Chapter 9

The Epidemiological Prospective

 6% due to environmental factors affecting gestation

Multifactorial Causation
 Cause of most high prevalence disorders involve genetic and environmental factors
o Similar to how phenotypes for height and weight are influenced by a combination of a number of genes
interacting with environmental conditions

Morphogenetic Disorders
 Morphogenesis: process by which tissues and organs assume their form — occurs mostly during fetal development
o Sensitive process
o Cells undergo rapid differentiation, proliferation and migration
 Malformation occurs when there is a defect in a tissue, organ, or anatomical region
 Teratology: fetal malformation
o Principle observations:
 Specific teratogenic factors cause abnormalities by acting at specific stages of development
 Exposure to severe teratogenic influences during the first 2 weeks after fertilization will usually
prevent further development, since injury to the embryo is likely to prevent implantation
 The first trimester is a highly sensitive period of development, since this is the period during which
organogenesis occurs. After the first trimester, it is mainly nervous system tissue that continues to
differentiate
 Fetotoxic effects in the last two trimesters mainly involve interference with the rate of cell division,
thus affecting the number of cells that make up specific tissue structures
 The susceptibility of a mother and fetus to specific teratogens is highly variable between individuals

Teratogens
 Teratogens: chemical, biological, or physical influences that disturb normal morphogenesis
o Class of toxins with effects on fetus and maternal tissues during gestation
o Main classes:

1|Page
  Radiation
 Chemical substances
 Alcohol
 Cocoaine
 Diethylstilbestrol (DES)
 Thalidomide
 Tetracycline
 Polychlorinated biphenyls
 Biphenols
 Tobacco smoke
 Infectious agents
 Treponema pallidum (causative agent for syphilis)
 Toxoplasma gondi (protozoal)
 Most common ones are viral
o b/c there is a variety of viruses that affect fetal development and there is a high
incidence of viral infections during pregnancy
o most prevalent ones:
 cytomegalovirus
 herpes simplex
 rubella
 varicella-zoster virus
 zika virus
o Cause — fetal death, growth retardation, malformation, or functional impairment
 Teratogenesis is dose-dependent
 Teratogens vs. Fetotoxins
o Teratogen: produces morphogenetic errors
o Fetotoxin: causes toxic effects (low birth weight, increase risk of premature delivery)

Examples of Morphogenic Errors and Teratogenesis

Neural Tube Defects

 Neural tube defects have been linked to a nutritional deficiency in folic acid — pregnant woman take folic acid
supplements
o Anencephaly: absence of a head
 Dysraphic defect of the neural tube — neural tube fails to close, leaving an absent, incomplete or
exposed brain
 Typically cranium is absent
o Spina Bifida: less severe
o Meningocele: meninges protrude through the vertebral column

Teratogenic Effects of Alcohol

 FAS: facial dysmorphisms
o Can have neurological manifestations, like learning disabilities
o Similar — Fetal Alcohol Effects or Fetal Alcohol Spectrum Disorders
 Clinical signs of FAS
o Abnormal facial features (smooth ridge between the nose and upper lip)
o Small head size
o Shorter than average height
o Low body weight
o Poor coordination
2|Page
 o Hyperactive behaviour
o Difficulty with attention
o Poor memory

Thalomide – prescribed drug

 Was prescribed to alleviate morning sickness
 Phocomelia: severely impaired limb development (especially upper limbs), multiple organ malformations

Congenital Syphilis – a bacterial teratogen

 Because it can be transmitted vertically, it leads to congenital malformations
o Can often lead to prematurity or miscarriage
 Malformations
o Skeletal system (saddle nose, palate and jaw defects)
o Lower extremities (sabre shins and knee swelling)
o Teeth (Hutchinson teeth)
o Eyes (keratitis)
o Ears (deafness)
o Anemia
o Jaundice
o Rash
o Hepatosplenomegaly

Single-Gene Disorders
 Gene mutations at a single locus are the simplest class of genetic conditions
 Single gene disorders are uncommon in comparison to polygenic disorders
 Why is the relationship between the number of possible mutations and the number of single-gene disorders complicated?
o Variety of functions of genes
o Higher rates of mutation at some gene loci than others
o High lethality of some mutations
o Multiple levels of gene regulation and expression control during development and maturation
o Existence of gene functional redundancies
 Basic features of single-gene disorder
o Gene mutations may be found on one (heterozygous) or both (homozygous) copies of diploid cells.
o Inheritance of many single-gene disorder fall into 4 classic Mendelian patterns:
 Autosomal dominant
 Autosomal recessive
 X-linked dominant
 X-linked recessive
o Dominance occurs where a mutant allele in a heterozygote gives rise to the disease phenotype
o Recessive requires both copies of the mutated gene to be present in order for clinical manifestations to occur
(homozygous for the mutant gene)
o Genes not on sex chromosomes are autosomal
o X-linked: genes on the X chromosome
 There are few Y-linked disorders because of the few number of genes found on the Y chromosome
o A recessive gene on the X chromosome of a male will be expressed because it has no counterpart, since males
only have one X chromosome

Single-Gene Disorders with Mendelian Patterns of Inheritance

Autosomal Dominant Disorders

3|Page
 Genetic disorder that is caused by mutation in one of the genes on an autosomal chromosome
o A person only needs to inherit one copy of the mutated gene to develop the disorder
 Usually, heterozygous
 When heterozygous dominant disorders display milder phenotypes than when they are homozygous
o Heterozygous mutation of the FGFR3  dwarfism (mild)
o Homozygous at same locus  hydrocephalus and severe mental deficits
 Autosomal dominant pattern displays the following traits
o Affected person usually has an affected parent
o Affected persons mating with normal persons have an equal chance of producing affected and unaffected
offspring
o Unaffected children born to affected parents will have unaffected children
o Males and Females have an equal chance of being affected

 Huntington Disease
o A progressive neurological disorder that causes loss of motor control and is characterized by delayed onset
o Only manifests well into adulthood, allows affected person to reproduce
 Protects the mutant allele from natural selection and maintains its prevalence of 1/2500

