CANCER

GENETICS

2016
 Cancer, like other diseases, have accompanied man from his very
beginning.
First mention about cancer was found in Egyptian papyruses, about
1600 year BC

Hipokrates (about 400 year BC) introduced the term karkinos

(crab, cancer) into medical terminology.
He used it to describe breast cancer.
 CANCER

An uncontrolled proliferation of host cells, which are changed

both morfologically and functionally.
 CANCER

Occurs when the cell escapes from control mechanisms,

which normally decide about cell division and localization.
(Robert A. Weinberg)

In physiologic conditions there is tight balance between cell

proliferation and cell death in our bodies
 CANCER

Unlimited growth results from genomic instability,

increased proliferation, decreased apoptosis (programmed
cell death), inhibition of differentiation, gain of migration
and invasion properties

→ by invading adjacent tissues cancer cells are dangerous

to the whole organism
 CLASSIFICATION:

→ solid tumors and leukemias

Tumor is not synonymous with cancer. While cancer is by definition
malignant, a tumor can be benign, pre-malignant, or malignant, or can
represent a lesion with no cancerous potential whatsoever.
→ benign tumors (non-malignant), malignant tumors and locally
malignant tumors (classification based on histological findings and clinical
observations)

Neoplastic tumor of the cheek skin,

here a benign neoplasm of the sweat
glands called Hidradenoma, which is
not solid but is fluid-filled.
Malignant neoplasm - is a class of diseases in which a group of cells display
fast, uncontrolled growth (division beyond the normal limits), invasion
(intrusion on and destruction of adjacent tissues), and sometimes metastasis
(spread to other locations in the body via lymph or blood).

These three malignant properties of cancers differentiate them from benign

tumors, which are self-limited, and do not invade or metastasize.
.

Normal epithelium Benign tumor Malignant tumor

Locally malignant tumors – grow fast and may invade and destruct
adjacent tissues, but they do not metastasise.

Example: glioma, heterogeneous group of tumors of central nervous

system (anatomical brain-blood barrier).
Malignant tumor cell histological characteristics:

• low grade of differentiation and maturation

• cells are spread chaotically against each other and against stromal
layer (architectonical chaos)

• cells display big nucleus, decreased number of organelles (e.g.

mitochondria), abnormal structure of cytoplasmic membranes

• cells which are localized in different parts of the tumor differ in size
and shape
 BENIGN AND MALIGNANT TUMORS

TUMOR
FEATURE
BENIGN MALIGNANT

Growth Slow Fast

Capsule Yes No

Invasion properties No Yes

Relapse No Yes

Blood vessel infiltration No Yes

Histology Similar to normal tissue Differs from normal

tissue
Impact on organism Slight Results in weakness
and death
Classification by histological type

Cancers are classified by the type of cell that resembles the tumor and,
therefore, the tissue presumed to be the origin of the tumor. These are
the histology and the location, respectively.

Carcinoma: Malignant tumors derived from epithelial cells. This group

represents the most common cancers, including the common forms of
breast, prostate, lung and colon cancer.

Sarcoma: Malignant tumors derived from connective tissue, or mesenchymal

cells.

Lymphoma and leukemia: Malignancies derived from lymphatic tissue and

hematopoietic (blood-forming) cells
Classification ctd

Melanoma: A cancer that develops in melanocytes, the pigment

cells present in the skin

Germ cell tumor: Tumors derived from totipotent cells. In adults

most often found in the testicle and ovary; in fetuses, babies, and
young children most often found on the body midline, particularly
at the tip of the tailbone.

Blastic tumor or blastoma: A tumor (usually malignant) which

resembles an immature or embryonic tissue. Many of these tumors
are most common in children
CANCER

GENETIC DISEASE
 Cancer results from a number of subsequent mutations

Each successive mutation gives the cell a growth advantage, so that it forms an expanded clone,
thus presenting a larger target for the next mutation.
TRANSFORMATION
(carcinogenesis)

a change of a normal cell into a cancer one

 Transformed cells

Much of what we know about cancer is derived from studies of transformed cells

These have abnormal growth parameters and behaviors:

 Immortality: can grow indefinitely
 Reduced requirement for serum growth factors
 Loss of capacity for growth arrest upon nutrient deprivation
 High saturation densities
 Loss of contact inhibition
 Anchorage independent (can grown in soft agar)
 Altered morphology (rounded and refractile)
 Tumorogenic: can cause tumors when transplanted into animals
TRANSFORMATION

