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180
Board Review Series Genetics
TP53
tumor suppressor
gene
Expression of target genes whose
gene products suppress cell cycle
Suppression of cell cycle at G1 checkpoint
No expression of targe genes whose
gene products suppress cell cycle
No suppression of cell cycle
at the G1 checkpoint
Tumor
FIGURE 16-5. Diagram of TP53 tumor-suppressor action.
The TP53 tumor-suppressor gene is located on chromosome
17p13 and encodes for normal p53 protein (a zinc finger gene regulatory protein) that will cause the expression of target
genes whose gene products suppress the cell cycle at G1 by inhibiting Cdk-cyclin D and Cdk-cyclin E. Therefore, there is
suppression of the cell cycle at the G1 checkpoint. A mutation of TP53 tumor-suppressor gene will encode an abnormal
p53 protein
that will cause no expression of target genes whose gene products suppress the cell cycle. Therefore, there
is no suppression of the cell cycle at the G1 checkpoint. The TP53 tumor-suppressor gene is the most common target for
mutation in human cancers. The TP53 tumor-suppressor gene plays a role in Li-Fraumeni Syndrome.
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Chapter 16
Genetics of Cancer
181
C
D
B
A
F
E
FIGURE 16-6. Cancer genetics. (A, B) Retinoblastoma (A)
Photograph shows a white pupil (leukokoria; cat’s eye) in the left
eye. (B) Photograph of a surgical specimen shows the eye is almost completely filled a cream-colored intraocular
retinoblastoma. (C) Neurofibromatosis type I. Photograph shows a woman with generalized neurofibromas on the face
and arms. (D) Breast cancer. Mammogram shows a malignant mass that has the following characteristics: shape is irreg-
ular with many lobulations, margins are irregular or spiculated, density is medium-high, breast architecture may be dis-
torted, and calcifications (not shows) are small, irregular, variable, and found within ducts (called ductal casts). (E,F)
Familial adenomatous polyposis. (E)
Light micrograph of 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 mem-
brane intact. (F) Photograph shows the colon, which contains thousands of adenomatous polyps.
VIII. PHOTOGRAPHS OF SELECTED CANCERS (FIGURE 16-6)
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182
Board Review Series Genetics
t a b l e
16-1
A List of Proto-Oncogenes
Protein Encoded by
Cancer Associated With Mutations of the
Class
Proto-oncogene
Gene
Proto-oncogene
Growth factors
Platelet-derived growth
PDGFB
Astrocytoma, osteosarcoma
factor (PDGF)
Fibroblast growth factor
FGF4
Stomach carcinoma
Receptors
Epidermal growth factor
EGFR
Squamous cell carcinoma of lung;
receptor (EGFR)
breast, ovarian, and stomach cancers
Receptor tyrosine kinase
RET
Multiple endocrine adenomatosis 2
Receptor tyrosine kinase
MET
Hereditary papillary renal carcinoma,
hepatocellular carcinoma
Receptor tyrosine kinase
KIT
Gastrointestinal stromal tumors
Receptor tyrosine kinase
ERBB2
Neuroblastoma, breast cancer
Signal transducers
Tyrosine kinase
ABL/BCR
CML t(9;22)(q34;q11)*
Serine/threonine kinase
BRAF
Melanoma, colorectal cancer
G-protein
KRAS
Lung, colon, and pancreas cancers
Transcription factors
Leucine zipper protein
FOS
Finkel-Biskes-Jinkins osteosarcoma
Helix-loop-helix protein
N-MYC
Neuroblastoma, lung carcinoma
Helix-loop-helix protein
MYC
Burkitt’s lymphoma t(8;14)(q24;q32)
Retinoic acid receptor
PML/RAR
APL t(15;17)(q22;q12)
(zinc finger protein)
Transcription factor
FUS/ERG
AML t(16;21)(p11;q22)
Transcription factor
PBX/TCF3
Pre-B cell ALL t(1;19)(q21;p13.3)
Transcription factor
FOX04/MLL
ALL t(X;11)(q13;q23)
Transcription factor
AFF1/MLL
ALL t(4;11)(q21;q23)
Transcription factor
MLLT3/MLL
ALL t(9;11)(q21;q23)
Transcription factor
MLL/MLLT1
ALL t(11;19)(q23;p13)
Transcription factor