 Neurofibromatosis
o Found in two forms:
 NF1 — Recklinghausen’s disease
 Mutation in the NF1 gene
o Encodes for neurofibromin — acts as a tumour suppressor by interacting with ras
protein to control cell growth and division
 Lesions in nerves and skin — has a range of severities
 Less severe: manifests as two or more light brown spots on the skin
 More severe: presence of neurofibromas at peripheral nerve endings
o Includes tumours of the eye and optic nerve and skeletal abnormalities (scoliosis)
 Large portion of NF cases arises as de novo mutations in the NF1 gene
 NF2
 Affects the auditory and vestibular systems

 Polycystic Kidney Disease

o Features delayed onset and enlarged kidneys with multiple cysts
o Leads to kidney dysfunction, infections, hematuria, proteinuria, hypertension
o Identified two genes: PKD1 and PKD2

 Marfan Syndrome
o Disorder of connective tissue (1/10 000)
o Manifests in a wide range of severities — affects:
 Skeletal
 Abnormally long and spindly limbs and digits
 Tall body habitus with characteristic features of thoracic bones (pectus excavatum and pectus
carinatum)
 Vertebral column alteration (scoliosis)
 Cardiovascula
 Aortic weakness  aortic aneurysm and aortic dissection
 Pulmonary
 nervous and ocular tissues
o found to occur in fibrillin gene on chromosome 15
4|Page
  affects formation and maintenance of the elastic component of connective tissue

Autosomal Recessive Disorders

 Heterozygotes, who are able to contribute a single copy of the affected gene are genetic carriers
o Can pass the allele to the offspring but are not affected themselves
 What results in clinically observed manifestations
o Homozygosity for the mutant allele at the particular gene locus
 This means that there is a mutation in both maternally and paternally derived chromosome
 Typical autosomal recessive disorder as the following features:
o The mutant allele is masked by a normal allele in the heterozygote individual
o Only the homozygous genotype gives rise to clinical manifestations
o The trait appears in siblings, but not in parents
o If a child is born affected by phenotypically normal parents, the probability of another child being affected is
one in four
o Males and females are equally affected
o Both genetic parents of the affected child carry the recessive allele
o The parents of an affected, and therefore homozygous person, may (or may not) be consanguineous (incest is
not wincest)
o A number of the highest prevalence autosomal recessive disorders are concentrated in specific and distinct
ethno-geographic populations

 Thalassemia
o Most prevalent autosomal recessive disorder
o Caused by mutation in hemoglobin
o Usually hemoglobin molecule is formed from two α-globin (chromosome 16) and two β-globin (chromosome
11) subunits
 This creates the optimum oxygen binding function for erythrocytes
 However, the homozygous occurrence of an error on one of these genes will lead to abnormal
erythrocytes
 They then get destroyed when they pass through the spleen  anemia
o Type and severity depend on the mutations
o Prevalence is high in people with genetic origins from: Mediterranean, Middle East, Southeast Asia, China,
India, and Africa

 Sickle Cell Disease

o Mutations in the hemoglobin gene cause the protein to assume an abnormal form in hypoxic conditions
 This abnormal folding leads to deformation of RBC
o The deformed RBC collect and occlude small blood vessels throughout the body and particularly in the spleen
 The captured RBC are hemolyzed  anemia
o Sickle cell crises can be life-threatening

 Tay-Sachs Disease
o Lipid storage abnormality due to lysosomal dysfunction — causes severe neurological toxicity and
maldevelopment
o Infantile form of disease is the most common and severe
 Severe brain degradation in the first months  early death

 Cystic Fibrosis
o Presence of abnormally viscous mucus that is not easily cleared from the patient
o Accumulation of mucus in lungs and digestive tract leads to severe manifestations of respiratory problems:

5|Page
  Infections
 Impaired digestion
 Absorption
 Pancreatic function

o Caused by mutation in the CTFR gene

 Encodes for chloride ion channel protein  formation of secreted mucus with less water content
making it more viscous
o CF allele has been selected for heterozygosity because it protects against dehydration due to diarrhea

X-linked Disorders
 Gene mutations on chromosome 23 (sex chromosome)
 Syndromes distribute differently among males and females because of one X on male and two X on female
o So females can have heterozygosity with respect to recessive disorders
o Males will express their only copy of X-linked alleles; therefore, recessive sex-linked disorders appear more
frequently in males
 X chromosome has a lot of genes while Y only has a few, therefore most sex-linked single-gene disorders are x-linked
recessive gene disorders

X-Linked Dominant Disorders

 Heredity displays the following genetic patterns
o Affected males have normal sons and affected (heterozygous) daughters
o Heterozygous females have a 50% risk of producing an affected offspring
o Disorders are more serious in females because of hemizygous for affected genes
 X-linked dominant disorders are uncommon compared to X-linked recessive disorders.

 Fragile X Syndrome
o Features an excessively long sequence of CGG triplet repeats on the X chromosome
 Reduces concentration of FMRP — required for normal development of neuronal connections
o Mild to moderate intellectual disability, low muscle tone, long face, large ears and testicles
o Autism, hyperactivity and seizures
o Clinical manifestations become diagnosable after puberty

X-Linked Recessive Disorders

 Genetic patterns
o Males are more affected than females
o Affected males can transmit the gene to daughters, but not to sons
o Sons of female carriers have a 50% chance of being affected
o Daughters of female carriers have a 50% chance of being carriers
 Duchenne Disease (Duchenne Muscular Dystrophy
o Severe, passed down from the mother 2/3rds, 1/3rd is de novo
o Manifests:
 Severe muscle wasting
o As disease progresses you lose the use of legs and arms and the ability to maintain normal spinal position

Single Gene Disorders: Caveats and Considerations

Delayed Age of Onset

 Some genetic disorders manifest later in life

6|Page
 Gene Penetrance
 Probability that a gene is expressed
 Percentage of those who are known to carry an allele who clinically manifest with the disease
 For example:
o High penetrance: Retinoblastoma manifests in 90% of those with the mutated gene
o Incomplete penetrance: osteogenesis imperfect
 Genetic mutation that results in defective production of type 1 collagen
 But not everyone who has the mutation present with the disease
 Manifestation: bone formation, decreased height and brittle bones

