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000479068

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Original Articles
Oncol Res Treat
DOI: 10.1159/000479068
Received: March 11, 2017
Accepted: June 29, 2017
Published online: October 24, 2017
Evidence for an Association of ERCC1 Expression
and Mismatch Repair Status with Overall Survival in
Colorectal Cancer Patients
Pan Li a Zhi-Tao Xiao b Todd A. Braciak a Qing-Jian Ou b Gong Chen b Fuat S. Oduncu a
a
Department of Hematology and Oncology, Medizinische Klinik und Poliklinik IV, Ludwig Maximilians University, Munich, Germany;
of Colorectal Surgery, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center,
Guangzhou, China
bDepartment
Summary
Background: The aim in this study was to determine if an
association of excision repair cross-complementing
group 1 (ERCC1) gene and mismatch repair (MMR) status with overall survival (OS) could be found from our
analysis of a large cohort of Chinese colorectal cancer
patients (CRC). Methods: In total, 2,233 tissue samples
isolated from individual CRC tumors were assessed by
immunohistochemistry for the expression of ERCC1 and
4 MMR genes. Results: The rates of proficient MMR
(pMMR) and ERCC1 expression were 89.6 and 90.7%, respectively. We found that patients with positive ERCC1
expression and deficient (d)MMR status had higher overall survival (OS) than those with either positive ERCC1
and pMMR, negative ERCC1 and dMMR, or negative
ERCC1 expression and pMMR status (OS 79 vs. 69 vs. 66
vs. 61%, hazard ratio (HR) 0.90, 95% confidence interval
(CI) 0.80–1.00; p = 0.043). Despite this finding, we found
no statistical difference in OS between ERCC1-positive
and -negative CRC patients when ERCC1 expression was
considered alone (OS 70 vs. 62%, HR 0.82, 95% CI 0.65–
1.04; p = 0.11). Conclusion: Our results indicate that the
combined examination of ERCC1 expression and dMMR
status can be used to aid OS assessment in CRC patients.
© 2017 S. Karger GmbH, Freiburg
Correspondence can also be addressed to: Dr. Gong Chen, Department of Colorectal Surgery, State Key Laboratory of Oncology
in South China, Sun Yat-sen University Cancer Center, East Dongfeng Road 651,
510060 Guangzhou, China, chengong@sysucc.org.cn
© 2017 S. Karger GmbH, Freiburg
Fax +49 761 4 52 07 14
Information@Karger.com
www.karger.com
Accessible online at:
www.karger.com/ort
Introduction
There are at least 4 pathways of DNA repair that operate on specific types of damaged DNA; these comprise the base excision repair (BER), the nucleotide excision repair (NER), the mismatch
repair (MMR), and the double-strand break repair (DDSBR) pathway [1]. Mismatch repair defects are produced from germline mutations in any one of the MLH1, MSH2, MSH6, or PMS2 genes. It is
estimated that approximately 1 in 3,000 persons within the general
population carry a mutation in at least 1 MMR gene and have a
deficient (d)MMR status [2]. This is in contrast with observations
in CRC patients where a dMMR status has been shown to be present in approximately 15–20% of all CRCs in Western countries [3,
4]. Because of this large discrepancy between healthy individuals
and cancer patients, guidelines in the 2009 Evaluation of Genomic
Applications in Practice of Prevention (EGAPP) recommended
screening of the MMR status for all newly diagnosed CRC patients
[5]. MMR corrects mismatched nucleotides and insertion-deletion
loops in DNA caused by polymerase errors, chemical modifications, and recombination between heterologous DNA sequences,
and therefore could affect both cancer etiology and response to
therapy in CRC patients [6]. In support of MMR effects on response to therapy, it was more recently demonstrated that stage II
CRC patients with dMMR had a better prognosis than those with
proficient (p)MMR status but could actually be harmed by 5-fluorouracil (FU) treatment as treatment-induced DNA damage could
go unchecked in these dMMR patients [7].
