(CANCER RESEARCH 53. 957-%l.
March I. 1993]
Advances in Brief
T\ircot's Syndrome of Glioma and Polyposis Occurs in the Absence of Germ Line
Mutations of Exons 5 to 9 of the p53 Gene1
Tetsuro Kikuchi, Sandra A. Rempel, Hans-Peter Rutz, Nicolas de Tribolet, Lois Mulligan, Webster K. Cavenee,
Serge Jothy, Lam Leduy, and Erwin G. Van Meir2
ÎMboratoireîle
Génétique
et Biologie des Tumeurs, Service de Neurochirurgie IT. K.. N. d. T., E. C. V M.I, and Laboratoire de Radiobiologie. Service de Radiothérapie ¡H-P.RJ.
Centre Hospitalier Universitaire Vaudois. rue du Bugnon 5. CH-lOll Lausanne. Switzerland; Ludwig Institute for Cancer Research. San Diego Branch ¡S.R., E. G. V M.,
W. K. C.I. and Department of Medicine and Center for Molecular Genetics, University of California San Diego [W. K. C.¡,La Jolla, California 9209.Ì-0660;Department of
Palhologv. University of Cambridge, Tennis Court Road. Cambridge, United Kingdom l L M. ¡:and Department of Palholog\; McGill University, Montreal, Quebec, H3A 2B4,
Canada ¡L.L. S. ].]
consideration, the occurrence of the two rare diseases together seemed
stochastically unlikely to be due to chance.
Recently, the Li-Fraumeni syndrome of associated breast and soft
tissue tumors has been shown to be often due to the germ line trans
mission of mutations in the tumor suppressor gene, p53 (5, 6). This
gene, which is resident in the chromosome 17p region of the genome,
is the most commonly altered target for mutations in human cancer
(reviewed in Refs. 7 and 8). Particularly interesting with regard to the
phenotype of the Turcot syndrome is the well-established high fre
quency ofp53 alteration in colon carcinomas (9-12) and gliomas (10,
13-18) and it is noteworthy that in the latter these alterations occur
Abstract
The term "Turcot's syndrome" has been used to describe approxima
tive!} 55 patients with an association of colonie polyposis and primary
neuroepithelial tumors of the central nervous system. The p53 tumor
suppressor gene is a possible candidate underlying the syndrome because
(a) mutations in the p53 gene are ubiquitous in human cancer, including
colon carcinoma and gliomas, and (/»somatic or germ line mutations of
the p53 tumor suppressor gene cause the Li-Fraumeni syndrome, which is
characterized by the association of breast and soft tissue tumors. We
determined the DNA sequence of the conserved regions of the p53 gene
(exons 5 to 9) in the tumor tissues and lymphocytes of two patients with
glioma-polyposis and found that mutations did occur as independent tu
mor-specific alterations but did not involve the germ line of these patients,
early in their malignant progression (13, 15).
Here we have tested the hypothesis that constitutional mutation of
the regions of the p53 gene that are commonly altered in sporadic
colon and astrocytic tumors is the underlying etiology of the rare
Turcot's syndrome. We describe DNA sequencing analysis of the p53
suggesting that p53 may play a role in progression but not initiation of the
disease.
Introduction
genes in the normal and tumor tissues of a familial and a sporadic case
of this syndrome. The analyses indicate that p53 mutations in exons 5
to 9 do occur in the tumors of these patients but that significant
mutations in these evolutionarily conserved regions do not occur in
their germ line.
The rare association of colonie polyposis with primary neuroepi
thelial tumors of the central nervous system was described as early as
1949 by Crail (1) and a genetic basis for this association was first
proposed by Turcot in 1959 (2). Since then the term "Turcot's syn
drome" has been used to describe this association but controversy has
continued as to the mode of inheritance of such a trait and whether the
syndrome is a genetic disorder distinct from familial polyposis,
whether it represents a random association between two separate
diseases (colonie polyposis and gliomas), and whether the sporadicsimultaneous occurrence of the diseases results from similar lesions as
the familial form. In an attempt to address this, Lewis et al. (3) divided
the reported cases into 3 types: type I, those with two or more siblings
with multiple colonie polyps and a malignant brain tumor, with neither
the parents or other generations being affected with either; type II,
affected individuals having an autosomal dominant colonie polyposis
syndrome and polyps occurring in several generations; and type III.
isolated nonfamilial cases that could not be classified in the two first
groups. This analysis led to the proposal that Turcot's syndrome was
most likely autosomal dominant and that it should be considered as an
additional phenotypic variant of familial polyposis. In contrast, Itoh
and Ohsato (4) divided the reported cases into 3 groups based on the
number or size of colonie polyps and concluded that Turcot's syn
drome was distinct from familial polyposis. Nonetheless, under either
Received 12/14/92; accepted 1/15/93.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance with
18 U.S.C. Section 1734 solely to indicate this fact.
' Supported by Advanced Researcher Fellowship #823A-030692 (to E. G. V. M.).