Expressivity
 Degree of which trait expression differs between individuals
o Related to the type of mutations that affect protein formation
o E.g., Marfan Disease (fibrillin gene)

Genomic Imprinting
 Observation that genes will expressed in an individual differently depending on which parent it came form
 Thought to involve a chemical signature left behind on an inherited gene that alters its expression
 For example: deletion on chromosome 15
o Mother: Angelman syndrome (mental deficit, seizures)
o Father: Prader-Willi syndrome (short stature, obesity, hypogonadism)
 Another one: Huntington’s
o Mother: average age of onset — 42 years old
o Father: average age of onset — 33 years old

Chromosomal Aberrations

Abnormalities of Chromosome Number

 Polyploidy
o Multiple copies of the entire chromosome set
o Euploid: 23 chromosomes in germ cells and 46 (2n) in somatic cells
o Triploidy: 69 (3n)
o Tetraploidy: 92 (4n)
o Both occur due to failed disjunction
o Mixoploidy: mix of triploid and euploid
 More common
 Aneuploidy
o Cells that have an abnormal number of chromosomes due to having too many or too few specific chromosome
o A result of improper segregation of a individual chromosome during meiosis
o 46 is not achieved — may have plus or minus of the non-disjoined chromosome
o Most prevalent:
 Trisomies — set of three: total 47
o If there is an overdose or underdose of an entire chromosome will not survive
o Most common aneuploid conditions are on the smaller chromosome
 E.g., trisomy 21 and chromosome 23
 Sex chromosomes X and Y (Klinfelter Syndrome; XXY; XXXY, Turner Syndrome; X0)

7|Page
o Klinfelter Syndrome
 Most prevalent of the aneuploid conditions
 Feminization of the male — noticeable after puberty
 Smaller than normal testes and penis
 Sterility
 Sexual disinterest
 Sparse body and facial hair
 Feminizied but taller than usual body habitus
 Weaker than usual musculature
 Higher risk of intellectual impairment
o Triple X Syndrome in Women
 not as apparent as Klinfelter
 taller than usual body height, possible intellectual impairment
 psychological/behavioural alterations

o Monosomy X and Turner Syndrome

 Monosomy at chromosome 23  Turner syndrome
 Webbed neck
 Lymphedema
 Foot and hand swelling
 Skeletal and kidney defects
 Cardiovascular defects

o Aneuploid Mosaics
 Karyotype mosaicism is common
 Most commonly observed are those of the X chromosome
 Can be monosomy, trisomy and tetrosomy

o Trisomy 21 and Down Syndrome

 Presence of 3 copies of chromosome 21  down syndrome
 Down syndrome characteristics:
 Delayed childhood development
 Intellectual impairment
 Impaired immunity
 Elevated risk of:
o Leukemia
o Defects in the heart
o Kidneys
 Characteristic facial appearance
 Down syndrome increases with maternal age of pregnancy, peaks at 35

o Trisomy 13 and 18
 Most are lethal to the fetus so we do not see them in live births
 Trisomy 13 (Patau syndrome)
 Trisomy 18 (Edward’s syndrome)
 Twice as common as Patau syndrome
 Multiple effects on the development of the head and organ systems
o Kidney malformations
o Structural heart defects
o Externally protruding intestines

8|Page
 o Esophageal atresia
o Microephaly
o Microagnathia

Abnormalities of Chromosome Structure

 Chromosomal errors:
o Deletion of a segment (e.g., Cri du Chat syndrome)
o Duplication of a segment (e.g., MECP2 duplication syndrome)
o Inversion of a segment
o Translocation of a segment to a non-homologous chromosome (e.g., CML)

 Chromosomal deletion: when there is a chromosomal break which leads to the loss of a chromosomal segment
o Often lethal to fetus but can lead to full term delivery in some
o Cri du chat syndrome
 Deletion on chromosome 5
 Microcephaly
 Severe intellectual impairment
 Hypotonia (weak muscle tone)
 Frequent cardiac defects
 Widely set eyes
 Low-set ears
 Microagnathia (small jaw)
 Children who survive one year generally survive into adulthood

Polygenic and Multifactorial Disorders

 Most genetic disorders involve two or more alleles as risk factors
 Two views:
o Each gene contributing specific effects that combine to form a complex syndrome
o Certain alleles contributing as risk factors to an existing syndrome

Chapter 10

Key Concepts and Terms

- Neoplasia translates to new growth — medically it refers to the state of new, abnormal, cell proliferation
- Neoplasm develops wfrom the proliferation of a single cell that has undergone specific DNA mutations
- Cell Transformation: the process by which a normal cell becomes neoplastic
- Neoplasm is a population of cell that arises from a single mutant cell (index cell) that proliferates relentlessly and without
normal cellular controls
- Most neoplasms form solid masses of tissue (tumour); but it can also be in a liquid state (neoplasms of blood cells)
- Neoplasms can be benign or malignant
o Malignant: invasive, can metastasize
- DNA locations that cause neoplasia are at specific gene loci that alter significant cellular function
o E.g., DNA repair, regulation of growth, cellular division, apoptosis, and differentiation
- Neoplastic cell is unable to differentiate normally and displays abnormal form (dysplasia) and behaviour
- Genome of malignant cells become more unstable as neoplasm develops  abnormal cell populations that display
heterogenous genetic and phenotypic features
- Carcinogenesis: process by which normal cells transform to malignant cells