Another protein that has the potential to impact CRC patient
outcomes is ERCC1. ERCC1 is a rate-limiting molecule in the
NER pathway, which is responsible for repairing DNA adducts induced by platinum drugs [8]. It has been shown to form a heterodimer with xeroderma pigmentosum group F to execute excision
repair of the DNA strand [9]. Because of this important role in
Prof. Dr. Dr. Fuat S. Oduncu
Department of Hematology and Oncology
Medizinische Klinik und Poliklinik IV, Ludwig Maximilians University
Ziemssenstr. 1, 80336 Munich, Germany
fuat.oduncu@med.uni-muenchen.de
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Keywords
Colorectal cancer · MMR status · ERCC1 · Biomarker ·
Prognosis
Fig. 1. Immunostainings.
Oncol Res Treat 2017;40:1–5
Patients and Methods
Patients
The ethics committee of the Sun Yat-sen University Cancer Center approved this study, and informed consent for all patients analyzed was obtained
at the beginning of the study. A total of 4,500 histologically confirmed consecutive CRC patients were recruited post-surgery from the Sun Yat-sen University
Cancer Center between May 2011 and May 2016. All patients were of Chinese
origin. The clinical and family histories of each patient were reviewed. Finally,
2,233 cases were selected for analysis after strict exclusion criteria were applied,
including age less than 18 years and more than 85 years, severe complications,
multiprimary cancer, synchronous and metachronous CRC, family history
(first-degree and second-degree relatives with any kind of cancer), familial adenomatous polyposis, and death not from tumor-related causes. The primary
tumor site was categorized as right colon if the tumor was located above the
splenic flexure, left colon if it was located at or below the splenic flexure, and
rectum. The median follow-up for living patients was 4.3 years.
Treatment and Follow-Up
Stage I (T1–2 N0) (332 cases) and stage II (T3–4 N0) CRC patients (648
cases) without high-risk clinical features (e.g., T4 stage, bowel perforation or
clinical bowel obstruction, inadequate lymph node sampling, poorly differentiated histology) were treated with radical surgery or endoscopic removal of the
tumor alone. Stage II (T3–4 N0) CRC patients with high-risk clinical features
(228 cases) were recommended to follow the XELODA regimen. Stage III (Tx
N1–2) patients (606 cases) were designated to receive radical surgery and 12
cycles of adjuvant mFOLFOX/XELOX treatment within a 6-month period. All
stage IV (Tx Nx M1) patients received palliative surgery (398 cases) or radical
surgery (22 cases). The first-line treatment for stage IV CRC was use of the
mFOLFOX/FOLFIRI regimen. 89 patients with rectal cancer within our study
also received neoadjuvant chemoradiotherapy. The patients’ clinical responses
were evaluated in accordance with the RECIST guidelines. After surgery, tumor
recurrence was determined by physical examination, serum carcinoembryonic
antigen assay, and abdominal or thoracic imaging every 3–6 months for the following 3 years, then every 6 months for the next 2 years, and finally at annual
check-ups. The duration of follow-up was defined as the time between surgery
and disease recurrence, death, or last hospital contact (scheduled follow-up or
telephone contact). The cutoff date for inclusion in this analysis was May 2016.
Li/Xiao/Braciak/Ou/Chen/Oduncu
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DNA repair, ERCC1 expression has been studied, and it has been
reported that a gene polymorphism of ERCC1 at codon 118 was a
predictive factor for tumor response to oxaliplatin/5-FU combination chemotherapy in patients with advanced CRC [10]. In addition, ERCC1 is also now considered a possible predictive biomarker for cisplatin use in non-small cell lung cancer (NSCLC)
based on the results obtained from an International Adjuvant
Lung Cancer Trial Collaborative Group (IALT) trial [11]. While
these results obtained with regard to patient response to therapy
and ERCC1 expression suggest the importance of this protein in
cancer progression, the definitive prognostic value of ERCC1 expression has not yet been established for patients with CRC in relation to disease outcome.
