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Human genetic diseases
Pace of disease gene discovery (1981 to 2000).
So far discovered 1112 (not including at least 94 disease-related
genes identified as translocation gene-fusion partners in neoplastic
disorders).
Numbers in parentheses indicate disease-related genes that are
polymorphisms ("susceptibility genes").
1
Molecular characterization of clinical
disorders (1981 to 2000).
1430 does not include the many neoplastic disorders caused by
translocation-related fusion genes.
PARADIGM SHIFTS IN BIOMEDICAL RESEARCH
Structural genomics
Functional genomics
Genomics
Proteomics
Map-based gene
Sequence-based gene discovery
discovery
Monogenic disorders
Multifactorial disorders
Specific DNA
Monitoring of susceptibility
diagnosis
Analysis of multiple genes in gene
Analysis of one gene
families, pathways, or systems
Gene action
Gene regulation
Etiology (specific
Pathogenesis (mechanism)
mutation)
One species
Several species
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Phenotypic variations in simplex
diseases
Even while dissecting the molecular basis of simple monogenic
diseases scientists sometimes facing problems.
Problem: there are modifying effects of other genes.
No genes operates in a vacuum: each busily interacts with either
directly or indirectly with many other genes and their products.
The genetic background of complex
disease
Identification of the genes involved in monogenic disease far more
trivial than for oligo- and monogenic disorders.
Diagnostic features of these complex diseases – called quantitative
trait locus (QTL) disorders are probably regulated by at least
several genes
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Inheritance of monogenic and complex
(multifactorial) disorders.
In monogenic diseases,
mutations in a single gene are
both necessary and sufficient to
produce the clinical phenotype
and to cause the disease.
Environment and life-style are
major contributors to the
pathogenesis of complex
diseases.
Both environmental and genetic factors have roles in the development of any
disease. A genetic disorder is a disease caused by abnormalities in an
individual’s genetic material (genome).
There are four different types of genetic disorders:
(1) single-gene,
(2) multifactorial,
(3) chromosomal, and
(4)
mitochondrial.
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(1) Single-gene (also called Mendelian or monogenic) This type is caused by changes or mutations that
occur in the DNA sequence of one gene. Genes code
for proteins, the molecules that carry out most of the
work, perform most life functions, and even make up
the majority of cellular structures.
When a gene is mutated so that its protein product can
no longer carry out its normal function, a disorder can
result.
There are more than 6,000 known single-gene disorders,
which occur in about 1 out of every 200 births.
Some examples are cystic fibrosis, sickle cell anemia,
Marfan syndrome, Huntington’s disease, and
hereditary hemochromatosis.
(2) Multifactorial (also called complex or polygenic) - This type is
caused by a combination of environmental factors and mutations in
multiple genes.
For example, different genes that influence breast cancer susceptibility
have been found on chromosomes 6, 11, 13, 14, 15, 17, and 22. Its
more complicated nature makes it much more difficult to analyze than
single-gene or chromosomal disorders.
Some of the most common chronic disorders are multifactorial
disorders.
Examples include heart disease, high blood pressure, Alzheimer’s
disease, arthritis, diabetes, and obesity. Sometimes – cancer.
Multifactorial inheritance also is associated with heritable traits such as
fingerprint patterns, height, eye color, and skin color.
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Seeking Genetic Clues to Heart Disease
- clues from the sudden death of the Olympic champion
The Russian Grinkov and his wife, Ekaterina Gordeeva, had won two Olympic
gold medals, four world championships and three European championships.
Parents of a beautiful 4-year-old daughter, Daria, the couple exuded health and
vitality.
But on Nov. 20, 1995, at the age of 28, Grinkov died suddenly of a massive heart
attack, collapsing while in the middle of a practice session.
For cardiologist Dr. Pascal Goldschmidt, at Duke University Medical Center, this
unexpected death didn't seem to make sense, at least on the surface.