9|Page
The Multistage Nature of Carcinogenesis
 Exposure of cells to certain chemicals lead to an initial mutation, followed by subsequent exposure to other chemicals
that completed the process
 Carcinogenesis: involves multiple steps, triggered by multiple exposures
 Tumour development involves 4 stages
o Initiation
 Specific chemical changes induce the initiating changes that lead to neoplasia
 Consists of persistent gene mutations
 Chemical agents that bind and alter DNA expression  transformation of normal cells to neoplastic
cells
 Cyclophosphamide
 Polycyclic aromatic hydrocarbons (PAHs)
 Nitrosamines
 Aromatic amines
 Ionizing radiation can also act as initiators
o Promotion
 Tumour promotion involves the stimulation of robotic cell division  expanding cell mass (consists of
clones of the initiated cells)
 As the initiated cells divide, more mutations occur  mixture of cells with different mutations
 More rapid the division the higher the rate of error will be  more diverse cell population
 The new population of diverse and abnormal cells will now be subject to selective survival pressures
 Cells that proliferate fastest gradually overgrow slower mutants
 Chemicals that are promoters are usually not mutagenic to DNA, they alter the intracellular signalling
systems that control cell division
 Chemical promotors:
 Dioxin
 Benzoyl peroxide
 Phenol
 Saccharin
 Tryptophan
 Estrogens
 Dichlorodiphenyltrichloroethane (DDT)
 Phenobarbital
 Polychlorinated biphenyls (PCBs)
 Cyclamates
 Non-Chemical factors
 UV light
 Chronic tissue irritation
 Bile acids
o Malignant Conversion
 Further genetic mutations in the destabilized cells of the promoted cell mass
 Requires the cell population to be constantly exposed by promoting chemical
 if exposure to promotor ceases, tumour often regresses (does not become malignant)
 rapidly expanding mass of cells is more susceptible to further mutations that have the capacity
to enable the conversion to malignancy
o if they are being continuously exposed to mutagens (i.e., initiators) they will be more
at risk for malignant conversion
o Tumour Progression
 Refers to the acquisition of malignantly aggressive traits in tumour cells

10 | P a g e
  Tumour cells display genotypic variability, this means that they have a wide variation in their abilities
to divide, invade and spread
 The variants that survive, proliferate and invade most successfully and aggressively makes up
a greater fraction of the tumour cell population
 Basically pathogenic features of cancel cells arises through natural selection
 Phenotypic traits that facilitate invasiveness and metastasis:
 Hyaluronidase and elastase
o Digest connective tissue and basement membranes
 Creates pathways for tumour cells  lets them proliferate and spread
 Genomic instability  greater variability in genotype and phenotype
 Inhibition of growth control or apoptosis
o Lack of tumour suppressor function
 Immunological resistance through the development of surface proteins
 Progressive loss of cohesive cell binding proteins
o Allows cells to break away more easily and metastasize through lymph or blood

Causes of Neoplasia
 Exogenous and Endogenous
o Environment and Genetics
 Environmental factors combine with genetic susceptibility to increase risk
 Environmental overshadows genetic
 Environmental Factors:
o Radiation
 Risk of carcinogenesis from radiation is dependent upon strength and duration of radiation exposure
 Radiation causes mutagenesis in cells by causing breaks in the DNA strands and increasing rate of
mutagenesis
 Types of radiation:
 X-rays
 Alpha, beta, and gamma rays
 Cosmic rays
 UV rays
o Chemical Agents
 Initiators and promotors
 Display a dose-response relationship
 The greater the exposure (concentration, duration, frequency), the greater the risk that
transformation will occur
 Each type of carcinogen has a specific dose-effect relationship
 Co-carcinogens: environmental carcinogens that act synergistically with each other
 Pro-carcinogens: exist in an inactive state
 They need to first undergo metabolic activation by the cell for them to initiate or promote
tumour development
 Group 1 carcinogens have the strongest association with cancers
 Polycyclic aromatic hydrocarbons
o Encountered in daily life
 Tobacco smoke, engine exhaust, BBQ grills, smoked meat and fish
 Associated with cancer of the lips, tongue, head, neck, larynx, lungs,
pancreas and bladder
 Aromatic amines
o Naphthalene (moth balls), some insecticides, certain food dyes
o Associated with cancer of the bladder

11 | P a g e
  Alkylating agents
o Compounds that covalently link alkyl groups to biomolecules (e.g., DNA)
o One of the molecular changes induced is the formation of cross-links between
strands of DNA
 This interferes with DNA replication, leads to altered transcription
o In medicine they are anti-neoplastic drugs
 Because they can disrupt cell division because they interfere with DNA
replication
 But they are non-selective, so they target both the tumour cells and healthy
cells
o In cancer research they are initiators
o Secondary malignancy: a malignancy that arises as a result of treatment of a pre-
existing malignancy with carcinogenic anti-neoplastic treatment
o Examples of agents
 Nitrogen mustard (chlorambucil and cyclophosphamide)
 Cisplatin
 Nitrosoureas (carmustine, lomustine and semustine)
 Alklysulfonates (busulfan)
 Ethyleneimines (thiotepa)
 Triazines (dacarbazine)
 Nitrosamines
o Metabolites of nicotine and chemicals that are used to preserve meat
o Associated with cancers of the GI tract
 Other carcinogens
o Biological toxins found in mold
o Metals
 Cadmium
 Chromium
 Nickel
 Nitroso compounds
o Carbon tetrachloride
o Benzene
o Cyclic petrochemicals
o Polyvinyl chloride (PVC)
o PCBs
o Dioxins
o Oxidative Injury as a Key Carcinogenic Process
 Oxidants are bitches that want to snatch someone else’s electron
 The molecules become oxidized as they lose their electron
 Oxidation
 Basis for the transfer of energy from the bonds of energy substrates (fats, carbs, proteins)
 Uncontrolled oxidation is damaging to cell structure
o Oxidative injury is the key source of protein denaturation and DNA mutation
 Free Radicals: Oxidizing chemicals with an unpaired electron in their 4th quantum number are highly
unstable and are more reactive in oxidation or reduction
 More injurious to cell structures
 Arise through outside sources (food or air) or through conversion of molecules to free radicals
(through loss or gain of a reactive, unpaired electron