* complex and multistage process

* is characterized by long latent pahase

 STAGES OF CARCINOGENESIS:

normal cell

• PREINITIATION
cell with mutation
• INITIATION
carcinoma in situ
• PROMOTION
invading cancer
• PROGRESSION

metastasising cancer
 PREINITIATION:

normal cell

• may last all the lifetime

cell with mutation
• time of exposition to
mutagenic factors:
- biological carcinoma in situ
- chemical
- physical
invading cancer

metastasising cancer
Most mutagenic factors are carcinogenic

Chemical mutagens:
Nitrosamines - a group of mutagens found in tobacco; may also be formed in in
smoked meats and fish via the interaction of amines in food with nitrites added as
preservatives. Some analgetics (from non steroid anti-inflammatory group –
fenacetine), cytostatic drugs, some antibiotics, hormones used as medication

Physical mutagens:
- radiation (non-ionizing UV radiation of 240-265nm vawelength and ionizing
radiation like X-rays, cosmic rays, α-particles, β-particles and gamma rays) –
diagnostic procedures and radiotherapy

Biological mutagens:
- acting directly - viruses
- acting indirectly - factors produced by bacteria and fungi (e.g. aflatoxines)
PREINITIATION

There are at least two groups of genes, which polymorphism

(individual diversity) may affect the sensitivity/resistance to
cancer:

- genes encoding molecules responsible for removal of genotoxic

factors

- genes encoding proteins important for DNA repair

(stabilizing/mutator genes)
 INITIATION:

normal cell

• begins with the first

cell with mutation
mutation
• may last from several to
20-30 years carcinoma in situ
• time of accumulation of
mutations leading to
transformation invading cancer

metastasising cancer
INITIATION

mutations may occur spontanically, or they result from the first mutation

subsequent mutations responsible for the transformation of a normal cell

into a cancer one create a pathway controlling tumorigenesis

some mutations are more dangerous than others: alterations of TP53

gene (guardian of the geneome) are seen in over 50% of human npls

the length of this step depends on genetic predispositions: will be

shorter in people which have inherited TS allelle mutation
 PROMOTION:

normal cell

cell with mutation

• lasts for less than several
years
• clonal selection
carcinoma in situ
• carcinoma in situ
• gain of invading properties
invading cancer

metastasising cancer
PROMOTION

the increase of mitotic activity of the cells

successive gene mutations

structural and mumerical chromosomal aberrations (translocations,

deletions, duplications, inversions, aneuploidy)

cancer cell subclones development (selective pressure)

result: carcinoma in situ – several subclones, 106-107 cells

 PROGRESSION:

normal cell

• lasts from several months

cell with mutation
to several years (depending
on the cancer)
• subsequent selection of carcinoma in situ
mutations
• gain of metastasising
properties invading cancer

metastasising cancer
PROGRESSION

starts with the development of tumor vascularisation (tumor

angiogenesis)

subsequent changes in the phenotype of cancer cells

selective pressure → cells which may migrate proliferate quickly →

migrate → distant metastases
Angiogenesis - the growth of new capillary blood vessels

In adult life – physiologically occurs only during wound healing and

during female menstrual cycle

Tumor progression begins when a subgroup of cells within the tumor

switches to an angiogenic phenotype by changing the local
equilibrium between positive and negative regulators of
angiogenesis,

Tumor starts to grow rapidly and becomes clinically detectable.

Tumor vessels are much more fragile than normal
ones (increased risk of hemorrhage)
and their wall is more permeable (metastases)
Metastatic cancer is cancer that has spread from the
place where it first started to another place in the body.

A tumor formed by metastatic cancer cells is called a

metastatic tumor or a metastasis. The process by which
cancer cells spread to other parts of the body is also
called metastasis.
Metastatic cancer has the same name and the same
type of cancer cells as the original, or primary, cancer.
For example, breast cancer that spreads to the lung
and forms a metastatic tumor is metastatic breast
cancer, NOT lung cancer.
Cancer cell metastasis usually involves the following steps:

Local invasion: Cancer cells invade nearby normal tissue.