It is likely that defects in the BER and NER pathways can impair
DNA repair capacity, resulting in an accumulation of DNA damage, carcinogenesis, and reduced chemotherapeutic sensitivity of
cancer cells [12, 13]. Nevertheless, so far, no study has shown a
prognostic role for combined ERCC1 and MMR status in CRC patients. Therefore, in this study, we determined whether there was
an association of ERCC1 expression and MMR status with overall
survival (OS) in CRC patients with stage I–IV disease. We were
aided in this analysis by having access to a large cohort of CRC patients who, following the recommendations of the EGAPP [5], underwent systematic immunohistochemistry (IHC) screening for
microsatellite instability. At the same time, testing for ERCC1 expression was also performed, which has become a routine test in
combination with IHC analysis with regard to patient prognosis.
The results obtained from this study indicate that measurement of
ERCC1 and MMR status in CRC patients has prognostic value and
can aid patient care.
Table 1. Clinicopathological characteristics of patients
Results
Association of ERCC1 and MMR with OS in CRC
Patients, n (%)
Sex
Male
Female
Age, years
20–39
40–59
60–85
Location
Right colon
Left colon
Rectum
Pathology
G1
G2
G3
Mucinous
Signet-ring
Stage
I
II
III
IV
Mismatch repair (MMR) status
Deficient (d)MMR
Proficient (p)MMR
ERCC1
Negative
Positive
MMR+ERCC1
dMMR+ERCC1(–)
dMMR+ERCC1(+)
pMMR+ERCC1(–)
pMMR+ERCC1(+)
Alive
Yes
No
Statistical Analyses
Patient data are described as frequencies (percentages). Differences in distribution between the variables examined were assessed with either the Χ2 or
the Fisher’s exact test. The primary end point was OS defined as the time
elapsed from the date of surgery to tumor-induced death. Surviving patients
were censored on the last follow-up date. Median follow-up and the 95% confidence interval (CI) were calculated using the reverse Kaplan-Meier method.
The survival curve was estimated with the Kaplan-Meier method and compared
using the log-rank test. Univariate and multivariable Cox proportional hazards
models were used to explore associations of MMR status, age, stage, differentiation grade, and sex. The score and likelihood ratio test p values were used to test
the statistical significance of each covariate in the univariate and multivariable
Cox models, respectively. All statistical tests were 2-sided, and p values of
≤ 0.05 were considered statistically significant. All statistical analyses were performed using SPSS software (IBM Corp., Armonk, NY, USA).
Of the 2,233 patients evaluated, 232 were found to have dMMR
with an overall prevalence of 10.4%. 208 patients were found to
have negative ERCC1 expression with a prevalence of 9.3%. When
patients were assessed with regard to ERCC1 expression in combination with MMR status, 1,839 were found to have positive ERCC1
and pMMR with a prevalence of 82.4%, 162 were found to have
negative ERCC1 and pMMR with a prevalence of 7.3%, 184 were
found to have positive ERCC1 and dMMR with a prevalence of
8.2%, and finally 47 patients were found to have negative ERCC1
and dMMR with a prevalence of 2.1%. Our study population
­included 1,316 males and 917 females of which 11.5 and 8.7%, respectively, were categorized as dMMR whereas 9.6 and 8.9%, respectively, were found to be ERCC1-negative. More detailed clinicopathological information for all patients is given in table 1.