Materials and Methods
Patients und Tissue Samples
Lausanne Patient. The clinical history of Caucasian patient G-A. J. has
been described previously (case 4 in Ref. 19: Ref. 20). Briefly he had a family
history of gastrointestinal and brain malignancies and was himself affected by
a glioblastoma in 1979 (Fig. \A). Five years later he developed a Dukes stage
B adenocarcinoma of the cecum measuring 6 cm with no synchronous polyps
(Fig. Iß).Rare foci of invasion were found in the lymphatic vessels but no
venous invasion was present. Another 8 years later, he presented with a Dukes
stage A adenocarcinoma of the rectosigmoid region measuring 6 cm. Three
synchronous polyps were found measuring 0.5 to 1.2 cm; two of them were
tubular adenomas and the third one was a hyperplastic polyp. Both colonie
carcinomas were histologically well differentiated and the 35 mesenteric
lymph nodes that were sampled showed no evidence of metastasis (20). The
patient is still alive with no evidence of recurrence (3 years after subtotal
colectomy) and has never undergone chemotherapy. It had been previously
established that his sister died of a brain tumor, most likely a glioblastoma
(case 3 in Ref. 19) and a new extended family history revealed that several
other members of the family had gastrointestinal malignancies, although only
one of these was of young age (Fig. 2). These features allowed the classifica
tion of patient G-A. J. as a familial case of Turcot's syndrome subclassified as
Lewis type I and Itoh and Ohsato group I (3, 4).
Montreal Patient. Patient G. G. (not previously reported) was a 47-yearold Caucasian male working in a fish plant. He developed seizures 10 years
prior to admission. The patient's parents, ages 70 and 78 years, his three sisters,
Grant 3.595.087 (to N. d. T. ) of the Swiss National Science Foundation. Medical Research
Council of Canada Grant MT-10315 do S. J.). and a "Paolo Baffi" fellowship from the
"Fondazione per la Formazione Oncologica" and the European Institute of Oncology,
one brother, and his daughter are alive and have no clinical evidence of
neurological or abdominal diseases. Two other brothers died by accident.
Patient G. G. presented with a tumor mass in the brain occupying the left
Milan. Italy (to E. G. V. M.).
- To whom requests for reprints should be addressed.
957
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pii
MUTATIONS
IN TURCOTS
SYNDROME
Ci *•
A- *t *Msfi
vi
A*->',-;
'¿¿a
yä^
r^ctw-si--;'
•¿
-..$&>/.;
•¿-•>•
is¡
Fig. 1. H & E-stained formalin-fixed, purat'fin-embedded sections of the glioblastoma (A ) and colon carcinoma of 1981 (B) of the Lausanne patient and the low grade asirocytoma
(C) and colon carcinoma (D) of the Montreal patient. Arrowheads in D, clusters of poorly differentiated ade noe arc inoma ceils invading the lamina propria and the submucosa. A, B.
andD. X -100; C. x -260.
index of 1.9 compared to the diploid peak of the same sample. Furthermore,
there was a high proliferation index with 25% S + G2/M fraction. Postoperatively the neurological condition of the patient deteriorated and he died 3
weeks after the resection of the colonie tumor. Although no autopsy was
performed his death was most likely due to disseminated intravascular coag
ulation. Patient G. G. was recognized as a sporadic case of Turcot's syndrome
0000
and subclassified as Lewis type III and lloh and Ohsato group I (3, 4).
Tissue Sample. DNA from lymphocytes and from paraffin-embedded tis
sue samples of the astrocytoma, glioblastoma, and the non-polyposis colon
(TI,
cancers were extracted by standard methods (21). A primary culture of the
second colon carcinoma of the Lausanne patient was established and could be
maintained for 4 months. It showed slowly growing, well differentiated ade-
Fig. 2. Pedigree of the family of the Lausanne patient. D, O, individuals without
evidence tor malignant disease including their offspring; •¿
glioblastoma ut age 21 years,
colon carcinoma Dukes stage B at age 26 years, colona Dukes stage A and colon polyps
at age 35 years; •¿brain tumor at age 16 years; HI. stomach cancer at age 37 years;
^, rectal cancer at age 75 years; §, intestinal cancer at age 78 years.
nocarcinomatous cells that were also used for DNA extraction. Histologies of
each of the tumors are shown in Fig. I.