 Role of Reactive Oxygen Species

12 | P a g e
  Endogenously generated ROS is a result of normal biochemical reactions that take place in
the mitochondria, peroxisomes, and ER
 Oxidation of DNA by ROS is a major pathway of mutation  several types of DNA damage
o E.g., deletion, cross-linkage and strand breaks
o Dynamic state of genomic instability can tilt towards carcinogenesis


Figure 1 the structure and functionality of the genome are in dynamic balance of injury and repair

 Balance of oxidative changes to DNA are assumed to be tilted towards carcinogenic changes
o More intensive exposure to oxidative reagents or a reduced capacity to defend
against a normal rate of oxidation

Genetics of Cancer

Heredity
 Stats
o 10% in those with one affected first-degree relative
o 15% in those with two affected family members
o 30% in those with three affected family members
 These stats are a reflection of inherited alleles
o A few cancers are inherited as autosomal dominant traits (retinoblastoma and multiple polyposis of the colon)

Oncogenes
 There are 100 genes that are crucial to maintaining normal cell genotype, cell division and differentiation control
o In their mutant forms they become highly associated with a higher risk of malignancy
 Oncogenes: mutated forms of genes that are strongly linked to carcinogenesis
 Cellular Oncogenes: unmutated version of the genes (aka proto-oncogenes)
o Found to be mutated into oncogenes when exposed to environmental, physical or chemical carcinogens
o Associated with key cellular functions
 Cell growth and division
 Cell differentiation
 Apoptosis

Classes of Oncogenes

Class of oncogene Examples Normal function Associated cancers

13 | P a g e
 Growth factors
Receptor tyrosine kinases
Cytoplasmic tyrosine
kinases
Serine/threonine kinase
GTPases
Transcription factors
Sis Cell growth stimulation
EGFR, PDGFR, VEGFR Receptor control of cell
growth and differentiation
src, BTK (families) Intracell signal for cell
division, differentiation,
survival
Raf Cell cycle control, division,
differentiation, apoptosis
Ras Cell division control
Myc Cell division control
through transcription
Osteosarcoma, breast
carcinoma, melanoma,
fibrosarcoma, glioblastoma
Breast cancer, GI stromal,
pancreatic cancer, non-
small cell lung cancer
Breast cancer, colorectal,
melanoma, ovarian cancer,
gastric cancer
Melanoma, thyroid cancer,
colorectal cancer, ovarian
cancer
Myeloid leukemia, thyroid
cancer, colorectal cancer,
pancreatic cancer
Breast cancer, pancreatic
cancer, retinoblastoma,
small cell lung cancer,
several leukemias

 Proto-oncogenes must be activated into mutagens for cells to advance to invasion and metastasis

Pre-neoplastic changes to tissue

Metaplasia: replacement of tissue by other tissue types that are not normally found at that particular site
 Sign that tissue irritation has occurred
 Metaplasia is associated with an increased risk of neoplasia because it is an indication of chronic tissue disturbance
Dysplasia
 Abnormal morphology of cells
 Dysplasia can be the result of chemical, physical injury or viral infection
 Pathologists use morphological criteria to determine the severity of dysplasia
o Important aspect of diagnosis as it determines if there is a need for further follow-up tests, further examination
or removal of the cells to avoid potential tumour occurrence

Structure and Function of Neoplastic Cells

 Behaviour of neoplastic cells determines the clinical picture of the tumour
 Neoplastic cells are not responsive to normal growth control and display varying degrees of abnormal morphology and
function

Pleiomorphism and Anaplasia

 Appearance and function of neoplastic cells arise from DNA mutation affecting specific genes leading to alterations to
regulation of gene expression
 Pleiomorphism: diverse and abnormal size, shape, staining and internal cell structure observable upon microscopic
examination
 Anaplasia: the abnormal morphology and functional behaviour of neoplastic cells
o State of uninterrupted or diverted differentiation
 Many kinds of neoplasm arise from stem cells
o Normal cells progress through an orderly control over gene expression to become fully differentiated mature
cell
o Neoplastic cells do not differentiate and mature

14 | P a g e
  The least differentiated of the neoplastic cells have a tendency toward more malignant behaviour and more extreme
pleiomorphic structures
o Less differentiated cells are unable to perform the function of fully differentiated cells, but they compete for
space and crowd out normal, fully functional parenchymal cells in an organ or tissue
 Anaplastic cells have a competitive advantage over their normal counterparts because they can go crazy with
proliferation
o Anaplastic cells express abnormal gene products  functional anomalies and proteins that are not normally
produced by the particular tissue type

Cell Recognition and Adhesion

 Normal cells of different types when mixed together organize themselves into layers according to type — this is a
normal process
o Relies on the presence of specific surface proteins and extracellular matrix proteins normally expressed by
specific cell types
 Linkage of cells forms via discrete junctional structures (e.g., desmosomes) — involves the binding together of cells
using fibrous proteins, tight junctions
 The neighbouring cell membranes are then fused together and forms a seal that prevents the movement of most
molecules, and gap junctions
 Abnormal gene expression of junctional proteins leads to loss of normal linkages to other cells and to the basement
membrane
o Neoplastic cells display decreased numbers of desmosomal, tight, and gap junctions, decreased cell adhesion,
loss of normal inhibition of division when in contact with other cells (contact inhibition)

Behaviour of Tumours
 Rate of tumour growth depends on the cell type, level of differentiation, vascularization, degree of anti-tumour response
and hormone levels
 Tumours arise from one clone of cells; growth rate depends upon the cellular doubling time
o Tumours usually have already gone through 30 cell divisions by the time they are clinically evident
 Degree of differentiation of the tumour cell is related to its behaviour
o More differentiation  more benign
o Poorly differentiated  more malignant
 More differentiated cells behave more like normal cells
 Proliferating cells at more immature stages of differentiation behave more abnormally
o Tissue formation
o Regulate growth
o Respond to signals limiting them to their normal site
 Also related to the genetic abnormalities that led to tumour development
o More severe genetic mutations  more aberrant gene expression  more abnormal cell behaviours

