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7.

How can cancer due to tumor suppressor genes be autosomal dominant when both
copies of the gene must be inactivated in order 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 cancer is inher-
ited in an 

autosomal dominant manner

, changes at the cellular level require the loss of both

alleles, which is a 

recessive mechanism

. 

8. Prevalence.

The prevalence of retinoblastoma is 1/20,000 births.

9. Clinical features include:

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.

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 premature STOP codon and a 

loss-of-function

mutation

. 

2.

The activation (i.e., phosphorylation) of p53 causes the transcriptional upregulation 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. Parents of the proband.

Most probands have a LFS affected parent. The frequency of de

novo mutations is not known. 

4. Siblings of the proband. 

The risk to each sibling of the proband of inheriting the TP53 gene

germline mutation is 50% if a parent has the same TP53 gene germline mutation identi-
fied in the proband. The risk to each sibling of the proband is low if neither parent has the
same  TP53 gene germline mutation identified in the proband; a de novo mutation is
assumed). No instances of germline mosaicism have been reported.

5. Offspring of the proband. 

The risk to the offspring of the proband is 50%.

6. Prevalence

. The prevalence of LFS is 1/400 families worldwide.

7. 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 develop 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 rela-

tive 

45 years of age with any cancer. 

C. Neurofibromatosis Type 1 (NF1; von Recklinghausen disease).

1.

NF1 is a relatively common 

autosomal dominant

genetic disorder caused by a mutation in

the 

NF1 gene

on 

chromosome 17q11.2

for the 

neurof ibromin 

protein. 

500 different muta-

tions of the NF1 gene have been identified which include missense, nonsense, frameshift,
whole gene deletions, intragenic deletions, and RNA splicing mutations; all of which
result in a 

loss-of-function mutation

. 

2.

Neurofibromin downregulates 

p21 RAS oncoprotein

so that the NF1 gene belongs to the

family of 

tumor-suppressor genes

and regulates cAMP levels.

3. Parents of the proband.

50% of probands have a NF1 affected parent. The other 50% of

probands have an unaffected parent and develop NF1 due to a de novo mutation.

4. Siblings of the proband.

The risk to each sibling of the proband of inheriting the NF1 gene

germline mutation is 50% if a parent has the same NF1 gene germline mutation identified in
the proband. The risk to each sibling of the proband is low (but 

 than that of the general

population because of the possibility of germline mosaicism) if the parents are unaffected.

5. Offspring of the proband.

The risk to the offspring of the proband is 50%.

6. Prevalence.

The prevalence of NF-1 is 1/3,000 births. The NF-1 gene has an unusually

high mutation rate although the exact cause is unknown. 

7. Clinical features include:

multiple neural tumors (called 

neurofibromas 

that are widely dis-

persed over the body and reveal proliferation of all elements of a peripheral nerve including

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neurites, fibroblasts, and Schwann cells of neural crest origin, numerous pigmented skin
lesions (called 

café au lait spots

) probably associated with melanocytes of neural crest ori-

gin, axillary and inguinal freckling, scoliosis, vertebral dysplasia, and pigmented iris
hamartomas (called 

Lisch nodules

).

D. Familial Adenomatous Polyposis (FAP).

1.

FAP is an autosomal dominant genetic disorder caused by a mutation in the 

APC gene

on

chromosome 5q21-q22

for the 

adenomatous polyposis coli protein

. 

800 different germline

mutations of the APC gene have been identified all of which result in a 

loss-of-function

mutation

. The most common germline APC mutation is a 

5-bp deletion

at codon 1309.

2.

APC protein binds 

glycogen synthase kinase 3b (GSK-3b)

which targets 

-catenin

. APC pro-

tein 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. Parents of the proband.

80% of probands have a FAP affected parent. The other 20% of

probands have an unaffected parent and develop FAP due to a de novo mutation.

4. Siblings of the proband. 

The risk to each sibling of the proband of inheriting the APC gene

germline mutation is 50% if a parent has the same APC  gene germline mutation identified
in the proband. The risk to each sibling of the proband is low (but 

 than that of the general

population because of the possibility of germline mosaicism) if the parents are unaffected.

5. Offspring of the proband. 

The risk to the offspring of the proband is 50%.

6.

A majority of colorectal cancers develop slowly through a series of histopathological
changes each of which has been associated with mutations of specific proto-oncogenes
and tumor-suppressor genes as follows: normal epithelium 

→

a small polyp involves

mutation of the APC tumor suppressor gene; small polyp 

→

large polyp involves mutation

of RAS proto-oncogene; large polyp 

→

carcinoma 

→ 

metastasis involves mutation of the

DCC tumor-suppressor gene and the TP53 tumor-suppressor gene.

7. Prevalence.

The prevalence of FAP is 3/100,000 individuals. FAP accounts for only 0.5% of

all colorectal cancers. 

8. Clinical features include:

colorectal adenomatous polyps appear at 7 to 35 years of age,

inevitably leading to colon cancer; thousands of polyps can be observed in the colon; gas-
tric polyps may be present; and patients are often advised to undergo prophylactic colec-
tomy early in life to avert colon cancer. 

E. BRCA1 and BRCA2 Hereditary Br east Cancers.

1.

BRCA1 and BRCA2 hereditary breast cancers are autosomal genetic disorders caused by a
mutation in either the 

BRCA1 gene

on 

chromosome 17q21

for the 

br east cancer type 1 sus-

ceptibility protein

or a mutation in the 

BRCA2 gene

on 

chromosome 13q12.3

for the 

breast

cancer type 2 susceptibility protein.