Grinkov's father died at the age of 52 of a heart attack, and like his son had none
of the risk factors associated with heart disease.
Yet on autopsy, he was found to have severe coronary artery disease.
Sergei had none of the risks we associate with heart disease, such as smoking,
diabetes, old age, being sedentary, high blood pressure or elevated cholesterol
levels," Goldschmidt said.
"There had to be something else going on."
While at Johns Hopkins University, Goldschmidt tested a sample of Grinkov's
blood and found that he had a variation of the PlA2 gene carried by about 20
percent of the population which seems to predispose people to early heart
disease.
The normal gene is involved in platelet formation, and it appears that those
people with this specific variant possess platelets that clump together too easily.
"While environmental factors are important in the development of heart disease,
they aren't the only factors," Goldschmidt continued. "There is a multitude of
different gene variants that might come into play in combination with different
environmental factors to produce heart disease. It is a very complex process."
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(3) Chromosomal - Chromosomes, distinct structures made up of DNA
and protein, are located in the nucleus of each cell. Because chromosomes
are carriers of genetic material, such abnormalities in chromosome
structure as missing or extra copies or gross breaks and rejoinings
(translocations), can result in disease.
Some types of major chromosomal abnormalities can be detected by
microscopic examination. Down syndrome or trisomy 21 is a common
disorder that occurs when a person has three copies of chromosome 21.
(4) Mitochondrial - This relatively rare type of genetic disorder is caused
by mutations in the nonchromosomal DNA of mitochondria.
Mitochondria are small organelles that are involved in cellular respiration
and found in the cytoplasm of plant and animal cells. Each mitochondrion
may contain 5 to 10 circular pieces of DNA.
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General Aspects of Mitochondrial Genetic Diseases
Maternal inheritance due to the fact that all of the mitochondria in the
fertilized egg came from the egg
affected women transmit to all offspring
affected men transmit to none of their offspring
Human mitochondrial DNA (mtDNA) is a circular molecule containing
16,569 base pairs and has been completely sequenced. Most
mitochondria have 5 to 10 copies of mtDNA. mtDNA codes for two rRNA
subunits, 22 tRNA molecules, and 13 polypeptides
All diseases resulting from changes in mitochondrial DNA are
fundamentally the result of malfunctions of the respiratory chain for
oxidative phosphorylation.
Mitochondria code for 7 subunits of NADH dehydrogenase; 1 subunit
of ubiquinol-cytochrome C oxidoreductase; and 3 subunits of
cytochrome c oxidase. In addition, mitochondrial DNA codes for 2
subunits of ATP synthase as well as mitochondrial rRNA.
The phenotypic effects of mitochondrial mutations reflect the extent to
which a tissue relies on oxidative phosphorylation; the central nervous
system is most sensitive, followed by skeletal muscle, heart muscle,
kidney, and liver.
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Models of disease
Well-established mouse models of disease will be crucial for
dissecting the molecular basis of complex disorders.
Major advantages:
Short generation times
High breeding efficiency
Data sets of mouse-human synteny are presented in the major
human and mouse databases:
www.ncbi.nlm.nih.gov/Homology
In a number of cases, the conserved synteny region that harbors a
disease or QTL has been identified.
Models of disease
Drosophila has served as a valuable model for analyses of normal
and aberrant development:
100 years of genetic
Very good catalog of transposon insertion – www.flybase.org
Targeted mutations can be introduced into the fly genome by
homologous recombination.
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Human disease genes –
functional classification
The functional classification of disease genes and their products
will reveal general principles of human disease.
Upon determination of functional categories for nearly 1,000
documented disease genes, striking correlations between the
function of the gene product and features of disease, such as age of
onset and mode of inheritance were found.
The functions of the protein products of disease genes
b–f, Disease genes
stratified according
to the typical age of
onset of the disease
phenotype. The
fraction of disease
genes encoding
transcription factors
in the in utero onset
disorders (25%)
differs from the
fraction encoding
transcription factors
for disorders with
onset after birth.
