School of Medicine, Health Sciences and Engineering
Susquehanna Township High School
Lecture Series  Week 6, September 2013
Clinical Relevance of This Week’s Topic
Genes, Mutations and Genetic Testing
Wen Jie Zhang, MD, PhD
Carcinogenesis
Environmental Factors
(Carcinogens)
Cancer
Genetic Factors
(Mutations)
Substitutions
Physical
Deletions
Chemical
Insertions
Biological
Translocations
Lifestyle
The Human Genome
23 pairs of chromosomes made of 3 billion base pairs
Extragenic
DNA
 Repetitive
sequences
 Control regions
 Spacer DNA
between genes
 Function mostly
unknown
~35,000 genes
70%
30%
ASCO
The chemical structure of
a four-base fragment of
A DNA double helix.
Genes
Chromosome and Gene
Gene Structure
Transcription and Translation
Polymorphism
DNA sequence changes that may or may not alter
protein function (common definition)
Functional protein
Functional protein
Disease-Associated Mutations
Alter Protein Function
Functional protein
Nonfunctional or
missing protein
ASCO
Common Mutations
Substitutions (point mutation)
In a DNA sequence, a single nucleotide is
exchanged for another (A G, C T), leading to
missense or nonsense mutation.
Insertions (insertion mutation)
The addition of one or more nucleotide base pairs
into a DNA sequence.
Deletions (deletion mutation)
Part of a chromosome or a sequence (base pairs)
of DNA is missing from a DNA sequence.
Missense Mutation
Missense Mutation (non-synonymous)
is a point mutation in which a single nucleotide
change (substitution) results in a codon that codes
for a different amino acid
 Example Genetic Disease
Sickle-cell disease (SCD) or sickle-cell anemia (SCA)
– a hereditary blood disorder, characterized by red
blood cells that assume an abnormal,
rigid, sickle shape.
A Missense Mutation
Mutations
Missense Mutation (cont’d)
Missense Mutation (non-synonymous)
is a point mutation in which a single nucleotide
change results in a codon that codes for a
different amino acid
 Example Genetic Disease
Sickle-cell disease (SCD) or sickle-cell anemia
(SCA) – a hereditary blood disorder, characterized
by red blood cells that assume an abnormal,
rigid, sickle shape.
Nonsense Mutations
Nonsense mutation
is a point mutation in a sequence of DNA that results in
a premature stop codon, or a nonsense codon in
the transcribed mRNA, and in a truncated, incomplete,
and usually nonfunctional protein product.
 Example Genetic Disease
β-Thalassemia – are forms of inherited autosomal
recessive blood disorders that originated in the
Mediterranean region. In thalassemia, the disease is
caused by the weakening and destruction of red blood
cells.
Simple Nonsense Mutation
Large Insertion Mutation
Large Deletion Mutation
Chromosomal Translocation
Genetic Testing
• Genetic testing is “the analysis of, chromosomes
(DNA), proteins, and certain metabolites in order
to detect heritable disease-related genotypes,
mutations, phenotypes, or karyotypes for clinical
purposes.”
• There were more than 1,200 clinically applicable
genetic tests available.
• Genetic tests are performed on a sample of
blood, hair, skin, amniotic fluid (the fluid that
surrounds a fetus during pregnancy), or other
tissue such as semen.
Types of Genetic Testing
Prenatal Diagnostic Testing
• Prenatal testing is used to detect changes
in a fetus's genes or chromosomes before
birth, offered to couples with an increased
risk of having a baby with a genetic or
chromosomal disorder.
• Sex determination (discernment)
Cleft Lip/Palate
Newborn Screening Test
• Newborn screening is used just after birth
to identify genetic disorders that can be
treated early in life. The routine testing of
infants for certain disorders is the most
widespread use of genetic testing
• Millions of babies are tested each year in
the United States.
Carrier Testing
• Carrier testing is used to identify people
who carry one copy of a gene mutation
that, when present in two copies, causes a
genetic disorder.
Pre-implantation Genetic Diagnosis
• Genetic testing procedures are performed
on human embryos prior to the
implantation as part of an in vitro
fertilization procedure.
Predictive and Presymptomatic
Testing
• Predictive and presymptomatic types of
testing are used to detect gene mutations
associated with disorders that appear after
birth, often later in life. These tests can be
helpful to people who have a family member
with a genetic disorder, but who have no
symptoms of the disorder themselves at the
time of testing (BRCA1/2).
BRCA1-Linked Hereditary
Breast and Ovarian Cancer
92
73
68
Breast,
86
dx 45, d. 89
71
Breast,
dx 36
Ovary, dx 59 Breast,
d. 62
dx 59
Noncarrier
BRCA1-mutation
carrier
Affected
with cancer
36
ASCO
Risk Assessment Models
Breast cancer at 69 y
Beth
(27)
Model
Diana
(32)
Risk (%)
Gail
19
Claus
39
Normal person
7
Cindy, 39
First menstrual period: 15 y
Prior biopsy: 0
Atypical hyperplasia: Unknown
First live birth: No birth
Predicted possibility of BRCA1
mutation=8.5% (Couch Model)
ASCO
BRCA1
l
l
l
l
Tumor suppressor gene on chromosome 17
Autosomal dominant transmission
Protein has role in genomic stability
>1,200 different mutations reported
Nonsense
Breast Cancer Information Core
Missense
Splice-site
ASCO
BRCA2
l
l
l
l
Tumor suppressor gene on chromosome 13
Autosomal dominant transmission
Protein has role in genomic stability
>1,200 different mutations reported
Nonsense
Breast Cancer Information Core
Missense
Splice-site
ASCO
Forensic/Identity Testing
• Forensic/identity testing uses DNA
sequences to identify an individual for legal
purposes.
• Can identify crime or catastrophe victims,
rule out or implicate a crime suspect, or
establish biological relationships between
people (for example, paternity).
Testing for Phamacogenomics
• A type of genetic testing that determines
the influence of genetic variation on drug
response.
Chromosome
Nomenclature &
Banding Patterns
Tumor Suppressor Genes
Gene
Human Disease
APC
DCC
E-cadherin
(CDH1)
DPC4
BRCA1
Colon cancer
Colon cancer
Breast cancer
BRCA2
ATM
P53
Function
Interacts with catenins
CAM domains
Intracellularly interacts
with catenins
Pancreatic cancer
TGF--related signaling
Mammary cancer/
DNA damage repair,
Ovarian cancer
checkpoint control, apoptosis
Mammary cancer
DNA damage repair, genomic
stability
Ataxia-telangiectasia DNA damage response
mutated gene
upstream in p53 pathway
Mutated in >50%
Transcription factor,
tumors
checkpoint control, apoptosis
Coda