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PROTO-ONCOGENES, ONCOGENES, AND TUMOR-SUPPRESSOR GENES
4.
Parents of the proband.
The proband may have an RB affected parent or an un-
affected parent who has an RB1 gene mutation. If the proband mutation is identi-
fied in either parent, then the parent is at risk of transmitting that RB1 gene muta-
tion to other offspring. If the proband mutation is not identified in either parent,
then the proband has a de novo RB1 gene germline mutation (90%–94% chance)
or one parent is mosaic for the RB1 gene mutation (6%–10% chance).
5.
How can cancer due to tumor-suppressor genes be autosomal dominant when both
copies of the gene must be inactivated for tumor formation to occur? The inher-
ited deleterious allele is in fact transmitted in an autosomal dominant manner and
most heterozygotes do develop cancer. However, while the predisposition for can-
cer is inherited in an autosomal dominant manner, changes at the cellular level
require the loss of both alleles, which is a recessive mechanism.
6.
Clinical features:
a malignant tumor of the retina develops in children
5 years
of age; whitish mass in the pupillary area behind the lens (leukokoria; the cat’s eye;
white eye reflex) and strabismus.
7.
The top photograph shows a white pupil (leukokoria; cat’s eye) in the left eye. The
bottom photograph of a surgical specimen shows an eye that is almost completely
filled a cream-colored intraocular retinoblastoma.
B. CLASSIC LI-FRAUMENI SYNDROME (LFS)
1.
Classic LFS is an autosomal dominant genetic disorder caused by a mutation in
the TP53 gene on chromosome 17p13.1 for the cellular tumor protein 53 (“the
guardian of the genome”). Mutations of the TP53 gene have been identified which
include missense (80%) and RNA splicing (20%) mutations which result in a pre-
mature STOP codon and a loss-of-function mutation.
2.
The activation (i.e., phosphorylation) of p53 causes the transcriptional upregula-
tion of p21. The binding of p21 to the Cdk2-cyclin D and Cdk2-cyclin E inhibits
their action and causes downstream stoppage at the G
1
checkpoint. p53 belongs to
the family of tumor-suppressor genes.
3.
Clinical features include
a highly penetrant cancer syndrome associated with soft-
tissue sarcoma, breast cancer, leukemia, osteosarcoma, melanoma, and cancers of
the colon, pancreas, adrenal cortex, and brain; 50% of the affected individuals de-
velop cancer by 30 years of age and 90% by 70 years of age; an increased risk for
developing multiple primary cancers; LFS is defined by a proband with a sarcoma
diagnosed
45 years of age AND a first-degree relative 45 years of age with any
cancer AND a first- or second-degree relative
45 years of age with any cancer.
C. NEUROFIBROMATOSIS TYPE 1 (NF1; VON RECKLINGHAUSEN DISEASE; Figure
9-5)
1.
NF1 is a relatively common autosomal
dominant genetic disorder caused by a
mutation in the NF1 gene on chromo-
some 17q11.2 for the neurofibromin pro-
tein. More than 500 different mutations of
the NF1 gene have been identified which
include missense, nonsense, frameshift,
whole gene deletions, intragenic dele-
tions, and RNA splicing mutations, all of
which result in a loss-of-function muta-
tion.
2.
Neurofibromin downregulates p21 RAS
oncoprotein so that the NF1 gene belongs
to the family of tumor-suppressor genes
and regulates cAMP levels.
● Figure 9-5 Neurofibromatosis Type 1.
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64
CHAPTER 9
3.
Clinical features include
multiple neural tumors (called neurofibromas that are
widely dispersed over the body and reveal proliferation of all elements of a periph-
eral nerve including neurites, fibroblasts, and Schwann cells of neural crest ori-
gin), numerous pigmented skin lesions (called café au lait spots) probably associ-
ated with melanocytes of neural crest origin, axillary and inguinal freckling,
scoliosis, vertebral dysplasia, and pigmented iris hamartomas (called Lisch
nodules).
4.
The photograph shows a woman with generalized neurofibromas on the face and
arms.
D. FAMILIAL ADENOMATOUS POLYPOSIS COLI (FAPC; Figure 9-6)
1.
