


approximately 15 kb of the telomeric repeat.

As cells differentiate, telomerase activity declines in all somatic tissues


except in the highly proliferative cells and tissues that must undergo selfrenewal, such as the bone marrow.

As telomerase function is lost, telomeres shorten.

After hundreds of cell divisions, the chromosome ends will become damaged.
DNA damage causes cells to stop dividing and enter G0 of the cell cycle and
ultimately undergo apoptosis

Telomerase expression persists in many tumors and permits tumor cells to


proliferate indefinitely

Telomerase overactivity is a tumor facilitator not initiator

The presence of telomerase activity is now being used as a sensitive


diagnostic tool for:

1. low levels of cancer in blood samples


2. In cells obtained by biopsy or needle aspiration of suspected cancerous lesions.

Tumor suppressor genes

Mutations in tumor-suppressor genes (TSGs) contribute to malignancy


through loss of function of both alleles

Tumor suppressor genes are either gatekeepers or caretakers

Gatekeepers are involved in cell cycle directly

Caretakers, are involved in repairing DNA damage and maintaining genomic


integrity.

Tumor suppressors cause tumors as a result of having 2 defective alleles so


theoretically, if there is a familial cancer that is caused by a tumor
suppressor, it should act in an autosomal recessive manner.

But when they looked at family pedigrees and looked at tumors that are
caused by mutations in gene suppressors , they found that they are passed in
an Autosomal Dominant manner This made them come up with what is
called the 2 hits origin captor

Linkage mapping

A linkage map is a genetic map that shows the position of genes relative to
each other in terms of recombination frequency

Distance is not expressed in terms of specific physical distance along each


chromosome

It depends on the tendency of alleles that are located close together on a


chromosome to be inherited together during the meiosis

Genes whose loci are nearer to each other are less likely to be separated onto
different chromatids during crossover.

These genes are therefore said to be genetically linked

Map distance between genes

By calculating the number of recombinants it is possible to obtain a measure


of the distance between genes

This distance is expressed in terms of a genetic map unit (m.u.) or a


centimorgan

A recombinant frequency (RF) of 1% is equivalent to 1 m.u.

The largest percentage of recombinants cannot exceed 50%

50% recombination frequency means that the two genes are:

1. The extreme opposite ends of the same chromosomes


2. Genes are at two different chromosomes

A linkage map is created by finding the map distances between a number of


traits that are present on the same chromosome

Lets assume that we have one pair of homologous chromosomes: one from
-Lets assume the gene of the bristle length = s
the father and the other from the mother.
where :
s+ allele of the long bristle.(dominant)
s allele of the short bristle.
- and the gene of the body color = e where:
e+ allele of gray color. (dominant)
e allele of white color.

- we mate a male who has a long bristle and


gray color and it is heterozygous for both alleles
- with a female who has short bristle and ebony
As a result of crossing over, we will end color
up with four different gametes:
- by recombination we get four different
1- parental : identical to the gametes of the
parentsinstead of two
gametes
2- recombinant : dont look like the parents
1- s+e+ 2- se 3- s+e 4- se+
The result offspring was as the following
1- long bristle, gray body (heterozygous) =537
2- short bristle , ebony body = 542
* both 1&2 are the same as parents nonrecombinants

Notes on the previous lectures


Heinz bodies = G6PD deficiency
Malignant Hyperthermia treatment =
Dantrolene = reduce the affinity of RYR-1 to
calcium