Download p53 Point Mutation and Survival in Colorectal

[CANCER RESEARCH55, 5217-5221, November 15, 1995]
Advances in Brief
p53 Point Mutation
and Survival
in Colorectal Cancer Patients'
Hak-Su Goh, Jocelyn Yao, and Duncan R Smith2
Colorectal Cancer Research Laboratory, Department of Colorectal Surgery, Singapore General Hospital, Outram Road, Singapore 0316, Republic of Singapore
Abstract
We have examined the relationship between point mutation of the p53
tumor
suppressor
gene
and survival
in colorectal
cancer
patients
We
found that patients with tumors harboring mutated p53 genes showed a
significantly poorer prognosis than did those patients with genes without
point mutations, and, moreover, patient response to postoperative thera
pies depended significantly on mutation status in both adjuvant and
palliative treatment cohorts. However, not all point mutations were the
same functionally; point mutations within the conserved domains of the
p53 tumor suppressor gene were inherently more aggressive than tumors
with point mutations outside ofthese domains, and mutations ofcodon 175
were
particularly
aggressive.
These
results
suggest
that knowledge
of a
patient's p53 status, both with respect to the presence of point mutations
and to the specific nature of the lesion, may be required to accurately
predict both the course of the disease and the response of the disease to
postoperative
therapeutic
interventions,
especially
those
on the induction of apoptosis in the neoplastic cell.
therapies
based
Introduction
The prediction of the biological behavior of a tumor is of primary
importance in the management of colorectal cancer patients. Many
staging systems have been introduced in an attempt to provide accu
rate prognostication, but, in general, these provide accurate informa
tion about cohorts of patients rather than individuals. Staging systems
are often used as a basis for deciding
patient
management,
especially
with regard to additional therapies such as radiotherapy, chemother
apy, or combinations thereof (1).
The mainstay of treatment for colorectal carcinoma is surgical
resection (1). The intent of surgical intervention may be either cura
tive or palliative, depending on the spread of the disease and the tumor
clearance
during
surgery.
Selected
patients
from
both curative
model system
that tumors
with functional
to treatment
became
unresponsive
whether
and
by
grants
from
the
Shaw
Foundation,
of the acquisi
the
Lee
requests
for reprints
should
or metachronous,
in the colon
were excluded.
consisted
of single
of the colorectum,
Patients
at the time of surgery
with dysplastic
were also excluded.
Dukes'
original
staging
modification
of
(13).
DNA Sequence Analysis. Templateswere analyzedby directsequencing
of cDNA-PCR
the dsCycle
products
Sequencing
corresponding
system
to exons 4—9of the p53 gene by using
(GIBCO-BRL,
Gaithersburg,
MD). Sequenc
ing was carried out by using a pane] of p53 cDNA-specific primers (sequences
available on request). Point mutations were confirmed
analysis
by DNA sequence
on both DNA strands.
Data Analysis and Statistics. Patient follow-up was determined to be the
time between surgery and the last departmental contact (scheduled follow-up,
or telephone
package
contact)
(interquartile
(SPSS,
range:
or patient
death. Median
14, 34 months).
patient
Survival
follow up
data was ana
plots (14) and the log rank test by using the SPSS
Inc., Chicago,
IL). Models
were tested by using Cox
regression analysis, with entry into the model dependent on P < 0.05. Data
Foundation,
and the Singapore Totalisator Board.
2 To whom
elsewhere
lyzed by Kaplan-Meier
18 U.S.C. Section 1734 solely to indicate this fact.
supported
The patient cohort is essentially as described pre
Tumors were staged Dukes' A—Daccording to Tumbull's
computer
charges. This article must therefore be hereby marked advertisement in accordance with
was
synchronous
adenomas
mail response,
Received 8/9/95; accepted 10/2/95.
