|Year : 2019 | Volume
| Issue : 3 | Page : 405-412
|Role of ERCC1 expression in colorectal adenoma-carcinoma sequence and relation to other mismatch repair proteins expression, clinicopathological features and prognosis in mucinous and non-mucinous colorectal carcinoma
Abd AlRahman Mohammad Foda1, Andrea Palicelli2, Abdelhadi Shebl1, Renzo Boldorini3, Khaled Elnaghi4, Amira K ElHawary1
1 Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Health Science, School of Medicine, University of Eastern Piedmont ”Amedeo Avogadro”, Novara; Unit of Pathology, ”Arcispedale Santa Maria Nuova-IRCCS”, Reggio Emilia, Italy
3 Department of Health Science, School of Medicine, University of Eastern Piedmont ”Amedeo Avogadro”; Pathology Unit, ”Maggiore della Carità” Hospital, Novara, Italy
4 Department of Internal Medicine, Medical Oncology Unit, Faculty of Medicine; Medical Oncology Unit, Oncology Center, Mansoura University, Mansoura, Egypt
Click here for correspondence address and email
|Date of Web Publication||26-Jul-2019|
| Abstract|| |
Background: There are several DNA repair pathways that protect cellular DNA from injury, such as nucleotide excision repair (NER) and mismatch repair (MMR). The protein product of the excision repair cross-complementation group 1 (ERCC1) gene plays a pivotal role in NER. The exact relationship between MMR proteins and ERCC1 is not well known in colorectal carcinoma (CRC). Aim of the Study: To investigate expression of ERCC1 and MMR proteins in colorectal mucinous carcinoma (MA) and non-mucinous carcinoma (NMA) using tissue microarray technique. Material and Methods: We studied tumor tissue specimens from 150 patients with colorectal mucinous (MA) and non-mucinous adenocarcinoma (NMA). Tissue microarrays were constructed using modified mechanical pencil tips technique and immunohistochemistry for ERCC1, MLH1, MSH2, MSH6, and PMS2. Results: NMA showed a significantly more frequent aberrant cytoplasmic expression than MA while MA showed a more frequent intact nuclear expression than NMA. There were no significant differences between the NMA and MA groups in the expression of MMR proteins. In NMA cases, ERCC1 expression was significantly related to MMR status while was not significantly related in MA cases. ERCC1 expression was not significantly related to overall and disease-free survival in both NMA and MA groups. Conclusion: this study is the first to investigate the relation between MMR status and ERCC1 expression in colorectal MA and NMA. ERCC1 expression was significantly related to MMR status only in NMA cases. Hence, the current study emphasizes that further research about the relation between various DNA repair pathways is needed.
Keywords: Colorectal, ERCC1, MMR, mucinous
|How to cite this article:|
Mohammad Foda AA, Palicelli A, Shebl A, Boldorini R, Elnaghi K, ElHawary AK. Role of ERCC1 expression in colorectal adenoma-carcinoma sequence and relation to other mismatch repair proteins expression, clinicopathological features and prognosis in mucinous and non-mucinous colorectal carcinoma. Indian J Pathol Microbiol 2019;62:405-12
|How to cite this URL:|
Mohammad Foda AA, Palicelli A, Shebl A, Boldorini R, Elnaghi K, ElHawary AK. Role of ERCC1 expression in colorectal adenoma-carcinoma sequence and relation to other mismatch repair proteins expression, clinicopathological features and prognosis in mucinous and non-mucinous colorectal carcinoma. Indian J Pathol Microbiol [serial online] 2019 [cited 2019 Aug 17];62:405-12. Available from: http://www.ijpmonline.org/text.asp?2019/62/3/405/263495
| Introduction|| |
Colorectal carcinoma (CRC) is one of the most prevalent cancers worldwide and it represents the fourth most common cause of cancer-related mortality. CRC is so heterogenous regarding its pathogenesis with many pathways.
One of the major pathways in colorectal carcinogenesis is the defect in the global “DNA damage response” that senses different types of damage and coordinates response. There are several recognized DNA repair pathways that protect cellular DNA from injury, such as nucleotide excision repair (NER), mismatch repair (MMR), double-strand break repair, base excision repair, and direct repair.