2.

BRCA type 1 and type 2 susceptibility proteins 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.

600 mutations different mutations of the BRCA1 gene have been identified all of which
result in a 

loss-of-function mutation

. 

4.

450 mutations different mutations of the BRCA2 gene have been identified all of which
result in a 

loss-of-function mutation

. 

5. Parents of the proband.

100% of individuals with a BRCA1 or  BRCA2 gene mutation

inherit the mutation from a parent. The parent may or may not have had a cancer diagno-
sis depending on the penetrance of the mutation, gender of the parent with the mutation,
age of the parent with the mutation.

6. Siblings of the proband.

The risk to each sibling of the proband of inheriting the BRCA1 or

BRCA2 gene germline mutation is 50% if a parent has the same BRCA1 or  BRCA gene
germline mutation identified in the proband. However, whether the sibling develops can-
cer depends on the penetrance of the mutation, gender of the sibling, and other variables.  

7. Offspring of the proband.

The risk to the offspring of the proband is 50%. However, whether

the offspring develops cancer depends on the penetrance of the mutation, gender of the
sibling, and other variables.

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8. Prevalence.

The prevalence of BRCA1 gene mutations is 1/1,000 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 associ-
ated with mutations in the BRCA1 gene and BRCA2 gene although the exact percentage
risk is not known and even appears to be variable within families. 

9. Clinical features include:

early onset of breast cancer, bilateral breast cancer, family history

of breast or ovarian cancer consistent with autosomal dominant inheritance, and a family
history of male breast cancer.

VII. LOSS OF HETEROZYGOSITY (LOH)

A.

Molecular genetic analysis of RB-affected individuals revealed heterozygosity at the RB1
gene locus in normal tissues but only one RB1 allele in the retinoblastoma tumor tissue. That
is, one RB1 allele simply vanished in the tumor tissue and this is called LOH.

B.

In other words, the tumor cells underwent LOH for a portion of chromosome 13q which
included the RB1 gene locus.

C.

The remaining RB1 allele contained the mutation and the lost RB1 allele was normal and
served as the second hit consistent with Knudson’s two-hit hypothesis. In fact, LOH is the
most common mechanism for the second hit in retinoblastoma. If LOH is not found, then a
point mutation of the RB1 allele is the most likely cause of the second hit.

D.

The mechanisms by which LOH occurs include: deletions in chromosome 13q, mitotic
nondisjunction resulting in the loss of one chromosome 13, and mitotic recombination.

E.

LOH has been observed in a number of other cancers besides retinoblastoma, which
include: prostate, bladder, lung, neurofibromatosis type1, familial adenomatous polyposis
coli, Wilms tumor, von Hippel-Lindau, breast, and ovarian cancers.

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RAS

RAS

(RAS oncoprotein)

RAS
oncoprotein

FIGURE 16-3. Diagram of RAS proto-oncogene and oncogene action.

The  RAS proto-oncogene encodes a normal G-

protein with GTPase activity. The G protein is attached to the cytoplasmic face of the cell membrane by a lipid called far-
nesyl isoprenoid. When a hormone binds to its receptor, the G protein is activated. The activated G protein binds GTP, which
stimulates the cell cycle. After a brief period, the activated G protein splits GTP into GDP and phosphate such that the
stimulation of the cell cycle is terminated. If the RAS proto-oncogene undergoes a mutation, it forms the RAS oncogene.
The RAS oncogene encodes an abnormal G protein (RAS oncoprotein) where a glycine is changed to a valine at position
12. The RAS oncoprotein binds GTP, which stimulates the cell cycle. However, the RAS oncoprotein cannot split GTP into
GDP and phosphate so that the stimulation of the cell cycle is never terminated.

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Suppression of cell cycle

at G1 checkpoint

No suppression of cell cycle

at G1 checkpoint

Target

gene

E2F

RB

Target

gene

E2F

RB

RB

Tumor suppressor

gene

FIGURE 16-4. Diagram of RB1 tumor-suppressor action.

The  RB1 tumor-suppressor gene is located on chromosome

13q14.1 and encodes for normal RB protein that will bind to  E2F (a gene regulatory protein)  such that there will be no
expression of target genes whose gene products stimulate the cell cycle. Therefore, there is suppression of the cell cycle
at the G1 checkpoint. A mutation of the RB1 tumor-suppressor gene will encode an abnormal RB protein that cannot bind
E2F (a gene regulatory protein) such that there will be expression of target genes whose gene products stimulate the cell
cycle. Therefore, there is no suppression of the cell cycle at the G1 checkpoint. This leads to the formation of a retinoblas-
toma 

tumor. There are two types of retinoblastomas. In hereditary retinoblastoma, the individual inherits one mutant copy

of the RB1 gene from his parents (an inherited germline mutation). A somatic mutation of the second copy of the RB1 gene
may occur later in life within many cells of the retina leading to multiple tumors in both eyes. In nonhereditary retinoblas-
toma, 

the individual does not inherit a mutant copy of the RB1 gene from his parents. Instead, two subsequent somatic

mutations of both copies of the RB1 gene may occur within one cell of the retina leading to one tumor in one eye. This has
become known as Knudson’s two-hit hypothesis and serves as a model for cancers involving tumor-suppressor genes. 

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