Genetics and Neoplasm

1
Genetics and Neoplasm
Let us read A.S. Gregor (quoted by Robbins), in
writing about Charles Darwin, drawing the
inferences of this sort of reasoning in a general
way Between the environment and the genes
that determine heredity there exists a highly
complex relationship. It seems that genes cannot
produce normal individuals unless the
environmental factors are also normal. What is
inherited is a packet of genes transmitted from
the parents with the capacity to respond to
environmental conditions in certain ways, some of
which are called normal for the species in its
normal environment.
2
Genetic counseling and amniocentesis
3
Causes of birth defects
4
Principles of Teratology

• susceptibility
• timing
• mode of action
• dose-relationship
• outcome of exposure
• species-specificity

5
Time frame for congenital defects

• 2-5 weeks CNS, heart
• 4-7 weeks Extremities, eyes
• 6-8 weeks External genitalia

6
Supernumerary arm
7
Cleft lip and palate
8
Mermaid syndrome (syndactyly)
Peru's "little mermaid" the baby born with legs
fused from her thighs to her ankles will
undergo delicate surgery Tuesday night to begin
repairing her rare birth defect, her doctors said
Monday. Milagros Cerron, who celebrated her first
birthday April 27, was born with a rare
congenital defect known as sirenomelia, or
"mermaid syndrome," which occurs in one out of
every 70,000 births.
9
Prenatal surgery for spina bifida,
myelomeningocele
The tiny hand of a fetus reaches out from a
mother's womb to clasp a surgeon's healing
finger. It is, by the way, 21 weeks old . . .
10
Spina bifida
11
Thalidomide
Thalidomide was never tested on pregnant animals
before it was used in humans. After the effects
of thalidomide had been established and the drug
withdrawn, the same effects were shown to occur
in mice, rats, hamsters, rabbits, macaques,
marmosets, baboons and rhesus monkeys.
As angiogenesis blocker
12
Torch Complex
13
Tardive syphilis
14
Types of Dwarfism
dwarf (dwarf) an abnormally undersized person.
achondroplastic d., a type of dwarf, having a
relay tively large head with saddle nose sad
brachycephaly, short extremities, and usually
lordosis see also achon. dropiasio.. Amsterdam
ci. a dwarf affected with do Langes syndrome.
asexuai ci., an adult dwarf with deficient sexual
development. ateliotic d., a dwarf whose skeleton
is infantile with persistent nonunion between
epiphyaes an diaphyses bfrd-headed ci.,
bfrd-headed d. of Seckel, a dwarf with a
proportionately small head, a narrow birdlike
face with a beaklike protrusion of the nose,
large eyes, antimongolaid slant of the palpebral
fissures, and receding lower jaw called also
nanocephajic d Briasauds ci., one with infantile
myxedema. cretin d., a thyroid-deficient dwarf
see cretinism. Called also hypothyroid d.
diastrophic d., a dwarf with progressive
structural deformities of the bones and joints,
including scoliosis, bilateral clubfoot,
deformity of the thumb, microineli4, joint
contractures and subluxations, malformation of
the pinna with calcification of the cartilage,
premature calcification of the costal cartilages,
and cleft palate. geleophysic ci., a dwarf with a
peculiar but pleasant facial appearance and bone
dysplasia, especially of the hands and feet.
hypophyseal ci., pituitary d. hypothyroid ci.,
cretin d. infantile ci., a person with marked
retardation of mental and physical developm.3nt.
Levi-Lorain ci., pituitary d. micromelic ci., a
dwarf with very small limbs. nanocephalic ci.,
bird-headed d. normal ci., a person who is
abnormally undersized, but is perfectly formed.
Paitaufs ci., pituitary d. phocomelic ci., a
dwarf in whom the diaphyses of the long bones are
abnormally short. physiologic ci., normal d.
pituitary ci., a dwarf whose retarded development
is due tohypofuaction of the anterior pituitary
called also hypophyseai d4 Levi-Lerain d., and
Paltauf.g d. primordial ci., pure ci., normal d.
rachitic ci., a person dwarfed by rickets, having
a high forehead with prominent boeses, bent long
bones, and Harrisons sulcus or groove. renal
ci., a dwarf whose failure to achieve normal bone
maturation is due to renal failure. Ruaseil ci.,
see under syndrome sexual ci., a dwarf with
normal sexual development. Silver ci., see under
syndrome thanatophoric ci., a micromelic dwarf
having very short ribs and bones of the
extremities, and vertebral bodies that are
greatly reduced in height with wide
intervertebral spaces death usually occurs in
the first few hours of life, true ci., normal d.b
15
TeratogenesisCongenital Malformations

• agenesis kidney, dens
• aplasia anlage of lung
• hypoplasia microcephaly
• dysraphic defect spina bifida
• involution fail. ductus arteriosis
• division failure syndactyly
• atresia esophagus
• dysplasia tuberous sclerosis
• ectopia hiatus hernia
• dystopia cryptorchidism