MMR proteins (namely MLH1, MSH2, MSH6, and PMS2) are nuclear enzymes, which participate in repair of base-base mismatch that occur during DNA replication in proliferating cells. Loss of MMR proteins leads to an accumulation of DNA replication errors, particularly in areas of the genome with short repetitive nucleotide sequences, a phenomenon known as microsatellite instability (MSI). Colorectal MMR profile provides useful prognostic information, as patients with microsatellite unstable neoplasms have a better overall survival rate and a modified response to conventional chemotherapy. MSI also helps in predicting the treatment response of CRC, and could modify the chemotherapy protocols.
On the other hand, nucleotide excision repair (NER) is perhaps the most flexible of the DNA repair pathways considering the diversity of DNA lesions it acts upon. The protein product of the excision repair cross-complementation group 1 (ERCC1) gene plays a pivotal role in NER. Low expression levels or loss of ERCC1 observed in cancer patients could be a cause of disease or a consequence of the same.
There is conflicting data about role of ERCC1 in oncogenesis. In patients with squamous cell carcinoma of the head and neck it was found that the levels of ERCC1 were significantly lower than in healthy controls and that this low expression of ERCC1 was associated with statistically significant increased risk for this tumor type. In contrast, no association between ERCC1 mRNA expression and risk of subsequent development of lung cancer was found.
ERCC1 has also a major impact on response to multimodality treatment of various tumors. A prognostic association between high ERCC1 expression level and low response rates to platinum-based chemotherapy and overall survival has been established in patients with advanced NSCLC, bladder, biliary tract, pancreatic, colorectal, and ovarian cancers.
In CRC, research in this area is highly desirable as the role of ERCC1 in CRC patient-tailored multimodality treatment is far from being firmly established for routine use. Moreover, the exact relationship between MMR proteins and ERCC1 is not yet well known in CRC. Most previous studies emphasized at metastatic CRCs, not primaries, and didn't clearly investigate the role of ERCC1 expression in various CRC subtypes. So, we aimed at this work to investigate the role of ERCC1 in colorectal adenoma-carcinoma sequence, expression of ERCC1 in CRC, its relation to clinicopathological, histological parameters, survival, and to MMR proteins expression in a large number of CRC cases, including various subtypes.
| Materials and Methods|| |
A total of 150 cases of CRC specimens were obtained from patients who underwent surgery for histologically confirmed CRC between January 2007 and January 2012. Files of all resected CRC cases during this period were revised.
Seventy-five cases satisfied 2010 WHO selection criteria for “mucinous adenocarcinoma”(MA) (extracellular mucin-containing malignant cells >50% of the tumor; 56 cases) or “signet ring cell carcinoma” (SRCC) (signet ring cells >50% of the tumor cells, with prominent intra-cytoplasmic mucin; 19 cases) and were all included in the mucinous group.
Seventy-five cases of non-mucinous adenocarcinoma (NMA) were randomly chosen for comparison from the same period, including 47 cases of “conventional adenocarcinoma not otherwise specified”(CA) and 28 cases of “adenocarcinoma with mucinous component” (AMC) (<50% of the tumor).
Hematoxylin and Eosin (H and E) stained sections were examined to evaluate histopathological parameters and choose representative areas for tissue microarray (TMA) construction. Grading and TNM staging were performed according to established criteria.
Exclusion criteria included: preoperative (neoadjuvant) chemotherapy; incomplete clinicopathological and follow-up information; insufficient tissue for immunostaining.
Thirty-five samples of normal colic mucosa and 45 adenomas were also included in the study.
The local scientific ethical committee approved the study and REMARK criteria were applied.