The costs of publication of this article were defrayed in part by the payment of page
work
and Tumors.
was 24 months
tion of p53 point mutations (5). Given that the p.5.3tumor suppressor
gene is one of the most commonly mutated genes in a wide variety of
tumors (6—8)these results are potentially of great clinical importance.
I This
and Methods
Patients
p.53 genes respond
because
although the basis of this is not readily apparent (1 1).
Nearly 98% of point mutations of the p53 gene detected to date fall
in an approximately 600-nucleotide-long stretch of the p53 message,
corresponding roughly to exons 4—9of the p53 gene (6, 7). The p53
protein shows a high degree of evolutionary conservation, but, in
particular, five domains (domains I—V)show almost complete con
servation from trout to man (12). Four of these domains (domains
II—V)occur within the 200-amino acid stretch encoded by the region
in which almost all point mutations occur (6, 7).
We have shown previously that point mutation of the p53 gene is
associated with disease progression, and in particular, with lymphatic
dissemination (9); in this study we wished to examine the influence of
PS3 point mutation in determining both the course of the disease and
how such lesions influence the response to postoperative therapies.
viously (9). All tumors selected for DNA sequencing
adenocarcinomas,
and patients with multiple carcinomas
to radiation and chemotherapeutic agents, whereas those tumors with
out functional p53 genes do not. Moreover, tumors that were initially
responsive
(8). Not all mutantproteinshavethe sameoncogenicpotential,
Materials
palliative cohorts may be judged to be suitable for additional postop
erative treatment in an attempt to either prevent the growth of sec
ondary cancers or to reduce the tumor burden of the patient. Such
postoperative therapies may consist of either radiotherapy, chemo
therapy, or a combination of both.
Currently, such postoperative therapies are believed to act through
the induction of apoptosis, or programmed cell death, in the neoplastic
cells (2), and several studies suggest that induction of apoptosis is
dependent on the presence of functional copies of the p.53 tumor
suppressor gene (2—4).More recently, Lowe et a!. (5) have shown in
a mouse
Point mutation of the p53 gene occurs in approximately 50% of
colorectal carcinomas (6—8) and has recently been shown to be
associated strongly with lymphatic dissemination (9) and possibly
with a poorer patient prognosis (10). The vast majority of point
mutations detected in p.5.3genes represent missense mutations, which
result in amino acid substitutions in the p53 protein (6—8). Such
mutant proteins have been shown to have an array of altered biolog
ical and biochemical properties, including an extended half-life and
the ability to cooperate with activated ras genes to transform cell lines
be addressed.
were entered
by using the Forward:Wald
method
of entry.
Results
The p53 point mutation status was determined for 192 colorectal
adenocarcinomas by single-stranded conformational polymorphisms,
with the cohort consisting essentially of tumors described previously
(9). Point mutations were detected in 57% (109 of 192) of cases.
Kaplan-Meier survival plots (14) were generated for patients with or
without point-mutated p53 genes (Fig. 1). Log rank analysis of this
5217
Downloaded from cancerres.aacrjournals.org on June 15, 2017. © 1995 American Association for Cancer Research.