Amplification
anil Sequencing of the p5J Locus
Lausanne Patient. One ug of genomic DNA was denatured for 5-8 min at
98°Cand then amplified for 20-30 cycles at 94°Cfor 40 s. 52°Cfor 1 min, and
74°Cfor 2 min with I unit of Thermus ciquiiticus DNA polymerase (Replith-
frontal lobe and extending to the corpus callosum. Surgery was performed, and
a low grade astrocytoma was removed (Fig. 1C). Two months later the patient
was found to have an 8-cm tumor mass in the ascending colon. A right
hemicolectomy was performed demonstrating a poorly differentiated adeno-
erm; Epicentre Technologies, Wl) in 10 msi Tris-HCI, pH 8.3-1.5 HIM
MgCl2-50 mM KC1-0.005% Tween 20-0.005% Nonidet P-40-0.01% gelatin in
the presence of l UMoligonucleotide primer sets p53IN4AL (5'-AGAGGAATTCTTCCTCTTCCTGCAGTAC-3')
and p53IN7BL (5'-TTGAGGATCCCAAGTGGCTCCTGACCTG3'-)
for exons 5, 6. and 7 or p53IN7AL (5'-AGAGGAATTCCCTATCCTGAGTAGTGGT-3')
and p53IN9BL (5'-TTGAGGATCCCAAGACTTAGTACCTGAA-3')
for exons 8 and 9. Three independent
carcinoma (Fig. IO) invading the full thickness of the colonie wall. There was
conspicuous invasion of veins and lymphatic vessels by the tumor. In addition,
examination of the colonie mucosa away from the tumor showed 21 adenomatous polyps including one with focal early invasive carcinoma. Metastasis was
present in all ten mesenteric lymph nodes that were removed. There was no
evidence of liver metastasis and therefore the carcinoma was classified as
Dukes stage C. Flow cytometry performed on a cell suspension prepared from
the fresh colonie specimen showed an aneuploid cell population with a DNA
polymerase
chain reaction-amplified
DNA sequences
were mixed and the
amplified fragment of 1100 base pairs was isolated and cloned into the EcoRii
958
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p53 MUTATIONS
IN TURCOT'S
SYNDROMI-
Lausanne patient:
LC splice defect
LCI 73
T
G
C
5'
Fig. 3. Sequencing data presenting the muta
tions (arrows) found in the different alÃ-elesof the
colonie and brain tumors of the Lausanne (Li and
Montreal (Mi patients. The sequence can he read
from 5' to 3' starting from the top of the lane\.
Lausanne patient: LC, colon adenocarcinoma of
1981 or 1WO. Mutations: LCI73, OTO ('"Val) to
ATG (Mel); LC splice defect, G to T al -I position
of the splice acceptor site of intron 6; LC228. GAC
(""Asp) to GGC (Gly); LC235, AAC (2"Asn) lo
A
=
s
¡
3'
T
G
C
LC228
A
T
G
C
LC235
A
T
G
C
A
AAC
GTG
0
-I
GAG
T
GGC
ATG
{V
0
AGC
Montreal patient:
AGC (Ser). Montreal patient: MC, colon carci
noma; MA. low grade astrocytoma. Polymorphism
in all tissues analy/ed: M splice polymorphism.
G lo A at -4 position of the splice acceptor site of
intron 4. Mutation: MA282. CGG (2K-Argl lo TGG
M splice
polymorphism
G
(Trp).
A
T
C
MA 282
G
A
T
C
-^
CGG
0
TGG
~~~
3'
we mixed the amplification products of three independent analyses,
picked at least six independent clones from each, and determined their
sequence individually whenever possible.
Lausanne Patient. The DNA sequence obtained with DNA from
paraffin-embedded colon adenocarcinomas that occurred in both 1981
(14 clones sequenced) and 1990 (27 clones sequenced) showed the
presence of 3 different alÃ-eles(Fig. 3). One alÃ-ele(7 of 14 and 10 of
27 clones sequenced) had 3 mutations: a GTG (Val) to ATG (Met)
transition at codon 173, an AAC (Asn) to AGC (Ser) transition at
codon 235, and disruption of the splice acceptor site of intron 6 by a
point mutation (AG to AT), suggesting the possible generation of
aberrant p53 transcripts from this alÃ-ele.The second alÃ-ele(2 of 14 and
5 of 27 clones sequenced) had a GAC (Asp) to GGC (Gly) transition
at codon 228. The third alÃ-ele(5 of 14 and 12 of 27 clones sequenced)
was wild type, suggesting either that tumor cells with different com
binations of mutant and wild type alÃ-elescoexisted in the tumor or that
normal tissue was present within the specimens used for DNA se
quencing. Interestingly neither the 3 missense mutations nor the splice
acceptor site mutation have been described previously for colon can
cer (7, 8, 23). The occurrence of the same mutated alÃ-elesin the colon
carcinomas from 1981 and 1990 (operated in two different hospitals,
thus excluding trivial sample mixing) suggests that these tumors had
a common clonal origin.