Benign and Malignant Tumour Behaviour

Benign Tumours
 Benign tumour cells bear closer resemblance to parent cell than malignant cells
 Benign tumours:
o Do not invade or metastasize
o Cells are regular shape and size
o Cells display few mitotic figures that are normal in appearance
o Cells divide and grow slowly compared to malignant tumours
o Tumour is well-organized with respect to vascular and connective tissue structure
o Tumour is often encapsulated in stromal tissue
15 | P a g e
 o Benign tumours tend to be less vascularized than malignancies
o Benign tumours do not ulcerate or bleed
o Benign tumours produce less serious complications than malignant tumours
 Surgical incision for benign tumours is less complicated.
 Do not usually recur
 But can cause serious complications due to their expansion
o They can cause atrophy of adjacent tissue
o Can cause obstructions — CNS, GI, airways and ducts of endocrine glands
o Especially harmful if they develop within the fixed space of the cranium or spinal cord because they can lead to
increased pressure and compression of the surrounding delicate tissue
 Benign tumours can undergo further transformation into malignancies

Malignant Tumours
 Characterized by poor differentiation
 Defining features:
o Invasive and metastatic
o Display abnormal and weak cohesiveness  cells breaking away from the main mass
o Tumour cells spreads along the plane of least resistance in “fingers” giving the mass the “crab” appearance
o Display abnormal mitotic figures resulting in polyploid cells and mitosis resulting in three instead of two cells
o Tumour mass is well vascularized, has tendency to leak blood
o Malignant cell populations vary in their cell division rate  uneven cell borders
o Tumour typically ulcerate along any free surface leading to chronic bleeding and anemia and contributes to
infection if the free surface is a non-sterile field (e.g., colon)
o The stromal tissue in the tumour is chaotic and no capsule separates the mass from surrounding tissue
 Key concept: local invasion and dissemination of tumour emboli are among the defining traits of malignant tumours
 Invasion
o Invasion: process in which malignant tumours push into areas normally occupied by other tissues
o Malignant tumours typically migrate into spaces (e.g., body cavities, lumen of blood vessels, ducts, tracts) by
dissolving through the basement membrane and endothelial cell layer
o They express proteolytic enzymes (collagenase and elastase); allows for erosive process [of basal membrane] to
occur
 Dissemination
o Dissemination: process in which malignant cells break away from the primary tumour and are shed into the
lymphatic ducts and blood vessels
 More commonly in veins because their walls are skinny legends
o Lymphatic dissemination results in tumour emboli trapped in the lymph nodes
 Causes node enlargement because of:
 Inflammation response to the presence of tumour cells
 Volume expansion of the dividing cells
o Tumour cells may be prevented from disseminating further if the lymph-based immune response is sufficient
o Tumour emboli that move through the nodes will flow into the venous system  further dissemination through
the venous and arterial blood
o Once it is in the bloodstream, it will eventually become entrapped in capillary networks of organs where they
may establish a secondary or metastatic tumour
o Emboli can also be protected from immune destruction by the deposition of fibrin around them
 Establishment and Proliferation
o Once emboli are entrapped in the microcirculation, malignant cells continue to invade
 Breaking through the blood vessel walls
 Migrating into the interstitium and establishing new centers for tumour growth
o Normal cells at the site tend to retract from the growing mass
16 | P a g e
 o As the neoplastic mass divides and expands, it stimulates the development of its own blood supply
 They do this by secreting tumour angiogenesis factors
 These prompt the growth of new capillaries from surrounding blood vessels
 Lets it achieve faster growth rate because a greater fraction of its cells are surviving
 Sites of Metastasis
o Specific malignancies frequently metastasize to specific secondary sites
o Factors for sites of metastasis:
 Location of the tumour
 Vascularization
 Route of blood flow
 Biological traits of the malignant cells and the cells of where the tumour cells land
o Soft tissues (lungs and liver) tend to be favoured

o
o Frequent sites of metastases that lead to blood effects (i.e., anemia and hemorrhage)
 Bone marrow
 Leads to suppression of hematopoiesis
 Liver
 Liver is the main site of synthesis for coagulation factors, therefore patients with liver tumour
commonly manifest with anemia
 Kidney
 Impaired production for erythropoietin which is needed for erythropoiesis to occur
 Large intestine
 Reduces the absorption of vitamin B12, also required for erythropoiesis

Effects of Malignant Tumours

 Mechanical pressure exerted by new growing mass, obstruction of normal physiological flows of blood, air, or other
fluids
 Most common alterations of function caused by the presence of tumours
o Inflammation — chronic inflammation can set the stage for some types of tumours, but the presence of a
tumour can also provoke inflammation in the surrounding tissues
o Mechanical pressure and obstruction — as tumour grows it may either:
 Press on adjacent structures  push into abnormal positions
 Obstruct the flow of fluids through vasculature, or through channels, ducts, etc.
o Tissue destruction — as tumour invades it releases digestive enzymes that damage or destroy adjacent tissue
o Hemorrhage — blood loss is common in cases of malignancies due to tumour erosion of blood vessels
o Anemi — relentless hemorrhage
o Infection — because of the disruption of barriers that normally render deeper tissues sterile
 Chemotherapy also causes immunosuppression
o Starvation and cachexia — starvation in advanced cancer cases
o Hormone abnormalities — obstruction of endocrine organs and ducts, and abnormal release of suppression
hormones from anaplastic tumour cells
17 | P a g e
  Hematological Effects
o Major effects: hemorrhage, anemia, coagulation abnormalities and immunosuppression leading to infection
o Anemia
 Result from erosion of blood vessels  slow blood loss (usually occult)
 Also result of bone marrow neoplasia  suppression of hematopoiesis
o Hemorrhage
 Results from suppression of thrombopoiesis (platelet production)
o Other cases of anemia caused by malignancies can also be the result of:
 The activation of cytokines, TNF, IL and IF — release of these promote hemolysis

Natural Defences Against Neoplasia

 Injured and mutant cells die by apoptosis, necrosis or autophagy
 What is necessary for tumour cells to survive and proliferate
o Dysfunction of the genetic and mitochondrial controls over cell death