dMMR versus pMMR CRC were more likely to be stage IIA
(16.6%) versus other stages (stage I: 9.1%, stage IIB: 8.0%, stage IIC:
19.0%, stage IIIA: 10.9%, stage IIIB: 8.4%, stage IIIC: 11.9%, stage
IVA: 5.3%, stage IVB: 4.3%) (p < 0.001), right colon (22.5%) versus
left colon (7.4%) and rectum (6.2%) (p < 0.001), occurring in men
(11.6%) versus women (8.7%) (p = 0.031), poorly or undifferentiated (23.6%) versus well or moderately differentiated (9.6%) (p
< 0.001), occurring in young age (20–39 years, 13.8%) versus older
age (40–59 years, 12.2%; 60–85 years, 8.3%) (p = 0.001), ERCC1-
Characteristics
1,314 (58.9)
917 (41.1)
188 (8.4)
1,023 (45.9)
1,021 (45.7)
521 (23.3)
740 (33.1)
972 (43.5)
104 (4.7)
2,002 (89.7)
18 (0.8)
95 (4.3)
14 (0.6)
332 (14.9)
876 (39.2)
606 (27.1)
419 (18.8)
232 (10.4)
2,001 (89.6)
207 (9.3)
2024 (90.7)
47 (2.1)
184 (8.2)
162 (7.2)
1,839 (82.4)
1,542 (69.1)
689 (30.9)
Table 2. Multi-analysis of overall survival
Variable
Age
Sex
Stage
Location
Grade
ERCC1
MMR
Hazard
ratio
95% confidence interval
lower
upper
2.38
1.41
3.19
1.75
2.23
0.92
1.56
2.36
1.39
3.23
1.66
2.07
0.91
1.18
2.42
1.44
3.85
1.86
2.26
0.93
2.06
p value
< 0.001
0.032
< 0.001
0.001
0.001
< 0.001
0.002
negative (23.1%) versus ERCC1-positive (9.1%) (p < 0.001). The
multi-analysis results are shown in table 2.
Overall, we found that most CRC patients with a pMMR status
also tended to simultaneously express the ERCC1 protein (p
< 0.001). One important finding of this study was that we found
dMMR status to be a better predictor for survival benefit than
pMMR status (OS 77 vs. 68%, hazard ratio (HR) 0.66, 95% CI 0.50–
Oncol Res Treat 2017;40:1–5
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Immunohistochemical Staining for MMR and ERCC1 Proteins
Blocks of formalin-fixed, paraffin-embedded adenocarcinoma tissue comprising an area of normal colorectal mucosa adjacent to the tumor were selected in each case. Cases with complete nuclear loss of expression in invasive
tumor cells with retained expression in inflammatory cells and/or adjacent
normal tissue as positive controls were considered MMR-deficient or ERCC1negative. Staining was performed using the following primary antibodies:
mouse anti-­human MLH1 (dilution 1: 50, clone OTI1C1, zhongshan jiqiao,
Beijing), rabbit anti-human MSH2 (dilution 1: 200, clone ZA0622, zhongshan
jiqiao), mouse anti-human MSH6 (dilution 1: 100, clone OTI5D1, zhongshan
jiqiao), mouse anti-human PMS2 (dilution 1: 50, clone OTI2G5, zhongshan jiqiao), and mouse anti-human ERCC1 (dilution 1: 200, clone OTI1A3, zhongshan jiqiao). Whole tissue sections were read separately by 2 pathologists
blinded to the patients’ clinical characteristics. Discordant cases were reviewed
by a supplementary pathologist to reach a consensus. Illustrative immunostainings are shown in figure 1.
Fig. 2. Survival plots of patients showing both ERCC1 expression and MMR status.
Discussion
In this study, we evaluated a large cohort of Chinese CRC patients for any associations of ERCC1 expression and MMR status
for possible prognostic application. In adherence to the EGAPP
recommendations [5], we followed the clinical outcomes of 2,233
CRC patients in search for any evidence of an association with
DNA repair pathways. From this Chinese patient-based population
analysis, we were able to demonstrate that use of the combination
of ERCC1 expression and MMR status harbors prognostic value
that might aid patient care.