FAPC is an autosomal dominant genetic
disorder caused by a mutation in the APC
gene on chromosome 5q21-q22 for the
adenomatous polyposis coli protein. More
than 800 different germline mutations of
the APC gene have been identified all of
which result in a loss-of-function muta-
tion. The most common germline APC
mutation is a 5-bp deletion at codon 1309.
2.
APC protein binds glycogen synthase ki-
nase 3b (GSK-3b) which targets
-
catenin. APC protein maintains normal
apoptosis and inhibits cell proliferation
through the Wnt signal transduction
pathway so that APC gene belongs to the
family of tumor-suppressor genes.
3.
A majority of colorectal cancers develop
slowly through a series of histopathologi-
cal changes each of which has been asso-
ciated with mutations of specific proto-
oncogenes and tumor-suppressor genes as
follows: normal epithelium S a small
polyp involves mutation of the APC tumor-
suppressor gene; small polyp S large
● Figure 9-6 Familial Adenomatous
Polyposis Coli.
polyp involves mutation of RAS proto-oncogene; large polyp S carcinoma S
metastasis involves mutation of the DCC tumor-suppressor gene and the TP53
tumor-suppressor gene.
4.
Clinical features include
colorectal adenomatous polyps appear at 7–35 years of
age inevitably leading to colon cancer; thousands of polyps can be observed in the
colon; gastric polyps may be present; and patients are often advised to undergo
prophylactic colectomy early in life to avert colon cancer.
5.
The top light micrograph shows an adenomatous polyp. A polyp is a tumorous
mass that extends into the lumen of the colon. Note the convoluted, irregular
arrangement of the intestinal glands with the basement membrane intact. The bot-
tom photograph shows the colon that contains thousands of adenomatous polyps.
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65
PROTO-ONCOGENES, ONCOGENES, AND TUMOR-SUPPRESSOR GENES
E.
BRCA1 AND BRCA2 HEREDITARY BREAST
CANCERS (Figure 9-7)
1.
BRCA1 and BRCA2 hereditary breast can-
cers are autosomal genetic disorders
caused by a mutation in either the BRCA1
gene on chromosome 17q21 for the
breast cancer type 1 susceptibility pro-
tein or a mutation in the BRCA2 gene on
chromosome 13q12.3 for the breast can-
cer type 2 susceptibility protein.
2.
BRCA type 1 and type 2 susceptibility pro-
teins bind RAD51 protein which plays a
role in double-strand DNA break repair
so that BRCA1 and BRCA2 genes belong to
the family of tumor-suppressor genes.
3.
More than 600 different mutations of the
BRCA1 gene have been identified all of
which result in a loss-of-function mutation.
4.
More than 450 different mutations of the
BRCA2 gene have been identified all of
which result in a loss-of-function mutation.
● Figure 9-7 Mammogram of Breast
Cancer.
5.
Prevalence.
The prevalence of BRCA1 gene mutations is 1/1000 in the general
population. A population study of breast cancer found a prevalence of BRCA1 gene
mutations in only 2.4% of the cases. A predisposition to breast, ovarian, and
prostate cancer may be associated with mutations in the BRCA1 gene and BRCA2
gene although the exact percentage of risk is not known and even appears to be
variable within families.
6.
Clinical features include
early onset of breast cancer, bilateral breast cancer, fam-
ily history of breast or ovarian cancer consistent with autosomal dominant inheri-
tance, and a family history of male breast.
7.
The mammogram shows a malignant mass that has the following characteristics:
shape is irregular with many lobulations; margins are irregular or spiculated; den-
sity is medium-high; breast architecture may be distorted; and calcifications (not
shows) are small, irregular, variable, and found within ducts (called ductal casts).
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66
Mitosis is the process by which a cell with the diploid number
of chromosomes, which in humans is 46, passes on the diploid number of chromosomes to
daughter cells. The term “diploid” is classically used to refer to a cell containing 46 chro-
mosomes. The term “haploid” is classically used to refer to a cell containing 23 chromo-
somes. The process ensures that the diploid number of 46 chromosomes is maintained in
the cells. Mitosis occurs at the end of a cell cycle. Phases of the cell cycle are as follows:
A. G
0
(GAP) PHASE. The G
0
phase is the resting phase of the cell. The amount of time a
cell spends in G
0
is variable and depends on how actively a cell is dividing.