FLI1/EWSR1
Ewing Sarcoma t(11;22)(q24;q12)
PDGFB, platelet-derived growth factor beta gene; FGF4, fibroblast growth factor 4 gene; EGFR, epidermal growth factor receptor gene; RET, rearranged
during transfection gene; MET, met proto-oncogene (hepatocyte growth factor receptor); KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene
homolog; ERBB2, v-erb-b2 erythroblastic leukemia viral oncogene homolog 2; ABL/BCR, Abelson murine leukemia/Breakpoint cluster region oncogene;
BRAF, v-raf murine sarcoma viral oncogene homolog B1; KRAS, Kirsten rat sarcoma 2 viral oncogene homolog; FOS, Finkel-Binkes-Jinkins osteosar-
coma; N-MYC, neuroblastoma v-myc myelocytomatosis viral oncogene homolog; MYC, v-myc myelocytomatosis viral oncogene homolog; PML/RAR
,
promyelocytic leukemia/ retinoic acid receptor alpha; FUS/ERG, fusion (involved in t(12;16) in malignant liposarcoma)/ v-ets erythroblastosis virus E26
oncogene homolog; PBX/TCF3, pre-B-cell leukemia homeobox/ transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47);
FOX04/MLL, forkhead box O4/myeloid/lymphoid or mixed-lineage leukemia; AFF1/MLL, AF4/FMR2 family member 1/myeloid/lymphoid or mixed-lineage
leukemia, MLLT3/MLL, myeloid/lymphoid or mixed-lineage leukemia translocated to 3/myeloid/lymphoid or mixed-lineage leukemia; MLL/MLLT1,
myeloid/lymphoid or mixed-lineage leukemia/myeloid/lymphoid or mixed-lineage leukemia translocated to 1; FLI1/EWSR1, Friend leukemia virus inte-
gration 1/Ewing sarcoma breakpoint region 1.
*ALL, acute lymphoblastoid leukemia; CML, chronic myeloid leukemia; APL, acute promyelocytic leukemia; AML, acute myelogenous leukemia.
t a b l e
16-2
A List of Tumor-Suppressor Genes
Protein Encoded by
Cancer Associated With Mutations of the
Class
Tumor-Suppressor Gene
Gene
Tumor-Suppressor Gene
Gatekeeper
Retinoblastoma associated
RB1
Retinoblastoma, carcinomas of the breast,
protein p110
RB
prostate, bladder, and lung
Tumor protein 53
TP53
Li-Fraumeni syndrome; most human cancers
Neurofibromin protein
NF1
Neurofibromatosis type 1, Schwannoma
Adenomatous polyposis coli
APC
Familial adenomatous polyposis coli,
protein
carcinomas of the colon
Wilms tumor protein 2
WT2
Wilms tumor (most common renal
malignancy of childhood)
Von Hippel-Lindau disease
VHL
Von Hippel-Lindau disease, retinal and
tumor suppressor protein
cerebellar hemangioblastomas
Caretaker
Breast cancer type 1 susceptibility
BRCA1
Breast and ovarian cancer
protein
Breast cancer type 2 susceptibility
BRCA2
Breast cancer
protein
DNA mismatch repair protein MLH1
MLH1
Hereditary nonpolyposis colon cancer*
DNA mismatch repair protein MSH2
MSH2
Hereditary nonpolyposis colon cancer*
APC, familial adenomatous polyposis coli; VHL, von Hippel-Lindau disease; WT, Wilms tumor; NF-1, neurofibromatosis; BRCA, breast cancer; RB,
retinoblastoma; TP53, tumor protein; MLH1, mut L homolog 1; MSH2, mut S homolog 2.
*See Chapter 11-II-G-5.
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1.
In some cases of retinoblastoma, tumors
are often bilateral, their development occurs
soon after birth, and other cancers, espe-
cially sarcomas, may appear later in life. In
other cases, retinoblastoma displays a later
age of onset and the tumors are unilateral
with little increased risk of further develop-
ment of cancer. What is the most likely
explanation for the two different disease
courses?
(A)
There is a large environmental compo-
nent in the bilateral cases.
(B)
In the bilateral cases, the retinoblastoma
proto-oncogene (Rb) is activated by a
chromosome translocation.
(C)
In the bilateral cases, there is already an
inherited deletion of one of the Rb genes,
and a second deletion or mutation
occurs bilaterally.
(D)
The unilateral cases are caused by the
inheritance of a mutated Rb gene.