16
Karyotype
17
Evolution of the Y chromosome
DEGENERATION OF THE Y chromosome occurred in four
discrete episodes starting about 300 million
years ago, after a reptilelike ancestor of
mammals acquired a new gene (SRY) on one of its
autosomal chromosomes. Each of the episodes
involved a failure of recombination (DNA
exchange) between the X and the Y during meiosis,
the cell division that yields sperm and eggs. If
recombination is blocked, genes in the affected
region stop working and decay. The sequence shown
is highly simplified. For instance, theY actually
expanded temporarily at times (by stitching
autosomal DNA into areas still able to
recombine), before failures of recombination led
to a net shrinkage.
18
Meiosis
19
Karyotypic Disorders

• Klinefelters XXY
• Superfemales XXX
• Supermales XYY
• Turners X0
• No-X males Y0
• Autosomal trisomies
• Downs (21)
• Edwards (18)
• Pateaus (13)
• Deletions (Cri du chat), etc.

20
Down Syndrome
Characteristics Some of the facial features
which identify an individual as having Down's
syndrome include Low set ears Up slanting
palpebral fissures Low nasal bridge and
dorsum Abnormal and excessive facial fat
distribution Protruding, enlarged tongue
21
Pataus Syndrome
The karyotype here demonstrates trisomy 13 (47,
XX, 13) also known as Patau's syndrome. It is
rare for fetuses with this condition to go to
term, so it occurs in only 1 in 6000 live births.
It is rare for babies to survive for very long if
liveborn because of the multitude of anomalies
that are usually present.
22
Edwards Syndrome (18)
23
Cri-du chat

• Partial deletion of the short arm of chromosome 5
• Hypertonicity, small and narrow face, dropped
  jaw, and open-mouth expression secondary to
  facial laxity.

24
Turners Syndrome
25
XYY Supermen?
XYY syndrome males inherit an extra Y
chromosome--their genotype is XYY. As adults,
these "super-males" are usually tall (above 6
feet) and generally appear and act normal.
However, they produce high levels of
testosterone. During adolescence, they often are
slender, have severe facial acne, and are poorly
coordinated. They are usually fertile and lead
ordinary lives as adults. Many, if not most, are
unaware that they have a chromosomal abnormality.
The frequency of XYY syndrome is not certain due
to statistical differences between different
studies. It may be as common as 1 in 900 male
births to as rare as 1 in 1500 or even 1 in
2,000. Early studies of XYY syndrome done in
European prisons initially led to the erroneous
conclusion that these men were genetically
predisposed to antisocial, aggressive behavior,
below average intelligence, and homosexuality . .
. Some researchers suggest that the high
testosterone levels of XYY men can make them
somewhat more prone to violence and that this may
cause higher rates of wife beating.
26
Hereditary retinoblastoma

• Often caused by partial deletion chromosome 6
• Multifocal (multiple) tumors in retinoblastoma
  eye
• 30 cases, 90 penetrance, bilateral tumors

27
Mendelian defects(single-gene, inborn errors of
metabolism)

• Autosomal dominants
• Autsomal recessives
• Sex-linked dominants
• Sex-linked recessives
• Codominance

28
Marfans Syndrome
29
Ehlers Danlos
30
Neurofibromatosis (Elephant Mans Dx)
31
Achondroplasia
32
Lysosomal storage diseases (lipid)
33
Alkaptonuria and associated ochronosis
34
Faces of albinism
Ocular form
35
Multifactorial inheritance

• Inherited predisposition requires a specific
  environmental trigger. Examples include
• Birth Defects some of the abnormalities present
  at birth such as cleft palate/lip, spina bifida,
  anencephaly
• Cancer includes bowel, breast, colon, melanoma,
  ovarian, stomach and others
• Cardiovascular high blood pressure, some causes
  of heart disease, high cholesterol
• Metabolic diabetes
• Mental illness schizophrenia, manic depression
  (bipolar disorder)
• Muscular/skeletal arthritis, rheumatic
  disorders, osteoporosis
• Neurological/psychiatric schizophrenia, manic
  depressive illness
• Respiratory asthma, allergies, emphysema
• Skin disorders psoriasis, moles, eczema

36
Polygenic Inheritanceexample of human height
One locus for height, with three alleles. Allele
h2 adds 2 inches to the average 68-inch height.
Allele h0 neither adds nor subtracts from the
average height of 68 inches. And allele h-
subtracts 2 inches from the average height.
Suppose h0 is twice as frequent as either h2 or
h-.
people
64
72
height
37
Degree of familial relationship twin concordance
38
Cancer etiology

• Host factors
• genetic predisposition
• hereditary neoplasms (retinoblastoma)
• somatic mutations
• pschological makeup
• immune competence
• endocrine/metabolic factors
• Environmental factors/exposures
• chemical carcinogens
• radiation
• sunlight
• viruses other infectious agents

39
Cancer increase
40
Cancer incidence
41
Cancer deaths
42
Malignant vs. Benign tumors