Intravasation: Cancer cells invade and move through the walls of nearby lymph
vessels or blood vessels.
Circulation: Cancer cells move through the lymphatic system and the
bloodstream to other parts of the body.
Arrest and extravasation: Cancer cells arrest, or stop moving, in small blood
vessels called capillaries at a distant location. They then invade the walls of the
capillaries and migrate into the surrounding tissue (extravasation).
Proliferation: Cancer cells multiply at the distant location to form small tumors
known as micrometastases.
Angiogenesis: Micrometastases stimulate the growth of new blood vessels to
obtain a blood supply. A blood supply is needed to obtain the oxygen and
nutrients necessary for continued tumor growth.
Virtually all cancers, including cancers of the blood and
the lymphatic system (leukemia, multiple myeloma, and
lymphoma), can form metastatic tumors.

Although rare, the metastasis of blood and lymphatic

system cancers to the lung, heart, central nervous
system, and other tissues has been reported.
Alterations of genome of cancer cells
Cancer happens because of a combination of three mechanisms:

Some mutations enhance cell proliferation,

creating an expanded target population of cells for the next mutation

Some mutations affect the stability of the entire genome,

at either the DNA or the chromosomal level,
increasing the overall mutation rate

Some mutations alter the mechanisms of cell death (apoptosis)

MAIN TUMOR DEVELOPMENT PATHWAY
GENES:

 PROTOONCOGENES

 TUMOR SUPPRESSOR GENES

 MUTATOR (STABILIZING) GENES

 GENES ENCODING microRNAs

PROTOONCOGENES
 Viral and cellular oncogenes

Viral disease v-onc c-onc Location Function

Simian sarcoma v-sis PDGFB 22q13.1 Platelet-derived
growth factor B
subunit
Chicken v-erb-b EGFR 7p13-q22 Epidermal growth
erythroleukemia factor receptor
McDonough feline v-fms CSF1R 5q33 Macrophage colony-
sarcoma stimulating factor
receptor
Harvey rat sarcoma v-ras HRAS1 11p15 Component of G-
protein signal
transduction
Abelson mouse v-abl ABL 9q34.1 Protein tyrosine
leukemia kinase
Avian sarcoma 17 v-jun JUN 1p32-p31 AP-1 transcription
factor
Avian v-myc MYC 8q24.1 DNA-binding protein
myelocytomatosis (transcription factor)
Mouse osteosarcoma v-fos FOS 14q24.3-q31 DNA-binding
transcription factor

The viral genes are sometimes designated v-src, v-myc etc. and their cellular counterparts c-src, c-myc etc.
The forms of the c-onc genes in normal cells are properly termed proto-oncogenes. Nowadays it is common
to ignore these distinctions and simply use the term oncogenes for the normal genes. The abnormal versions
can be described as activated oncogenes
Protoncogenes

These are genes whose normal activity promotes cell proliferation.

Gain of function mutations in tumor cells create forms that are excessively
or inappropriately active.
A single mutant allele may affect the phenotype of the cell.
The mutant versions are called ocogenes.
 PROTOONCOGENES

Genes encoding proteins responsible for regulation of proliferation.

Their products may be divided into:

1. cell cycle regulators

2. apoptosis regulators

3. other (e.g. proteins forming ion channels)

 Selected protooncogenes and their function

Group Gene name Protein function

SRC, YES, FGR, ABL, FPS, KIT, Protein kinases:
SEA, ROS tyrosine
RAF, MOS serine/treonine

I Growth factors:
SIS PDGF
INT FGF
Growth factors’ receptors:
ERB-B (HER2) EGF
FMS M-CSF
ERB-A thyroid hormone
MAS angiotensine
H-RAS, K-RAS, N-RAS GTP-binding proteins
MYB, MYC, FOS, JUN, ETS, REL, Transcription factors
SKI
BCL2, BAX Mitochondrial and nuclear membrane proteins
II FAS/APO1, FASL Extracellular membrane proteins and their
ligands
III Proteins forming ion channels
 PROTOONCOGENES

are dominant genes (mutation of one allelle is enough to change the

phenotype of the cell)

once mutated, it may become oncogene – a gene, which constitutively

expressed on high level may contribute to uncontrolled growth and
proliferation of the cell

may become a part of fusion gene, resulting from chromosomal

translocations (e.g. BCR/ABL)

in most cases protooncogenes are not mutated in germ cells,

which are responsible for familial tumors
Mechanisms activating protooncogenes:

viral infection (common)