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The functions of the protein products of disease genes
Similarly, the
fraction of disease
genes encoding
enzymes causing
a disorder with
onset in the first
year of life (47%)
is different from
the fraction
encoding enzymes
causing disorders
with other ages of
onset.
The functions of the protein products of disease genes
An extraordinarily high fraction of diseases with onset in the first
year of life that caused by defects in genes encoding enzymes fits
with biological expectations and clinical evidence.
The developing fetus has access to its mother's metabolic
homeostatic systems through the placenta.
Thus, infants with inborn errors caused by enzyme deficiencies are
typically normal at birth and develop symptoms only after the
defect in their homeostatic system is exposed by demands on their
own metabolism.
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The functions of the protein products of
disease genes
The fraction of disease genes encoding enzymes falls with later
disease onset. Disorders with onset after age 50 are an apparent
exception, with the fraction of genes encoding enzymes increasing
to more than 33%. But the number of disorders in this category
(18) is small.
Characteristics of
disease arranged by
function of the
protein encoded by
the disease gene
a, Disease genes encoding
enzymes; b, disease genes
encoding modifiers of protein
function; c, disease genes
encoding receptors; d, disease
genes encoding transcription
factors. The columns of disease
features are labelled at the top.
AR, autosomal recessive; AD,
autosomal dominant; early
adulthood, puberty to <50
years; late adulthood, >50 years.
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The functions of the protein products of
disease genes
Comparison of the inheritance patterns shows that disorders caused
by genes encoding enzymes are primarily recessive,
whereas those caused by genes encoding modifiers of protein
function and receptors are split more-or-less evenly between
recessives and dominants.
Disorders caused by genes encoding transcription factors, by
contrast, are more likely to be dominant.
These results fit well with our understanding of how proteins of
various functions contribute to development and homeostasis.
The functions of the protein products of
disease genes
Perhaps disorders of receptors are most likely to present in
childhood because this is a time of rapid growth and, especially
during puberty, of intense signalling activity between various cells
and tissues.
Similarly, disorders involving modifiers of protein function may
present later in life because the homeostatic systems are not
completely disrupted by these defects; rather, they respond in ways
that are less congruent with the demands placed on the organism
and so become symptomatic more gradually.
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Human genetic diseases
associated with DNA repair
deficiency
Due to DNA's absolutely critical role to life, mutations in human
genes related to the normal DNA replication process would very
likely be lethal.
In contrast, mutations in human genes involved in at least some
components of DNA repair processes are highly deleterious, but
not necessarily lethal.
Many human genetic diseases which are related to defects in DNA
repair enzymes have been identified.
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Human syndromes with defective
genome maintenance
Syndrome
Affected
maintenance
mechanism
Main type of
genome
instability
Major cancer
predisposition
NER(±TCR)
Point mutations
UV-induced skin
cancer
Cockayne syndrome
TCR
Point mutations
None*
Trichothiodystrophy
NER/TCR
Point mutations
None*
Ataxia telangiectasia
DSB response/
repair
Chromosome
aberrations
Lymphomas
AT-like disorder
DSB response/
repair
Chromosome
aberrations
Lymphomas
Nijmegen breakage
syndrome
DSB response/
repair
Chromosome
aberrations
Lymphomas
Xeroderma
pigmentosum
Human syndromes with defective
genome maintenance
BRCA1/BRCA2
HR
Chromosome
aberrations
Breast (ovarian)
cancer
Werner syndrome
HR?/TLS?
Chromosome
aberrations
Various cancers
Bloom syndrome
HR?
Chromosome
aberrations (SCE^)
Leukaemia,
lymphoma, others
RothmundThomson syndrome
HR?
Chromosome
aberrations
Osteosarcoma
Ligase IV
deficiency **
EJ
Recombination
fidelity
Leukaemia(?)