@
@,
—@
p53 AND PROGNOSIS
A. Suiv1v@
@tIa@
D. Swvival
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E. Survival fimctlo
B. Suavivalftanctios@
krco..srved aid
@
@
i_
I
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@I
@ir@whcte
@‘s
aiwive
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.,
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TTIM
3
.3
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I
SI
a
a
•
a
a
?0@
F. Survivslñmctions
f@p@ie,@s
where
tr@M is pslllMivsin heeiit
C. Survival
fbnctioai
ofcodon 175
aid allothermsgalons
I
I
I
I
F.—
F.—
Fig. 1. Mutation status and survival. A, Kaplan-Meier survival analysis for 192 patients with respect to p53 mutation status. Deaths due to causes unrelated to colorectal cancer were
treated as censored events. The two curves are significantly different (P = 0.0054 by log rank analysis). , no p53 point mutation detected. —, point mutation detected. B,
Kaplan-Meier plots for 53 patients with characterized mutations of the p53 gene. Patients are analyzed after dividing into two groups based on the presence (—)or absence (
of point mutations in the conserved domains. The two groups are significantly different (P = 0.0201 by log rank analysis). C, Kaplan-Meier survival plot for 53 patients with
characterized point mutations of the p53 gene. Patients are divided into two groups, those with mutations of codon 175 (—) and those with other mutations (
). The two groups
are significantly different (P = 0.0007 by log rank analysis). D, Kaplan-Meier plots for 54 colorectal cancer patients who underwent postsurgical therapies and includes both palliative
and adjuvant therapy patients. Patients are divided into two groups based on the presence (—)or absence (
) of a point mutation in the p53 gene. The two groups are significantly
different (P = 0.0006 by log rank analysis). E, Kaplan-Meier plots for colorectal cancer patients who underwent curative resection and therapy. Patients are divided into two groups
based on the presence (—) or absence (
) of a point mutation in the p53 gene. The two curves are significantly different (P = 0.038 by log rank analysis). F, Kaplan-Meier plots
for colorectal cancer patients who underwent palliative treatment. Patients are divided into two groups based on the presence (—) or absence (
) of a point mutation in the p53
gene. The two curves are significantly different (P = 0.0048 by log rank analysis).
@
plot showed a significant association between point mutation and a in the nature of point mutations, we examined 50% of the mutation
positive tumors from the above cohort to determine the exact nature of
poorer patient prognosis (P = 0.0054). Cox regression analysis was
the point mutation. Hence, 53 templates were subjected to a full DNA
used to determine the contribution of several factors toward patient
sequence analysis. Results are shown in Table 1. The point mutation
survival. Factors available for entry into the model included Dukes'
spectrum determined is representative of the local population (15),
Stage, differentiation, and mutation status, as well as patient age and
which is consistent with, but not identical to, that published on other
sex. Entry into the model was via the Forward:Wald method and
population cohorts (6, 7), and as such probably reflects regional
conditional on P < 0.05. The final model contained the terms for
influences in mutation events (7, 15). Fig. 2 shows an analysis of point
Dukes' Stage (P < 0.0001) and mutation status (P = 0.0310). Overall
mutation distribution with respect to lymph node involvement. We
significance of the model was
= 65.001 (P < 0.0001).
note that point mutations occurring within the highly conserved do
To determine whether there were qualitative differences occurring
5218
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p53 AND PROGNOSIS
Table 1 p53 point mutations characterized in 53 colorectal carcinomas.
Characterization
of 53 carcinomas carrying mutated p53 genes and associated clinicopathological
parameters.
CodonLab
no.Base
changeAmino