MMR is a strand-specific repair pathway which is initiated with
the recognition of damaged DNA [14]. When MMR is deficient,
unrepaired areas of DNA can accumulate and result in microsatellite instability [15]. It has been found that MMR deficiency is most
commonly caused by epigenetic inactivation of the MLH1 gene in
sporadic CRCs, with changes in MSH2 and MSH6 accounting for
the next smaller percentage of deficiencies in patients [16]. For
CRC, it has previously been demonstrated that stage II patients
with dMMR have a better prognosis, and in these patients, 5-FU
treatment may actually cause additional harm [7]. In our study, we
evaluated the OS of 2,233 CRC patients representing all 4 stages of
disease (I–IV) and found that some patients with a dMMR status
had statistically significantly better OS. However, this association
Oncol Res Treat 2017;40:1–5
with better survival required inclusion in the analysis of tumor
ERCC1 protein expression.
The ERCC1 protein plays many roles in tumorigenesis. ERCC1
has been shown to act as an endonuclease in the NER pathway that
incises 5’ to any damaged DNA strand, allowing the removal of the
damaged strand, polymerization, and religation [17]. Although
ERCC1 has been used as a prognostic marker in NSCLC [11], only
few studies have evaluated the potential role of this protein as a
prognostic marker in CRC, and most of the previous data generated
about this protein was gathered in the metastatic setting [18, 19] or
from the analysis of ERCC1 polymorphisms [20–22]. Previous work
suggested that positive tumor expression of ERCC1 can predict inferior survival outcomes for cancer patients [18]. With regard to CRC,
the Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases(CONFIRM)-1 and CONFIRM-2
­trials have previously shown that high ERCC1 expression was associated with shorter OS in patients receiving first-line chemotherapy
[23]. Yet, another study did not conclude that there was any significant association between ERCC1 expression and the prognosis of
CRC [24]. In our current study, we found that most CRC patients
with a pMMR status tended to have tumors that simultaneously expressed the ERCC1 protein. Moreover, we found that there was a
prognostic effect for patients with dMMR when combined with a
positive ERCC1 expression profile. This effect suggests that there
may be an interaction between the BER and NER pathways in CRC.
While our findings here are novel and possibly useful for use in
patient care, there are some limitations with respect to gaining a
full understanding within this current study. One possible limitation is that we incorporated all stages (I–IV) of CRC into 1 group
to examine the effects of ERCC1 expression and MMR status on
OS. The examination of each separate stage of colon or rectal cancer might provide additional prognostic value for ERCC1 and
MMR status in tumor pathogenesis. Finally, we only focused on
looking for associations with clinical outcome for ERCC1 expression and MMR status. It is likely that other important pathways are
involved that could aid the prognosis of CRC patients. Thus, it is
important to identify other relevant mechanisms or pathways of
action that contribute to the pathogenesis of CRC.
Li/Xiao/Braciak/Ou/Chen/Oduncu
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0.87; p = 0.003). Yet, we found no statistical differences in OS between ERCC1-positive and -negative CRC patients (OS 70 vs. 62%,
HR 0.82, 95% CI 0.65–1.04; p = 0.11). Most importantly, we were
able to show a prognostic effect following the measurement of both
ERCC1 and MMR status of patients. Here, we were able to demonstrate that patients with both a positive ERCC1 expression and
dMMR status had greater OS than all other patient groups including those with positive ERCC1 and pMMR, patients with negative
ERCC1 and dMMR, and finally those with negative ERCC1 expression and pMMR status (OS 79 vs. 69 vs. 66 vs. 61%, HR 0.90, 95%
CI 0.80–1.00; p = 0.043). The survival plots of patients showing
both ERCC1 expression and MMR status are provided in figure 2.
Conclusion
Our study represents one of the first to incorporate a large dataset of CRC patients to investigate the effects of ERCC1 and dMMR
status on clinical outcomes following the EGAPP recommendations for research in CRC. Our results indicate that determining
both ERCC1 expression and dMMR status can be of benefit when
establishing the prognosis of CRC patients. Even though ERCC1
expression alone was not significantly correlated with OS, we were
able to show that when combined with dMMR status it was useful
in the assessment of OS in Chinese CRC patients.
Disclosure Statement
The authors have declared no conflicts of interest. No funding was provided
for this study.
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