HNPCC
MMR
Point mutations
Colorectal cancer
Xeroderma
pigmentosum
variant
TLS***
Point mutations
UV-induced skin
cancer
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Human syndromes with defective
genome maintenance
*- defect in transcription-coupled repair triggers apoptosis, which
may protect against UV-inducing cancer
** - one patient with leukaemia and radiosensitivity described
with active-site mutation in ligase IV.
*** - specific defect in relatively error-free bypass replication of
UV-induced cyclobutane pyrimidine dimers.
Xeroderma Pigmentosum
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Xeroderma Pigmentosum
Some 20% of patients with XP incur progressive degeneration of
previously normally developed neurons resulting in cortical, basal
ganglia, cerebellar, and spinal atrophy, cochlear degeneration, and
a mixed distal axonal neuropathy.
Cultured cells from patients with XP are hypersensitive to killing
by ultraviolet (UV) radiation.
Xeroderma Pigmentosum
Complementation groups known:
XPC – binds damaged DNA as complex (RAD23B, CETN2)
XPA – binds damaged DNA in preincision complex (RPA1,2,3)
XPB (ERCC3) – 3’ to 5’ DNA helicase
XPD (ERCC2) – 5’ to 3’ DNA helicase
XPG (ERCC5) – 3’ incision
XPF (ERCC4) – 5’ incision subunit (with ERCC1)
XPE – binds damaged DNA
XPV (DNA polymerase η) – defective only in the replication of
UV-damaged DNA (is able to carry out trans-lesion DNA
synthesis).
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Cockayne syndrome
CS is a multisystem disorder that causes both profound growth
failure of the soma and brain and progressive cachexia, retinal,
cochlear, and neurologic degeneration, with a leukodystrophy and
demyelinating neuropathy without an increase in cancer.
Cultured cells from patients with CS are hypersensitive to killing
by ultraviolet (UV) radiation. CS cells have defective DNA
nucleotide excision repair of actively transcribing genes.
CSA (CKN1) – Cockayne syndrome; needed for transcription
coupled repair
CSB (ERCC6)
Cockayne syndrome
The damaged DNA has to be processed prior to the transcription.
CSB protein apparently helps to displace the polymerase complex
stolen on the site of DNA damage within ~ 50 nucleotides around
transcription start.
On the molecular level CSB deficiency results in defective
transcription-coupled repair (TCR) in such manner that repair of
the transcribed strand falls to the level of the non-transcribed
strand.
The molecular basis for the TCR phenomenon is thought to
originate in an efficient recruitment of repair proteins toward
RNAP stalled at the site of DNA damage.
Possible candidates for re-recruiting of TFIIH toward RNAPII
stalled at the site of DNA damage are the Cockayne syndrome
(CS) group A and B gene products.
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Cockayne syndrome
The RAD26 protein is likely candidate to function as a TRCF in
yeast with proposed role to modulate contacts of the elongating
transcription complex with the DNA at sites of base damage.
However, in contrast to the E. coli TRCF, the CSB protein is not
able to displace the RNAPII from the DNA in vitro but in
agreement with the E. coli model, CSB can interact with
components of the human NER pathway TFIIH and XPA.
Bloom's Syndrome
This is another recessive autosomal genetic disease characterized
by lupus-like erythematous telangiectasias of the face, sun
sensitivity, stunted growth infertility and immunodeficiency and
that exhibits -- among many other characteristics -- sensitivity to
sunlight and greatly elevated cancer incidence.
The BS gene product, BLM, is a 159 kDa DNA helicase enzyme
belonging to the RecQ family.
ATPase that is strongly stimulated by either single- or doublestranded DNA.
BLM exhibits ATP- and Mg2+-dependent DNA helicase activity
that displays 3'-5' polarity
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Bloom's Syndrome
•BS cells are characterized by an increased rate of sister chromatid
exchange (SCE)
•blm gene has been mapped to human chromosome 15 band q26.1
•BLM is targeted to specific nuclear structures and its expression
is enhanced during cell growth
•BLM colocalizes with replication protein A in meiotic prophase
nuclei of mammalian spermatocytes.