acid change'@Stage―LN'Dm
DF'Follow-up@CD@111333CTGtoCCGLeutoProA———45N12781TCCtoCCCSertoProC+——52Y132184AAG
to AGOLys
ArgC+—+{15}YI
35784TGC
1}Y141584TGC
PheC+—+35Y151185CCC
ThrB———10N157242GTC
PheB———22N157672GTC
PheB———32N162684ATC
to
to
to
to
to
StopA---31NI
to AATC
ATSdDm
to
to TyrD+—+{1
to
to
to
to
TACCys
‘Il'CCys
ACCPro
‘Il'CVal
T1'CVal
66138AGC
to AGGC
StopB———53N168194CACtoCGCHistoArgB———32NI
73825GTG
MetC+——{1}Y1751CGC
to ATOVal
to
HisD+++{20}Y17540CGC
to CACMg
to
HisC+—+{14}Y17568CGCtoCACArgtoHisC+—+{36}Y175120CGCtoCACArgtoHisD+——{5}Y175149CGC
to CACMg
to
HisD+++{12}Y175246CGC
HisD+——{6}Y1
75731CGC
HisA———29Y175857CGC
to CACMg
to
to
to CACArg
to CACArg
to
HisD+++{5}Y175782CGCtoCTCArgtoLeuC+——25Y1755CGCtoCTCArgtoLeuD++—{5}Y17591COC
to
to CACArg
HisC+—+{24}Y179838CAT
to CACMg
to
LeuC+——25Y179864CAT
to CITHis
to
LeuC+——24Y18112CGC
to CTTHis
to
CysB———59Y197147GTG
to TGCArg
to
GlyC+——46N237190ATG
to 000Val
to
IleC+——51Y237356ATGtoAAGMettoLysA———43Y238630TGT
to ATFMet
to
to TATCys
TyrA———34Y242236TGC
to
to ‘fl'CCys
PheD+++{10}Y245297GGCtoAGCGlytoSerC+——46Y245792GGCtoAGCGlytoSerD+—+19Y248161CGG
to
TrpC+—+{32}Y248199COG
GlnA---50Y248257CGG
GlnC+—+{36}Y248654COG
TrpD++-1Y248852COG
GinD+++{5}Y249332AGO
TipD+++{7}Y257823Cr0
GluA---20Y266840GGA
to TGGMg
to CAGMg
to CAGMg
to TOGArg
to CAGMg
to
to TGGArg
to
to
to
to
to
to
to CAGLeu
to GAAGly
to ATGVal
to TOTMg
to TATCys
to TOOMg
to TOGArg
to TOGArg
GluC+——24N272681GTG
MetD+++29Y273817COT
CysD+—+{23}Y275321TOT
TyrC+—+{12}Y28275COG
TrpC+—+{36}Y282109COG
TrpC+——{36}Y282216COG
TrpC+——47Y282660COG
TrpD-++4Y282765COO
LeuD+++22Y282835COO
TrpB---8Y28285
1COG
TrpC+—+24Y282903COG
to
to
to
to
to
to
to
to
to
to
to TOGArg
to Cr0Arg
to TOGMg
to TOGArg
TrpD+++{2}Y285724CAOtoAAOAsptoLysA———29Y
to TOGArg
a Amino
acid
b Stage,
Dukes'
C LN,
presence
d Dm
ATh,
change,
amino
stage
(+)
presence
of tumor
or absence
(+)
acid
change
in three-letter
code.
according
to Tumbull's
modification
(—) of
or absence
detectable
lymphatic
(—) of detectable
e Dm DF, presence (+) or absence (—)of detectable
to
to
involvement
distant
organ
(13).
at time
metastasis
of
surgery.
at the time
of surgery.
distant organ metastasis at time of surgery or during
subsequent
follow-up.
1Follow-up, patient follow-up in months since surgery. Numbers in brackets indicate patient is deceased.
a CD, point mutation is in (Y) or outside (N) conserved domains.
mains of the p53 gene show a significant association with lymph node
involvement (Table 2; P = 0.001 by Fishers' exact test). Mutations
occurring
outside
of these regions
show a much lower rate of lymph
node involvement [Fig. 2; 22% (2 of 9) compared to 80% (35 of 44)].
There is no association between the presence of point mutations in
the conserved domains and the presence of distant metastasis at the
time of surgery (Table 2). However, when all cases are analyzed
during the follow-up period, there is a strong association between
point mutation in the conserved domains and patients who have or
develop distant organ metastasis (Table 2). Indeed, as yet, none of the
patients with mutations outside of the highly conserved regions has
developed distant metastasis, although the sample population of mu
tants outside of the conserved regions is relatively small (nine pa
tients). In contrast 52% of patients with point mutations in the con
served regions have been diagnosed with metastatic disease
dissemination. Similarly, of the 22 deaths in the mutation-positive
cohort, all have occurred in patients with mutations in the conserved
regions of the p53 gene. Patients with mutations in the conserved
regions of the p53 gene showed a significantly poorer prognosis than
did patients with mutations outside of these regions (Fig. 1; P = 0.02,
as assessed by log rank analysis). In particular, mutations of codon
175 were associated with aggressive cancers. We note that 82% (9 of
11) of patients with mutations in codon 175 had died of causes related
to cancer, in contrast to 3 1% of patients with mutations at other bases
(see Fig. 1; P = 0.0007).