2.
In familial polyposis coli, a deletion of the
APC gene predisposes carriers to colon can-
cer. However, the cancer will not develop
without the loss of the remaining APC gene.
Which of the following best describes the
APC gene?
(A)
proto-oncogene
(B)
tumor suppresser gene
(C)
mitochondrial gene
(D)
X-linked gene
3.
In which of the following is a loss of func-
tion mutation oncogenic when it occurs in
both alleles?
(A)
proto-oncogene
(B)
oncogene
(C)
tumor suppressor gene
(D)
growth factor gene
4.
Which one of the following is caused by a
fusion or chimeric gene created by a chro-
mosome rearrangement?
(A)
chronic myeloid leukemia
(B)
retinoblastoma
(C)
neurofibromatosis type I
(D)
Burkitt lymphoma
5.
Which of the following describes the
mode of inheritance of many hereditary can-
cers?
(A)
autosomal dominant
(B)
autosomal recessive
(C)
X-linked dominant
(D)
X-linked recessive
6.
Which of the following has been found to
be the most commonly mutated gene in
human cancers, most likely due to its “gate-
keeper” function?
(A)
the MYC proto-oncogene
(B)
the IGH gene
(C)
the CML fusion gene
(D)
TP53 tumor suppressor gene
7.
Which of the following is a likely mecha-
nism of proto-oncogene transformation to
an oncogene?
(A)
loss of heterozygosity
(B)
loss of function mutation
(C)
chromosome translocation
(D)
chromosome deletion
8.
Which one of the following is hereditary
cancer that is caused by a series of changes
involving both tumor suppressor genes and
proto-oncogenes?
(A)
Li-Fraumeni syndrome
(B)
von Recklinghausen disease
(C)
familial adenomatous polyposis
(D)
hereditary retinoblastoma
9.
Which one of the following is the most
likely diagnosis for a 35-year-old female
patient with osteosarcoma whose mother
was diagnosed with breast cancer at age 30
and who has a brother diagnosed with
leukemia at age 22?
(A)
Li-Fraumeni syndrome
(B)
BRCA1 and BRCA2 hereditary breast
cancer
(C)
familial adenomatous polyposis
(D)
neurofibromatosis type 1
183
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184
1. The answer is (C).
The retinoblastoma gene is a tumor suppressor gene so both alleles of the
gene must be deleted or mutated for oncogenesis to occur. Because there is already an
inherited deletion or mutation present in the case of hereditary retinoblastoma, a deletion
or mutation in the other allele, bilaterally, would lead to the development of bilateral
tumors. Development of retinoblastoma by a series of spontaneous deletions or mutations
is less likely to happen and most of the time causes only unilateral tumor development.
2. The answer is (B).
In tumor suppressor genes, both alleles of the gene must be deleted or
mutated for the tumor to occur.
3. The answer is (C).
In tumor suppressor genes, loss-of-function mutations are oncogenic
when they occur in both alleles.
4. The answer is (A).
In chronic myeloid leukemia (CML), a balanced reciprocal translocation
involving the long arms of chromosomes 9 and 22 juxtaposes the ABL and BCR proto-onco-
genes, creating a fusion or chimeric gene.
5. The answer is (A).
In most hereditary cancers, the predisposition to the disease is inherited
in an autosomal dominant fashion. However, because most hereditary cancers are caused
by deletions or mutations in tumor suppressor genes, both alleles must be mutated in order
for a malignancy to occur. In this respect, the majority of hereditary cancers arise through a
recessive mechanism.
6. The answer is (D).
The TP53 tumor suppressor gene, often called the “guardian of the
genome” has been found to be mutated in many human cancers. Most tumor suppressor
genes have “gate-keeper” or “caretaker” functions.
7. The answer is (C).
Proto-oncogenes are often activated by chromosome translocations,
which juxtapose them next to other proto-oncogenes or regulatory elements as occurs with
the 9:22 translocation that causes chronic myeloid leukemia (CML).
8. The answer is (C).
The tumor suppressor genes APC, DCC, and TP53 and the proto-onco-
gene RAS are all involved in the progression of colorectal cancer from normal epithelium to
a carcinoma.
9. The answer is (A).
Li-Fraumeni syndrome is suspected when there are sarcomas in a
proband who is less than 45 years of age and there are any other kinds of cancers in first or
second-degree relatives who are less than 45 years of age.
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