 Approx. 20% of all human cancers are of viral origin

 Viruses are major causes of liver and cervical cancers

 Malignancy can result as a consequence of a side effect of viral infection

or of host response to virus
OCOGENIC VIRUSES

* retroviruses – sarcomas, leukemias

* hepadnaviruses – liver cancer
* papowaviruses - papilloma, skin cancer, cervical cancer
* herpesviruses - lymphoma, esophago-laryngeal carcinoma, gastric
cancer
Activation of protooncogenes by retroviruses:

1. slowly transforming retroviruses – may inegrate with the host genome at random
sites, commonly interrupting the sequences of genes regulating protooncogene expression
(consequence: increased expression)

2. acute transforming retroviruses – include onc genes

Other mechanisms of protooncogene activation:

3. gene amplification (multiplication of protooncogene copies)

- HSR = Homogeneously Stained Regions
- DMs = Double Minute Chromosomes eg. C-MYC in breast cancer, lymphomas,
myeloproliferative syndromes
- an increase of copy number of N-MYC in neuroblastoma and cERB B2 (HER2) in
breast cancer -> poor prognostic factor

4. point mutations eg. RAS in bladder cancer

5. chromosomal translocations
- fusion genes (new genes of new function)
- increase of expression level of existing protooncogenes amplifikacja C-MYC
w chłoniaku
komórek płaszcza
(MCL)
Chromosomal translocations which activate oncogenes.

(A) activation by qualitative change in the t(9;22) in chronic myeloid leukemia. The chimeric BCR-
ABL fusion gene on the Philadelphia chromosome encodes a tyrosine kinase which does not
respond to normal controls.
 Chimeric genes produced by cancer-specific chromosomal rearrangements

Tumor Rearrangement Chimeric gene Nature of chimeric

product

CML t(9;22)(q34;q11) BCR-ABL Tyrosine kinase

Ewing sarcoma t(11;22)(q24;q12) EWS-FLI1 Transcription factor
Ewing sarcoma (variant) t(21;22)(q22;q12) EWS-ERG Transcription factor
Malignant melanoma of soft t(12;22)(q13;q12) EWS-ATF1 Transcription factor
parts
Desmoplastic small round cell t(11;22)(p13;q12) EWS-WT1 Transcription factor
tumor
Liposarcoma t(12;16)(q13;p11) FUS-CHOP Transcription factor
AML t(16;21)(p11;q22) FUS-ERG Transcription factor
Papillary thyroid carcinoma inv(1)(q21;q31) NTRK1-TPM3(TRK oncogene) Tyrosine kinase
Pre-B cell ALL t(1;19)(q23;p13.3) E2A-PBX1 Transcription factor
ALL t(X;11)(q13;q23) MLL-AFX1 Transcription factor
ALL T(4;11)(q21;q23) MLL-AF4 Transcription factor
ALL t(9;11)(q21;q23) MLL-AF9 Transcription factor
ALL t(11;19)(q23;p13) MLL-ENL Transcription factor
Acute promyelocytic leukemia t(15;17)(q22;q12) PML-RARA Transcription factor+retinoic
acid receptor
Alveolar rhabdomyosarcoma t(2;13)(q35;q14) PAX3-FKHR Transcription factor

Note how the same gene may be involved in several different rearrangements. CML, chronic myeloid leukemia; ALL, acute
lymphoblastoid leukemia.
Chromosomal translocations which activate oncogenes.

(B) Activation by quantitative change in the t(8;14) in Burkitt's lymphoma. The MYC gene from
chromosome 8 is translocated into the immunoglobulin heavy gene chain. In B-cells this region
is actively transcribed, leading to over-expression of MYC.
Tumor suppressor (TS) genes

TS gene products inhibit events leading towards cancer.