Immunity and Neoplasia

 Adaptive immunity mediated by T cells, and innate resistance, mediated by macrophages and NK cells play a significant
role in host defense mechanisms against tumour survival
 Spontaneous regression: when malignancies spontaneously resolve without treatment
o The immune system is suddenly provoked into attacking the tumour
 Possibly because of new expression of an antigenic protein
o Shows that the immune system has the ability to destroy tumour cells even after the tumour has advanced
Immune Surveillance and Immuno-Editing
 One of the functions of the immune system is the ongoing detection of abnormal antigens present on abnormal cells 
suppression of tumour development
 Immune surveillance: process of removing abnormal cells by cell mediated action of NK and cytotoxic T cells
 Immuno-editing: process of removing abnormal cells from tissue
 Cancer occurs when a tumour cell invades normal immune detection, allowing progression
 In early stages of tumour growth, it is thought that the immune system is imperfectly activated
o They don’t destroy the tumour cells, but they keep them at bay (immune equilibrium)
o Eventually the unedited cells proliferate and the immune system fails to completely eradicate it
 This allows for further mutations, eventually mutations arise that completely block the immune system
from being able to detect/destroy the abnormal cell
 The progeny of the tumour cell are able to invade and metastasize
Tumour Specific Antigens
 Tumour specific antigens are present on the cell surface of tumour cells
o Detection of these antigens may be diagnostic for specific tumour types
o Blood tests for tumour antigens can be used to check the progression or regression of a tumour
 Oncofetal proteins: normally expressed by specific cell types during embryonic development
o not expressed in mature cells
o expressed in neoplastic cells  cells fail to differentiate fully and abnormal expression of fetal genes
o e.g., alpha-fetoprotein
 Viral proteins: expressed by tumours that are caused by viral proteins

Classification and Naming of Neoplasms

 Classification of neoplasms based on:
o The cell of origin
o Whether the neoplasm is benign or malignant
 Solid tumours fall into categories of being either

18 | P a g e
 o Carcinomas which are epithelial in origin (can be derived from endoderm or ectoderm)
o Sarcomas, which are derived from mesoderm
 Neoplasms of the blood do not form solid tumours

Screening and Diagnosing Neoplasia

 Screening implies testing asymptomatic at risk individuals in a population in order to achieve early diagnosis

Imaging
 CT scan: provides higher resolution, but carries radiation exposure risk
 Ultra-sound (sonography): may not provide the resolution necessary for detecting a smaller tumour, but is inexpensive
and non-hazardous
 MRI: provide the highest level of detail for detection of early stage tumours
o But expensive and have limited availability

Biopsy
 Sample of tissue is surgically removed from patient in order to carry out analysis
o Analysis can be:
 Cellular: microscopic determination of cell or tissue morphology
 Chemical: involving various staining techniques
 Immunological: searching for telltale antigens on or in tissue samples
 Molecular: analysis of DNA or proteins
Endoscopy
 Visualization of the interior of a body structure using fiber-optic technology combined with other tools
o They insert a fiber optic line with a lens and then the image is relayed to a screen
o It can be accompanied by another procedure, like taking a tissue sample for biopsy purposes

Staging of Neoplasms
 Staging of neoplasm provides a rough index of the state of advancement of the disease
o Major factors that determine clinical manifestations and prognosis
 cell type, degree of anaplasia, tumour size, and extent of invasion and metastasis
 TNM system: most widely applied, but does not apply to neoplasia of the blood
o A number gets assigned to each of the letter indicating the extent of development for each criterion
o T – tumour
 Refers to the size and extent of
tumour growth
o N – lymph nodes
 Refers to the number of local lymph
nodes in which tumour cells are
found
o M – metastasis
 Refers to the extent of metastasis

Anti-Neoplastic Strategies
 Encompasses prevention and treatment for the cancer itself
 Prevention includes public health interventions that address preventable environmental risk factors; includes 4 principal
arms:
o Public Education:
 Applies to highly avoidable causes of cancer, like those strongly linked to environmental factors
 E.g., smoking and lung cancer, HPV infection and reproductive tract cancers, and asbestos
exposure and mesothelioma

19 | P a g e
 o Research
 Identification of causal pathways of cancer
 Important strides have been made in both understanding cancer mechanisms and identifying preventive
therapeutic approaches
o Regulation
 Regulate environmental exposure to carcinogens — done by governments
 E.g., banning tobacco smoking in public places, bans on using asbestos as building material,
restriction use of PCBs
 WHO plays important role in research and making recommendations and guidance concerning
environmental exposure

Therapy
 Managed by a multidisciplinary team (surgeons, oncologists, radiologists, pathologists, nurses)
 Approach to treatment is dictated by the type and stage of the disease and general condition of the patient
Specialty Roles
Medical oncologist Chemo and other therapy
(biological, immune, hormonal etc.,)
Radiation oncologist External beam radiotherapy, brachytherapy, systemic
radiation
Palliative care specialist Symptom control, hospice care
Surgeon Therapeutic and palliative surgery
Cancer nurses Coordination of patient care, clinical trials, chemo and
other drug administration
Dietician, OT/PT, social worker, pharmacist, As required lol
psychologist

Principles of Cancer Therapy

General Principles
 Chemotherapy is most effective against small, active tumours where there is rapid division combined with an extensive
blood supply because it allows for better drug supply to the tumour cells
 Surgery, by reducing the tumour burden, can improve the effectiveness of chemo
 Use of adjuvant chemo (additionally cancer treatment given after the primary treatment) is common in order to reduce
micro-metastases
 Combination of treatment is usually preferred
o Use of two or more anti-neoplastic drugs can produce more effective cancer cell killing than a single
chemotherapy drug alone
o The benefits are due to the differing therapeutic and toxic mechanisms of action
o It permits the use of lower doses for each individual drug, reducing specific cellular damage caused by each
drug  reduces overall toxicity
Excising the Tumour
 Purpose to immediately and directly reduce the detrimental effects of the mass
o If tumour has metastasized to the lymphatic system, lymph nodes and channels are removed
 Challenges
o Difficult to remove the mass without destroying or disturbing normal tissue in the area
o Surgical manipulation tends to result in disruption of blood vessels along with the disruption of the tumour mass
 promotes formation of tumour emboli
 Through this surgery may accidentally promote metastases…oopsies
 Surgical Techniques