In order to determine if any of these mutations was present in the
germ line of this patient who had a cancer-prone familial history (Fig.
2), we determined the nucleotide sequence of these regions of the p53
gene in the DNA of his paraffin-embedded glioblastoma (12 clones
sequenced) and his peripheral blood lymphocytes (6 clones se
quenced). Neither these nor any other mutations of the p53 gene were
detected in either tissue (Fig. 4). In addition, to test whether the patient
could be a mosaic with mutations only in the endoderma! layer, we
amplified the DNA for exon 7 from a sample of normal colon epi
thelium and found no mutations (5 clones sequenced). This strongly
I sites of the pBluescript plasmici vector (Stratagene). Individual clones
were sequenced by the dideoxynucleotide method on alkali-denatured double
stranded templates.
Montreal Patient. Genomic DNA (0.5-1 (Jg) was amplified in a volume of
100 (4lcontaining I x PCR' reaction buffer: 50 HIMKC1; 10 ITIMTris-HCI, pH
8.3; 1.5 ITIMMgCU; 0.01% (w/v) gelatin; 200 UMdeoxynucleotide triphosphates; 250-500 ng of 5' and 3' end primers; and 2.5 units of Amplitaq DNA
polymerase (Perkin Elmer-Cetus. Norwalk. CT). Primer pair 5'-GTAGGAATTCTGTCCCAAGCAATGGATGAT-V
and 5'_CATCGAATTCTGGAAACTTTCCACTTGAT-3' amplifies a 2.8-kilobase fragment covering exons 4 to 9
(10). Primer pair 5'-GGAATTCCCAGAATGCCAGAGGC-3'
and 5'-GGAATTCATGTGCTGTGACTGCTTG-3'
amplify 0.5-kilobase-spanning regions
of exons 5 and 6 (9). Primer pair 5'-GGAATTCTGACTGTACCACCATCC-3'
and 5'-GGAATTCTCCATCCAGTGGTTTC-3'
amplify sequences from exons
7 to 9 (9). Finally primer pair 5'-CCCGAATTCTTATCTGTTCACTTGTGTGCCC-3' and 5'-GGAGGGGCCAGACCTAAGAGCA-3'
amplified exon 5 to
exon 6 sequences (a gift from Dr. Bernd Seizinger). Templates were denatured
for 2.5 min at 96°C,followed by 35 cycles of PCR with 1 min at 58°C,4 min
at 70°C.and I min at 95°C.Samples were subjected to a final elongation for
IO min at 72°C.The amplified PCR products were separated in a 1% agarose
gel, isolated using a Geneclean Kit (Bio 101). and ligated into the EcnRl site
of pGEM-3Z (Promega). Alkali-denatured double stranded templates were
sequenced by the Sanger dideoxynucleotide method using Sequenase (United
States Biochemical Corp.) and the T7 and SP6 primers.
Results and Discussion
We focused our attention on exons 4 or 5 to 9 of the p53 gene since
these genomic regions contain the great majority of sporadic p53
mutations found in brain, colon, and other tumor types (7. 8). These
hot spots overlap the highly evolutionarily conserved regions that are
likely involved in p53 function (22). In order to minimize the chances
of our detecting an amplification-generated artifact in the sequence.
' The abbreviation used is: PCR. polymerase chain reaction.
959
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pfj
Codons:
I2SExons'
fLausanne
33
Ì <1
MUTATIONS
331T
187
1173r
ilei
IN TURCOT'S
SYNDROME-:
224
225
\
261
~7
\
261
loi
307
io
patient:3Montreal
(Val to Met)
splice defect
Ser)V228
235 (Asn to
fly)splice
(Asp to
patient:Colon
polymorphism282
1carcinoma126
(Arg to Trp)
Mwr-X
Fig. 4. Summary of the p53 exons sequenced and mutations found in the p53 genes of both patients. AlÃ-elesare represented hy tltuhetl and plain line*. Plain line.\, regions sequenced
for eaeh patient; .v, position of detected sequence alterations the effects of which are indicated in parentheses, /-.i. individual alÃ-eles.
suggests that germ line mutations in exons 5 to 9 of the p53 gene do
not underly the Turcot's syndrome in this patient.