B. G
1
PHASE. The G
1
phase is the gap of time between mitosis (M phase) and DNA
synthesis (S phase). The G
1
phase is the phase where RNA, protein, and organelle syn-
thesis occurs. The G
1
phase lasts about 5 hours in a typical mammalian cell with a
16-hour cell cycle.
C. G
1
CHECKPOINT. Cdk2-cyclin D and Cdk2-cyclin E mediate the G
1
S
S phase tran-
sition at the G
1
checkpoint.
D. S (SYNTHESIS) PHASE. The S phase is the phase where DNA synthesis occurs. The
S phase lasts about 7 hours in a typical mammalian cell with a 16-hour cell cycle.
E.
G
2
PHASE. The G
2
phase is the gap of time between DNA synthesis (S phase) and mi-
tosis (M phase). The G
2
phase is the phase where high levels of ATP synthesis occur.
The G
2
phase lasts about 3 hours in a typical mammalian cell with a 16-hour cell cycle.
F.
G
2
CHECKPOINT. Cdk1-cyclin A and Cdk1-cyclin B mediate the G
2
S
M phase tran-
sition at the G
2
checkpoint.
G. M (MITOSIS) PHASE. The M phase is the phase where cell division occurs. The M
phase is divided into six stages called prophase, prometaphase, metaphase, anaphase,
telophase, and cytokinesis. The M phase lasts about 1 hour in a typical mammalian
cell with a 16-hour cell cycle.
1.
Prophase.
The chromatin condenses to form well-defined chromosomes. Each
chromosome has been duplicated during the S phase and has a specific DNA se-
quence called the centromere that is required for proper segregation. The centro-
some complex, which is the microtubule-organizing center, splits into two, and
each half begins to move to opposite poles of the cell. The mitotic spindle (micro-
tubules) forms between the centrosomes.
2.
Prometaphase.
The nuclear envelope is disrupted which allows the microtubules
access to the chromosomes. The nucleolus disappears. The kinetochores (protein
complexes) assemble at each centromere on the chromosomes. Certain micro-
tubules of the mitotic spindle bind to the kinetochores and are called kinetochore
microtubules. Other microtubules of the mitotic spindle are now called polar
microtubules and astral microtubules.
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67
THE CELL CYCLE
PROPHASE
Chromatin condenses to form well-defined chromosomes
Each chromosome has been duplicated during the S phase and has a specific DNA
sequence called the centromere that is required for proper segregation
The centrosome complex which is the microtubule organizing center (MTOC) splits
into two and each half begins to move to opposite poles of the cell
The mitotic spindle (microtubules) forms between the centrosomes
PROMETAPHASE
Nuclear envelope is disrupted which allows the microtubules access to the chromosomes
Nucleolus disappears
Kinetochores (protein complexes) assemble at each centromere on the chromosomes
Certain microtubules of the mitotic spindle bind to the kinetochores and are called
kinetochore microtubules
Other microtubules of the mitotic spindle are now called polar microtubules and astral
microtubules
METAPHASE
Chromosomes align at the metaphase plate
Cells can be arrested in this stage by microtubule inhibitors (e.g., colchicine)
Cells can be isolated in this stage for karyotype analysis
ANAPHASE
Kinetochores separate and chromosomes move to opposite poles
Kinetochore microtubules shorten and Polar microtubules lengthen
TELOPHASE
Chromosomes begin to decondense to form chromatin
Nuclear envelope re-forms
Nucleolus reappears
Kinetochore microtubules disappear
Polar microtubules continue to lengthen
CYTOKINESIS
Cytoplasm divides by a process called cleavage
A cleavage furrow forms around the middle of the cell
A contractile ring consisting of actin and myosin filaments is found at the cleavage furrow
M Phase
Last 1 hour
Vinb
lastin (V
elban),
Vincristine (onco
v
in),
P
azlitax
el (T
axol) are M phase specific
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