20 | P a g e
 o Cryosurgery: involves freezing tissues (usually with liquid nitrogen)
 Used for skin, oral, brain and prostate tumours
o Electrosurgery: electric current is used to destroy tumour tissue
 Used for skin, oral and rectal tumours
o Chemosurgery: uses caustic chemical agents (acids) for excision
 Primarily used for skin tumours
o Lasers: initially used for retinal tumours but is now getting used for other ones as its technology advances

Radiotherapy
 Doses the tumour mass/masses with ionizing radiation  destroys DNA and biomolecules  cell death
 External beam radiation is aimed at the tumour mass from outside the body with the help of imaging techniques (so they
know where to point at)
 Brachytherapy: implants a radioactive device in or near the tumour to localize and concentrate the radiation dose (aka
internal radiation)
 Various forms of radiation: X rays, gamma rays, photons, protons, and electrons
 Toxic effects
o Rapidly dividing cells (tumour and parenchymal) are more radio sensitive
o Many of the side effects of radiation therapy are in tissues that replace themselves very quickly
 Scalp (hair loss), mouth (stomatitis), digestive system (malabsorption) and hematopoietic bone marrow
(anemia, hemorrhage)

Chemotherapy
 Chemo refers to the use of anti-neoplastic drugs
 Main use as adjuvant to surgery or irradiation to:
o Improve effectiveness of other modalities
o Reduce risk of metastasis
o Reduce pain
 Administered before or after other modes of treatment, and in multiple rounds, and in combination of several drugs
 Drug therapy is based on oncogene-mediated pathway and the function of the immune system in cancer surveillance and
control
 Three broad categories:
o Traditional highly toxic, low specificity drugs that have been in use for much of the last century
o More recently developed, high specificity drug designed to engage cellular control pathways
o Immune mediators

Traditional Cytotoxic Drugs

 Primary drugs used in chemo, in most circumstances and in most cancer treatment centers
 Selected to attack target malignant cells based on the few biological traits that may distinguish them from normal cells
o Rates of cell division
o Rate of drug uptake
o Differential metabolic sensitivity of some tumour cells to drugs
o Sensitivity to hormones (for some tumours like breast and prostrate)
 Traditional anti-neoplastics can be broadly classified according to their specificity of action against actively dividing
cells
o Cell cycle non-specific agents kill cells in any phase of the cell cycle
o Cell cycle specific agents only effective on cells in the S or M phase of the cell cycle
 More effective to cells with a higher rate of cell division
 Also classified according to their mechanism of action
o Alkylating agents – cyclophosphamide, chlorambucil, dacarbazine, strezotocin, ilfosfamide
o Anti-metabolites – methotrexate, 5-fluorouracil, cytarabine, gemcitabine
21 | P a g e
 o Antibiotics – doxorubicin, bleomycin, dactinomycin
o Mitotic inhibitors – vinblastine, vincristine, paclitaxel, vinorelbine
o Other common drugs – cisplastin, carboplatin, hydroxyurea, procarbazine
 Traditional anti-neoplastic drugs are the most toxic drugs used in medicine
o Therapeutic index of close to 1 — means that the therapeutic dose is the same as the toxic dose; the safety index
does not exist
 Still widely used in conjunction with radiation or with newer drugs
 Actively dividing cells are often collateral damage – they get injured or killed in an effort to destroy the proliferating
tumour mass

The Challenge of Drug and Radiation Resistant Malignancies

 Because tumours are heterogenous collections of cells (made up of various populations of cell types) with unstable and
rapidly mutating DNA, their sensitivity to radiation or anti-neoplastic drugs may vary
 Multiple rounds of treatment exerts selective pressures that eliminate the most radio-sensitive or chemo-sensitive
variants
o So as the treatment and cell growth proceeds the malignancy can become more resistant to treatment
 Cellular phenotypes that allow resistance:
o Rapid DNA repair
o Rapid drug elimination and detoxification
o Drug target alteration
o Cell death inhibition

Hormonal Drugs
 Hormonal drugs take advantage of the sensitivity of some tumour types to hormonal growth control
o E.g., drugs that interact with estrogen (breast cancer), androgen (prostate cancer), and corticosteroid
(lymphocytic leukemias) sensitive tumours
Targeted Cancer Therapy
 Newer generation of drugs have become highly specific and less toxic, because they have a developed a better
understanding of the molecular biology behind malignancy
o They now have a better understanding of the pathways, especially the ones about controlling cellular
proliferation and cell death
 Many of these drugs are laboratory synthesized (monoclonal) antibodies
o They bind to specific receptors at the cell surface
o They have a suffix of ‘ab’ (e.g., rituximab)
 Other drugs are smaller molecules bind to intracellular enzymes (tyrosine kinase and serine kinase)
o Inhibits specific intracellular pathways that control cell division or apoptosis
o Have suffix ‘ib’ (e.g., imatinib or sunitinib)
o Thalidomide and sunitinib are angiogenesis inhibitors
 They’re meant to stop the formation of new blood vessels so it can cause tumour regression by starving
the tumour cells of a blood supply
o Imatinib: first targeted therapy drug to be approved
 Tyrosine kinase inhibitor
 Revolutionized the treatment for chronic myeloid leukemia — now considered a treatable leukemia

Immune Therapy
 Another advancement is the development of strategies to induce the immune system to recognize and attack tumour cells
o Because of the immune systems role in suppressing abnormal cell proliferation
 Immunotherapy approaches include:
o Immunization of tumour agents to reduce risk of metastasis
o Use of checkpoint inhibitors to allow T lymphocytes to proliferate
22 | P a g e
 mRNA vaccines also have the potential to create vaccines for individual tumours

23 | P a g e