Lesions of the p53 gene have been implicated recently in the
response of tumors to radiation and chemotherapy (5). Therefore, we
selected a new cohort of 54 patients who had undergone postsurgical
5219
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p53 AND PROGNOSIS
@
anim a@
Discussion
+
@
++
@1@
-
ICrYQOSYGFR LcwLH@iA@Ic@
svrmsp4u
Dou@nfl
m@n n@
I 10
120
-
wPcrmvkAM
130
140
ISO
The
160
+
+
+
+
+
+
+
+
-+
+
+
-
+
AIYKQSQHMT
LRVEYLDOftN 1FRNSVVvPY
Do@@inill
170
180
190
200
210
220
+
However,
+
+
+
________________________
++
+
++
EFS'EVGSDCITI*'NYMØJS
S@GGM?@P
@0
230
260
:
sGNIi.GRNs[@
270
EVRVCAL@(_@iii@k
KKG@1*ELP
290
300
Fig. 2. Lymphatic dissemination and p53 point mutation. Partial sequence of the p53
protein (amino acids 101—300)showing the distribution of 53 mutants detected by DNA
sequence analysis (Table 1). +, presence of lymphatic dissemination; —,absence of
lymphatic dissemination. Conserved domains are boxed.
@
@
@
properties
of mutant
p53
has
been
equivalent
observed
(1 1), and
that
not
the data
all
point
generated
mutations
by
DNA
are
sequenc
codon
175
mutants
being
particularly
aggressive.
within
+
+-
210
biochemical
mutations
occurring
within
these
regions.
Moreover,
point
mutations
+
+++
and
ing support this. We find that point mutations occurring within the
evolutionarily conserved domains show a significantly poorer prog
nosis than do those mutations occurring outside these domains. We
further note that lymphatic dissemination, and the occurrence of
subsequent distant organ metastasis are strongly associated with point
ILTIrn..Ebs
;
+
biological
it
functionally
Doi@n IV
230
specific
proteins have been the subject of intense investigation. The observa
tion that nearly 80% of mutations of the p53 gene are point mutations
leading to amino acid substitutions (missense mutations) has lead to
the speculation that such mutants may confer an additional growth
advantage over and above that resulting from the loss of suppressor
function (6). This speculation is apparently supported by experiments
that show a “gain
of function―for p53 mutants (16). These observa
tions would suggest that tumors with p53 point mutations would show
a growth advantage over tumors with no p53 mutation. In patient
terms, a growth advantage of a tumor would correlate to a poorer
patient prognosis, and we show here that patients with p53 point
mutations show a significantly poorer prognosis than do patients who
do not show such mutations.
radiotherapy or chemotherapy (or both). Tumors from these patients
were analyzed for point mutations of the p53 gene by single-stranded
conformational polymorphisms as described elsewhere (9, 15). Point
mutations were detected in 54% (29 of 54) of cases.
Analysis of patient survival with respect to point mutation was then
undertaken by Kaplan-Meier plots (Fig. 1). The two survival curves
are significantly different (P = 0.0006 by log rank analysis). Patients
with point mutations of the p53 gene showed a significantly higher
patient mortality rate than did those patients whose tumors did not
show evidence of point mutations occurring within the p53 gene.
However, this cohort of patients consists of patients who underwent
either palliative or curative resections. The data was therefore re
analyzed with respect to the surgical intent. When only curative
resections were considered, a smaller but still significant difference
was found between patients with and without mutations (Fig. 1).