•proteins from three missense alleles lack DNA helicase activity
•Blm could also be involved in transcription regulation.
Bloom's Syndrome
•BLM is apparently involved in the maintenance of the stability of
DNA.
•BLM protein may also play a role in the detection of certain types
of DNA damage and in the cellular response to that damage.
•Enzymatic activities of the BLM product (Helicase and ATPase)
are implicated in the upholding of genomic integrity.
•BLM and WRN appear to play distinct in processes such as DNA
repair and recombination as suggested by the nucleolar localization
of WRN, its invariant expression during the cell cycle, and the lack
of interaction between BLM and WRN.
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WRN
•WERNER SYNDROME is a premature aging disease that
begins in adolescence or early adulthood and results in the
appearance of old age by 30-40 years of age.
•Its physical characteristics may include short stature
(common from childhood on) and other features usually
developing during adulthood: wrinkled skin, baldness,
cataracts, muscular atrophy and a tendency to diabetes
mellitus, among others.
• The disorder is inherited and transmitted as an autosomal
recessive trait. Cells from WS patients have a shorter
lifespan in culture than do normal cells.
WRN
•The gene for Werner disease (WRN) was mapped to
chromosome 8 and cloned: by comparing its sequence to
existing sequences in GenBank, it is a predicted helicase
belonging to the RecQ family.
•However, it has yet to be shown to have real helicase
activity (as a DNA unwinder important for DNA replication).
•A yeast protein similar to the human WRN protein, called
SGS1, has been found.
•Mutations in SGS1 cause yeast to have a shorter lifespan
than yeast cells without the mutation, and shown other signs
typical of aging in yeast, such as an enlarged and
fragmented nucleolus.
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WRN
•The WRN gene product has RecQ-type helicase
domains in the central region of the protein.
•Subsequent studies also revealed that the WRN protein
displays exonuclease activity and acts as a
transcriptional activation factor.
•These biochemical studies, combined with cell biological
studies, suggested that this protein is likely to be
involved in the response to DNA damage during
replication, as well as recombination and transcription
processes.
•However, the precise molecular mechanisms by which
mutations in WRN cause the WS phenotype remain
unknown.
Fanconi anemia
FA has been typically described as
an autosomal recessive genetic disease which is characterized by
short stature,
short or absent thumbs,
dark skin pigmentation,
mental retardation,
childhood anemia,
and very frequent leukemia,
sensitivity of cells to DNA cross-linking agents, and
a predisposition to cancer.
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Fanconi anemia
Cultured cells from patients exhibit a high proportion of broken
chromosomes, and chromosome breakage can be greatly
accentuated by exposing cell cultures to DNA alkylating and
cross-linking agents.
This has suggested that the genetic defect is due to an inability to
repair DNA lesions, that this leads secondarily to chromosomal
breaks, and that this can lead to a variety of developmental
abnormalities and cancers.
However, the wide diversity of phenotypes associated with FA is
puzzling, and suggests that several different genes may be
involved.
Fanconi anemia
Eight complementation groups, A-H. Genes for FA-A (16q24.3)
and FA-C cloned. Group A accounts for 69% of FA-A, FA-C
accounts for 18%.
•FAA gene contains Alu sequences which predispose it to
intragenic deletion. FAA may also undergo slipped strand
mispairing.
•FAA and FAC genes encode novel proteins of unknown function.
It seems likely that FA proteins have a control function, perhaps
initiating protective systems including the processing of specific
lesions, rather than participating directly in DNA repair.
•Heterozygotes may have an increased cancer risk.
23
The FA proteins also play a role in the establishment of an intra-S
phase checkpoint.
Nijmegan breakage syndrome
(NBS)
•Characterized by short stature, progressive microcephaly and
increased risk of cancer, especially lymphoma.
•Autosomal recessive inheritance. Originally classified as a variant
of AT, with which it shares many features.