In conclusion, the results obtained with tissues from these two
patients [who fulfill the criteria of Turcot's syndrome according to its
Montreal Patient. The histopathologieal ehanges found in the coIonic tumor of patient G. G. were remarkable for tumor dedifferentiation and widespread vascular invasion, consistent with the aggressive
biological and clinical behavior which terminated in rapid death. In
order to determine whether small deletions or point mutations of the
p53 gene were present, we sequenced the majority of exon 4 to exon
9 sequences in PCR-derived clones from normal colon, astrocytoma.
and colon adenocarcinoma (Fig. 4). as well as exons 5 to 6 of an
adenomatous colon polyp (data not shown). In each tissue type (16
clones sequenced totally), a G to A change was observed at position
-4 at the intron 4 to exon 5 boundary (Fig. 3). This change occupies
the n position of the 3' acceptor splice site consensus sequence y,4 ts
original description (2)] strongly preclude the p53 gene as the under
lying factor in germ line predisposition to the syndrome (this analysis
could not rule out that the patients were mosaics of normal and mutant
alÃ-elesin a proportion too low to be detected). However, diverse
mutations were shown to occur in the tumor specimens of these
patients suggesting that p53 plays a role in the progression of the
disease. It should be noted that although the number of cases we have
been able to examine is small, only about 55 total cases have been
reported in (he literature. It may yet be that Turcot's syndrome is
y4 nCAG/g (24) where y = C or T (pyrimidine). t = thymidine, and
n represents any nucleotide. Position —¿I
(n) is considered to be a
functionally irrelevant position and its alteration would not be ex
pected to lead to a splicing alteration. We surmise that this base
substitution represents a DNA sequence polymorphism that is neutral
in effect. Precedent for a functionally neutral constitutional polymor
phism in the p53 gene has been reported in a breast cancer family (25).
A point mutation at codon 282 (CGG to TOG) was found in 1 of 4
clones for the astrocytoma which results in an 2S2Arg to Trp transition
(Fig. 3); a double mutation at this amino acid has previously been
reported in a non-small cell lung carcinoma (23). This mutation was
not observed in the normal colon (7 clones sequenced) or the colon
adenocarcinoma (3 clones sequenced). where all clones were found to
be wild type in sequence in the corresponding region (Fig. 4).
Although PCR amplification of the p53 gene in the paraffin-em
bedded tissues of this patient yielded only a limited number of clones
for each tissue type, the data suggest that a mutation may exist in the
p53 gene in the astrocytoma and that it is not inherited. In order to
determine whether mutations exist in the colon adenocarcinoma out
side the sequenced regions or may have been undetected by sequenc
ing due to the limited number of clones available, we analyzed p53
expression by immunohistochemistry
using monoclonal antibody
PAM801. Frozen tissue was unavailable for the brain tumor. Immunostaining of the frozen tissue sections prepared from the colonie tumor
of patient G. G. showed strong nuclear staining in approximately
one-half of the tumor cell nuclei (data not shown). The high expres
sion indicated by staining with this antibody suggests that a mutant
p53 was likely expressed in this tissue and that it may have played a
role in the progression of this tumor.
genetically heterogeneous with some cases arising by a germ line p53
mutation and others, like those we have examined here, by mutations
in other loci. One potential candidate is the adenomatous polyposis
coli gene which is the germ line cause of polyposis coli (26-28): its
sequence remains to be examined in Turcot's syndrome patients.
Acknowledgments
We would like to acknowledge the following persons who provided their
help for the study of patient G-A. J. The surgical specimens were provided hy
Drs. J. Costa. J-P. Derua/. R. Janzer. and M. Salmerón. We would also like to
thank Dr. P. Shaw tor the design and synthesis of the oligonucleotides and R.
Jauteerally who provided excellent technical assistance. The following persons
helped us with the study of patient G. G.: Drs. R. Leblanc. Y. Rohitaille. P.
Belliveau. R.P. Michel and L. Oligny gave us access to the surgical specimens:
and Dr. F. Halwani tested the colonie tumor for ploidy and proliferative
activity. We would also like to thank Dr. V. Cha/in for reading the manuscript.
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9ft I
Downloaded from cancerres.aacrjournals.org on July 31, 2017. © 1993 American Association for Cancer Research.
Turcot's Syndrome of Glioma and Polyposis Occurs in the
Absence of Germ Line Mutations of Exons 5 to 9 of the p53
Gene
Tetsuro Kikuchi, Sandra A. Rempel, Hans-Peter Rutz, et al.
Cancer Res 1993;53:957-961.
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