Mutant versions in cancer cells have lost their function.
Some TS gene products prevent cell cycle progression, some steer
deviant cells into apoptosis, and others keep the genome stable
and mutation rates low by ensuring accurate replication, repair
and segregation of the cell's DNA.
Both alleles of a TS gene must be inactivated to change the
behavior of the cell.
 TUMOR SUPPRESSOR GENES

Negative regulators of the cell cycle

They encode proteins responsible for inhibition of proliferation and

cell arrest at G0

Their products regulate cell proliferation and migration, thus

protecting them against transformation
 Selected TS and their function

TS Chromosome Protein function

localization
TP53 17p13.1 transcription factor, guardian of the genome,
regulation of proliferation and apoptosis
RB1 13q14 transcription factor, regulation of proliferation

APC 5q21 cytoskeleton protein, contact inhibition signal

transduction
WT1 11p13 transcription factor
NF1 17q11 cytoplasmic protein, GTP activator
VHL 3p23 elongation of transcription suppressor, part of
ubiquitine ligase system (protein degradation)
PTEN 10q23 antagonist of PI3 kinase andi FAK kinase, lipid
phosphatase, protein phosphatase
MTS1 9p21 inhibitor of CDK4 and 6 kinase, read from
alternate frame regulates TP53
BRCA1 17q21 transcription activator, part of DNA double strand
breaks repair system, role in chromatine
remodeling
transcription activator, part of DNA double strand
BRCA2 13q12-13
breaks repair system, has the activity of histone
deacetylase
 TUMOR SUPPRESSOR GENES

recessive genes (mutations of both allelles is required to change the

phenotype of the cell)

encode nuclear proteins which regulate expression of other genes

their products influence proliferation and differentiation of cells

may block oncogenes e.g. C-MYC

protect the cell against growth factors (like TGF – transforming growth factor)
and factors inducing differentiation, thus inhibiting uncontrolled cell
proliferation
Tumor suppressor genes inactivation mechanisms

 Deletion

 Point mutation

 Methylation of CpG islands of promoter regions

(epigenetic regulation)
Mutations of protooncogenes may be inherited

- predisposition to cancer development

 Familial cancers caused by TS gene mutations

Disease MIM No. Map location Gene

Familial adenomatous 175100 5q21 APC

polyposis coli
Hereditary non-polyposis colon 120435, 120436 2p16, 3p21.3 MSH2, MLH1
cancer
Breast-ovarian cancer 113705 17q21 BRCA1
Breast cancer (early onset) 600185 13q12-q13 BRCA2
Li-Fraumeni syndrome 151623 17p13 TP53
Gorlin's basal cell nevus 109400 9q22-q31 PTC
syndrome
Ataxia telangiectasia 208900 11q22-q23 ATM
Retinoblastoma 180200 13q14 RB1
Neurofibromatosis I (von 162200 17q12-q22 NF1
Recklinghausen disease)
Neurofibromatosis 2 101000 22q12.2 NF2
(vestibular schwannomas)
Familial melanoma 600160 9p21 CDKN2A
von Hippel-Lindau disease 193300 3p25-p26 VHL

References to the genes and diseases may be found in OMIM under the numbers cited.
MUTATOR (STABILIZING) GENES

are reccessive genes

encode proteins important for DNA repair (MMR, mismatch repair etc)

may repair mutations which unrepaired result in protooncogene activation

or tumor suppressor gene inactivation

mutations of mutator genes lead to genome instability – such mutations

are associated with an increased mutation ratio
MUTATOR (STABILIZING) GENES

 MSH2
 MSH3
 MSH6
 MLH1
 PMS1
 PMS2

Inherited mutations of these genes (mainly MSH2 i MLH1) are

responsible for familial syndrome of Hereditary Non-Polyposis Colon
Cancer (HNPCC). Second common cancer in case of this syndrome is
endometrial cancer.
HNPCC is inherited in an autosomal dominant fashion.
MicroRNAs (miRNAs)

negatively regulate gene expression by either inhibition of translation

or mRNA degradation

Gene
DNA

Transcription

mRNA

Translation

Protein
miRNAs

May behave both as TS (while controlling oncogenes) and as

oncogenes (controlling TS).

miRNA miRNA
RAS P53

Unfortunately....
changes in miRNA expression are observed in many cancers.
miRNAs

Expression in cancer cells may be altered by:

 mutations

 deletions

 rearrangements
Sequential genomic alterations resulting in cancer are
known as pathway of tumor development

Fearon and Vogelstein's model for the development of colorectal cancer.

An average solid tumor development pathway includes mutations
of five to twenty genes

Leukemias and lymphomas development pathways include lower

number of mutations

The most known is pathway of colon cancer development.

Slaby O et al. Mol Canc 2009, 8: 102-115
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