Again, patients with point mutations of the p.53 gene showed a
significantly poorer prognosis than did patients without detectable
point mutations [number of patients, 37; mutation rate, 51% (19 of
37); P = 0.038 by log rank analysis]. A more substantial difference
was seen in the palliative treatment cases (Fig. 1). The response of
patients to palliative therapy was markedly dependent on the p53
status of the primary colorectal cancer. All of the patients undergoing
palliative postoperative treatment who had point mutations of the p53
gene have died subsequently, in contrast to only one patient who died
from the cohort of patients not showing detectable point mutation
[number of patients, 17; mutation rate, 59% (10 of 17); P = 0.0048,
log rank analysis].
these
regions
clearly
show
differential
aggressiveness,
with
In this report, we have shown three levels of increasing risk for
colorectal cancer patients: (a) patients with point mutations of the p53
gene show a poorer prognosis than do patients without point muta
tions; (b) patients with point mutations in the conserved domains
show a poorer prognosis than do those with mutations outside these
domains; and (c) patients with mutations of codon 175 show the
poorest prognosis of all. Detecting point mutations of the p53 gene is
technically demanding and determining the specific nature of the
lesion by DNA sequencing is even more so. However, work from
other areas has shown that routine screening of colorectal carcinomas
for p53 point mutations may become a prime prerequisite in deter
mining patient management. Recently, Lowe et a!. (5) have shown
that the status of the p53 gene plays an integral role in determining a
tumor's responsiveness to adjuvant therapies. Tumors that have no
PS3 or have mutated p53 evince treatment resistance to both chemo
therapy and radiotherapy, probably by disruption of the cells' apop
totic pathways (5). Moreover, initially sensitive tumors may become
resistant by the selection of cells containing mutated p53 (5). Indeed,
in confirmation of this, in the two experimental cohorts reported here,
the response of patients with point-mutated p53 genes to therapies that
are believed
to act via the induction
of apoptosis
is significantly
Table 2 Conserved domain mutations and disease dissemination.
The distribution of p53 mutations was analyzed by Fishers' exact test in respect to
disease dissemination both at the time of surgery and during patient follow-up.
LN-―
LN+― Dm ATS@c
9
nCD―
P (Fishers')
a
absence
b LN+,
presence
DM ATS+― Dm DF@e
35
32
12
7
2
P = 0.0018
9
0
of
detectable
of detectable
involvement
lymphatic
at time
involvement
23
9
0
P = 0.0033
P = NS'
lymphatic
Dm DF+―
21
of
at time
surgery.
of surgery.
CDm ATh—,
absenceof detectabledistantorganmetastasisat time of surgery.
d Dii.
ATS+,
e Dm
DF—,
presence
absence
of
of detectable
detectable
distant
distant
organ
organ
metastasis
metastasis
at
at time
time
of
of surgery.
surgery
or
during
subsequent follow-up.
1Dm DF+, presence of detectable distant organ metastasis at time of surgery or during
subsequent follow-up.
gCD,mutation
present
inoneoftheconserved
domains.
,, nCD, mutation
S NS,
not
present outside of the conserved
domain.
significant.
5220
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p53 AND PROGNOSIS
poorer (asjudged by patient survival) than it is for patients who do not
show evidence of point-mutated p53 genes in their primary colorectal
adenocarcinomas.
Hence, in colorectal cancer patients, point mutation of the p53
gene plays a pivotal role, in both determining, to some extent, the
biological behavior of colorectal carcinomas, as well as modifying
the effectiveness of postoperative therapies. As such, correcting
defects of the p53 tumor suppressor gene would seem an ideal
target for novel gene-based therapies for the treatment of meta
static colon carcinoma.
Acknowledgments
We are grateful to Chui-Sien Chan for technical assistance and Stephanie
Fook Chong for statistical advice.
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p53 Point Mutation and Survival in Colorectal Cancer Patients
Hak-Su Goh, Jocelyn Yao and Duncan R. Smith
Cancer Res 1995;55:5217-5221.
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