•Inversions and translocations involving chromosomes 7 & 14 are
common. Breakpoints at Ig and TCR loci
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Nijmegan breakage syndrome
(NBS)
•Caused by mutations in the NBS1 gene (8q21). All mutations
reported to date are truncating. In US, 75% of patients are
homozygous for common mutation 657del5.
•NBS1 encodes nibrin, a protein which contains domains found in
other proteins involved in cellular responses to DNA damage.
Nibrin associates with other proteins putatively involved in DNA
repair and forms nuclear foci at sites where DNA repair has taken
place.
•Role in double-strand breakage repair, perhaps in same pathway
or with same function as ATM protein.
•Possible increase in susceptibility to cancer in heterozygotes.
Ataxia telangiectasia (AT)
•Clinical features: progressive cerebellar ataxia, oculocutaneous
telangiectasia, progressive neurological features, immune
deficiency, increased sensitivity to ionising radiation.
•Autosomal recessive inheritance. Incidence at birth ~1 in 300,000.
•10-20% risk of developing malignancy; usually lymphoma (60%)
or leukaemia (30%).
•Chromosomal aberrations: chromatid gaps, breaks and
interchanges in cultured fibroblasts, markedly increased by
exposure to X-radiation and radiomimetic agents. 7:14
translocation in 5-15% of cells.
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Ataxia telangiectasia (AT)
•ATM gene (11q22-23). 66 exons, >300 mutations reported, 72%
truncating. Founder mutations in certain populations. Although
four complementation groups were identified, all have mutations
in ATM.
•Normal gene product: senses double-stranded DNA breaks and
activates cell cycle checkpoints. ATM protein also associates with
meiotic prophase chromosomes - a frequent site of DNA breaks.
Mutation results in unstable protein, although mRNA detected in
most patients.
•Heterozygotes may have increased risk of cancer, especially
breast cancer.
Hereditary nonpolyposis colorectal
cancer syndrome
(HNPCC) is a heritable predisposition to the formation of sporadic
colorectal carcinomas.
The genetic lesion is due to mutations within the "strand-specific
mismatch repair" genes of which there are at least 4.
The errors are particularly noticeable
in single (e.g., AAAAAAAAA…) or
dinucleotide (e.g., CACACACACA….) base pair repeat regions of
other genes.
Tumor cells with the HNPCC genetic lesion exhibit a 100-fold
greater mutation rate in these sequences than normal cells from
the same individual;
thus the tumor cells are described as having a so-called "mutator"
phenotype.
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Hereditary nonpolyposis colorectal
cancer syndrome
The high frequency of uncorrected DNA mismatch mutations that
occur as such tumor cells replicate can give rise to yet other
cancer-causing and potentiating mutations,
thus making HNPCC tumors difficult to treat unless discovered
and removed very early.
For example, the TGFb type II receptor contains a polyadenine
tract;
90% of the colorectal cancers with HNPCC associated alleles
exhibited mutations of this polyadenine tract and inactivation of
the respective TGFb type II receptor allele.
Inherited Syndromes with Predisposition of Cancer
Fanconi Anemia
•Leukemia
Xeroderma Pigmentosa
•Skin cancer
•Melanoma
•Leukemia
Ataxia-Telangiectasia
•Leukemia
•Lymphoma
•breast cancer
Neurofibromatosis I
•gliomas
•meningiomas
•rhabdomyosarcomas
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Inherited Syndromes with Predisposition of Cancer
Bloom syndrome
•leukemia
•colon cancer
•Wilms tumor
Neurofibromatosis II
•acoustic neuromas
Von Hippel Lindau
•cell carcinoma
•hemangioblastomas
•Pheochromocytoma
Li-Fraumeni
renal
•Sarcomas carcinomas
APC
Multiple polyposis of the colon (APC, adenomatous polyposis
coli). The colon and often other areas of the intestinal tract have
hundreds to thousands of polyps, with inevitable transformation of
one or more into a malignant state. The APC gene has been
mapped to 5q21. Expression of the mutant alleles associated with
multiple polyps is dominant, the polyps usually appearing at 10 to
20 years of age.
