Surg Today (2013) 43:339340

DOI 10.1007/s00595-012-0294-6

SHORT COMMUNICATION

A CRP genetic polymorphism associated with the tumoral

expression of CRP in esophageal cancer
Satoru Motoyama Toshinobu Nakatsu
Masatomo Miura Yudai Hinai
Yoshihiro Minamiya Jun-ichi Ogawa

Received: 14 October 2011 / Accepted: 25 April 2012 / Published online: 22 August 2012
Springer 2012

Abstract C-reactive protein (CRP) produced locally

within esophageal cancer is associated with the prognosis
and the rate of recurrence. CRP genetic polymorphisms
reportedly affect serum CRP concentrations; however,
there are no reports of an association between genetic
polymorphisms and tumoral CRP expression. This study
enrolled 73 Japanese patients classified with Stage IIAIV
thoracic esophageal squamous cell cancer, and also
investigated their CRP genetic polymorphisms using DNA
extracted from their peripheral blood. The study then
assessed the association between CRP genetic polymorphisms and tumoral CRP expression. The results revealed a
significant association between the CRP 1846C[T genetic
polymorphism and tumoral CRP expression. This finding
suggests that tumoral CRP production controlled by CRP
genetics significantly influences tumor behavior.
Keywords C-reactive protein  Polymorphism 
Esophageal cancer

C-reactive protein (CRP) is one of the acute-phase proteins

that are mainly produced by hepatocytes in response to
acute and chronic inflammation [1]. However, there are
also reports that both esophageal and renal cancers produce
CRP locally within the tumor, and that its expression is
stimulated by tissue inflammation caused by tumor growth,

S. Motoyama (&)  T. Nakatsu  Y. Minamiya  J. Ogawa

Department of Surgery, Akita University Graduate School
of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
e-mail: motoyama@doc.med.akita-u.ac.jp
M. Miura  Y. Hinai
Department of Pharmacy, Kita University Hospital, Akita, Japan

or is indicative of an immune response to tumor antigens,

though no details are yet available [2, 3]. Tumoral CRP
expression is an independent factor associated with both a
poor prognosis and cancer recurrence in cases of thoracic
esophageal squamous cell cancer [4]. Although CRP
genetic polymorphisms reportedly affect serum CRP concentrations in individual patients, there have been no
reports of an association between polymorphisms in any
inflammation-related gene, including CRP, and the genes
tumoral expression [5, 6]. This study, therefore, investigated whether CRP genetic polymorphism is associated
with the tumoral expression of CRP.
This study was approved by the Ethics Committee of
Akita University Graduate School of Medicine (No. 600),
and all patients provided their informed consent and signed
a human subject institutional review board consent form.
The study enrolled 73 Japanese patients that were classified
as having Stage IIAIV thoracic esophageal squamous cell
cancer (TNM classification of malignant tumors, 6th edition), and who underwent curative (R0) esophagectomy
without preoperative chemotherapy or radiotherapy
between 2003 and 2008. The study investigated the CRP
1846C[T (rs1205), -717C[T (rs2794521), 1059G[C
(rs1800947) and 1444C[T (rs1130864) genetic polymorphisms using DNA extracted from peripheral blood.
Genotyping was done using the polymerase chain reaction
restriction fragment length polymorphism method.
Tumoral CRP expression was investigated using immunohistochemical techniques with resected specimens, and
tumoral CRP expression was assessed based on the intensity and area of CRP staining. Details of these methods
have been published elsewhere [4]. Those findings were
used to evaluate the association between CRP genetic
polymorphisms, tumoral CRP expression and serum CRP
levels.

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Surg Today (2013) 43:339340

Table 1 Relationship between

CRP genotypes and serum and
tumoral CRP levels

Serum CRP
Value (mg/L)

Tumoral CRP
p value

Positive (n = 43)

Negative (n = 30)

p value

CRP 1846C[T (rs1205)

C/C (n = 9)

4.1 4.2

C/T (n = 21)

4.7 9.2

12

0
9

T/T (n = 43)

4.7 6.6

0.9725

22

21

C/C (n = 9)

4.1 4.2

C/T ? T/T (n = 64)

4.7 7.5

0.4965

34

30

0.0050*
0.0013*

CRP -717C[T (rs2794521)a

C/C (n = 1)

3.1

C/T (n = 14)

2.6 3.8

T/T (n = 56)

5.3 7.8

11

0.4375

29

27

0.6354

38

29

38

29

0.0999

CRP 1059G[C (rs1800947)

G/C (n = 4)
1.9 1.6
G/G (n = 67)
CRP C-reactive protein
* Significant difference
a

Two patients were not

investigated

4.9 7.4

C/C (n = 67)

5.0 7.4

C/T (n = 4)

0.9 0.8

The patients included 58 males and 15 females with an

average age of 64 18 years. The depths of the tumors
were T1 in 13 patients (18 %), T2 in 12 (16 %), T3 in 47
(64 %) and T4 in 1 (1 %). Fifty-two (71 %) patients had
regional lymph node involvement, and 26 (36 %) had
distant metastasis.
The genotype frequencies of CRP 1846C[T (rs1205),
-717C[T (rs2794521), 1059G[C (rs1800947) and
1444C[T (rs1130864) are shown in Table 1. The tumors
of 43 patients (59 %) were positive for local CRP
expression, while those of the remaining 30 patients (41 %)
were negative. There was a significant association between
the CRP 1846 C/T genotype and tumoral CRP expression.
The CRP gene is located on chromosome 1q21-q23.
SNP rs1205, encoding the CRP 1846C[T genetic polymorphism in the 30 untranslated region, is associated with
changes in serum CRP levels; nonetheless, the preoperative
serum CRP concentrations did not substantially differ
among the CRP 1846 C/T genotypes in this series [5, 6].
An important limitation regarding the level of preoperative
serum CRP is that they are single measurements in time
and are easily influenced by age, smoking, and the presence
of any underlying inflammation. On the other hand, the
CRP 1846C[T genetic polymorphism was associated with
local production of CRP within tumors. CRP genetic
polymorphisms are key determinants of ones lifetime
exposure to CRP and, in cancer patients, may continuously
affect CRP production not only in the liver, but also in the
tumor itself. Tumoral CRP synthesis is too low to influence
the serum CRP levels, but it is comparatively stable and
may have a more important effect on the prognosis or

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0.4591

CRP 1444C[T (rs1130864)a

0.1623

0.4591

recurrence than serum CRP. The tumoral CRP levels

determined by CRP gene expression are a personalized
factor, and are therefore a potentially useful indicator that
could enable more personalized cancer treatment in the
future.
Conflict of interest Satoru Motoyama and other co-authors have no
conflicts of interest to declare.

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