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Retinoblastoma
Retinoblastoma is a malignant tumor that develops from
embryonic cells in the retina (retinoblasts) in young children.
After several years of age, retinoblasts are no longer present and
the risk of developing new retinoblastomas virtually disappears.
In many instances, the risk of retinoblastoma is transmitted as an
autosomal dominant trait, although penetrance is less than 100%.
The RB locus is at 13q14. Nonfamilial (isolated) cases of
retinoblastoma also occur.
Retinoblastoma
There is a curious class of tumors that do not fit the usual
characteristics in which the mutant oncogene is dominant over the
wild type.
In retinoblastoma, there appears to be a lesion that is recessive,
that is the cancer causing mutation causes a loss of function. Thus
it appears that the protein that is encoded in the retinoblastoma
(Rb) gene is a growth suppressor. If a homozygous mutation
occurs in the Rb gene, there will be no Rb gene product at all and
the cell will grow abnormally because the growth suppressor is no
longer present. The product of the Rb gene has been identified and
shown to be a nucleus-located protein of 105 kDaltons.
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BRCA1 and BRCA2
Breast Cancer
Reproductive, hormonal, dietary, genetic factors contribute
1/12 lifetime risk for women
• 1/8 risk if sister diagnosed 65-70 years of age
• 1/4 risk if sister diagnosed under 40 years of age
• 1/3 risk if first-degree relatives affected under under 40 years
A. Epidemiologic studies indicated dominant gene accounts
for 5-10% breast cancer
B. Linkage studies in familial breast/ovarian cancer families
identify genes
• BRCA1-17q
45-50%
• BRCA2-13q
35%, 15% male breast cancer
BRCA1 and BRCA2
A. Inherited mutation confers predisposition to breast/ovarian
cancer
• 80-90% lifetime risk to develop breast cancer
• 40-50% lifetime risk to develop ovarian cancer (BRCA1); less
for BRCA2
• increased risk to develop other tumors as well
A. BRCA1 and BRCA2 are tumor-supressor genes-loss of
heterozygosity• an individual who inherits either a BRCA1 or BRCA2
mutation must lose the function of the other allele to develop
cancer
30
BRCA1 and BRCA2
BRCA1
BRCA1 mutations found in familial breast/ovarian cancer
families and in sporadic tumors-70-kb gene, 22 exons,
chromosome 17
• >100 mutations identified
• Truncation mutations (frameshifts and nonsense mutations) are
common; missense mutations less common
•
•
•
Genotype-phenotype correlations: mutations more 3' in
gene seem to have lower-incidence ovarian cancer
Common mutation (185delAG) in Ashkenazi Jews
1% Ashkenazi Jewish population
20% Ashkenazi Jewish women with early-onset breast cancer
Male BRCA1 carriers have 3x increased risk of prostate cancer
BRCA1 and BRCA2
BRCA2
BRCA2 mutations account for both breast and a
proportion of ovarian cancer (chromosome 13)
• 15% male breast cancer
• 27 exons; 8 internal repeats
• Truncation mutations are common
A. Recurrent BRCA2 mutation (6174delT) in Ashkenazi
Jewish women with early-onset breast/ovarian cancer
B. Cancer at other sites may be more common than in general
population pancreatic, prostate, colon, stomach
C. Together BRCA1 185delAG and BRCA2 6174delT account
for 25-30% early-onset breast/ovarian cancer in Ashkenzai
Jewish women
31
References
Peltonen L. and McKusick V. Dissecting human disease in the postgenomic era. Science, 291: 1224-1229, 2001.
http://www.ornl.gov/sci/techresources/Human_Genome/medicine/assist.shtml
http://www.people.virginia.edu/~rjh9u/mitochon.html
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