Clinical parameters and histopathological evaluation
Clinical data of all cases were revised and all histological slides were re-examined, including the following parameters: age; gender; localization; size; shape; multiple tumors; histological type; grade; depth of invasion (T); tumor edges (pushing and/or infiltrative at microscopic examination); lymphovascular invasion; perineural invasion; peri- and intra-tumoral lymphocytic infiltration; extent of neutrophilic infiltrate; status of nearby and distant mucosa; whether the cancer was on the top of adenoma or not; number of lymph node metastases (N); distant metastases (M); TNM stage; status of surgical margins; associated schistosomiasis. Data regarding survival of the patients were obtained. Disease-free survival (DFS) was defined as the time from the date of surgery to the date of relapse or death, and overall survival (OS) was defined as the time from the date of surgery to the date of death. The median follow up of the patients was 30.7 months (Range from 1.3 to 111.1 months).
Tissue Microarray (TMA) construction
Three manual TMA blocks were constructed using modified mechanical pencil tip method as previously described. Three representative cores of 0.8 mm diameter were punched out from each case of CRC in addition to cores from normal and adenomatous tissues. Cores of various other normal tissues were included to serve as positive and negative controls. Four-μm thick sections from the TMA blocks were cut on ordinary slides for routine H and E evaluation and on charged slides for immunohistochemical studies.
Immunohistochemistry was performed using an automated immunostainer (BenchMark, Roche, Tucson, USA). The slides were stained with the following antibodies: anti-ERCC1 (mouse monoclonal, Clone 8F1, 0.2 mg/ml conc.) from Neomarkers (Freemont, California, USA); anti-MLH1 (mouse monoclonal, Clone M1, pre-diluted), anti-MSH2 (mouse monoclonal, Clone G219-1129, pre-diluted), anti-MSH6 (mouse monoclonal, Clone 44, pre-diluted) and anti-PMS2 (rabbit monoclonal Clone EPR3947, pre-diluted) from Roche (Ventana Medical Systems, Arizona, USA).
Positive external controls included sections of pulmonary squamous cell carcinoma for ERCC1 and sections of normal colic mucosa for other stains. As a negative control, phosphate buffered saline was used to replace the monoclonal antibody whereas normal goat serum was used to replace polyclonal antibody.
Examination of the slides was done on an Olympus CX31 light microscope. Pictures were obtained by a PC-driven digital camera (Olympus E-620).
Evaluation of IHC
MLH1, MSH2, MSH6, and PMS2expressions were assessed for each case according to College of American Pathologists (CAP) guidelines (CAP Technology Assessment Committee, 2011). Any positive reaction in the nuclei of tumor cells was considered as intact expression (normal), even if patchy or in only one core of the case. An interpretation of expression loss in tumor cells was made only if a positive reaction was seen in internal control cells, such as the nuclei of stromal, inflammatory, or non-neoplastic epithelial cells. For ERCC1, any staining either nuclear or cytoplasmic were reported as previously described., Similarly, a positive internal control was a must in each core to be interpreted. Whenever tissue cores of any case were lost, it was not included in the results, which led to different number of cases in each analysis.
Data were analyzed, applying SPSS, version 16.0 for Windows (SPSS Inc, IBM, Chicago, Illinois). χ2 (Chi-square) test was used to test significant differences in categorical variables between various groups. Survival data were analyzed using Kaplan-Meier test. A comparison of survival curves was carried out using the log-rank test. For multivariate analysis, Cox proportional hazard models were performed. A 2-tailed P ≤ 0.05 was considered significant in all tests.
| Results|| |
Clinicopathological and histological features of CRC cases
The age range of the 150 analyzed cases was 20–80 years (mean age: 52.7 years). The patients were 93 men and 57 women. The clinicopathological and histological features of all cases were previously reported. In brief, MA was significantly associated with younger age (P = 0.017), deeper invasion (P = 0.008), more frequent lymph node metastases (P = 0.008), and fewer peritumoral and intratumoral neutrophils (P < 0.001) than NMA. For the remaining factors, there were no significant differences between MA and NMA groups.
ERCC1 expression in colorectal normal, adenomatous, and carcinomatous tissues
ERCC1 showed loss of nuclear expression in 25.7% of normal colic mucosae, 33.3% of adenomas and 29.7% of carcinomas. ERCC1 expression was not significantly different between normal colic mucosae, adenomas and CRCs (P = 0.529). Aberrant cytoplasmic expression was also detected in 27 cases (18.2%) of CRC [Table 1] and [Figure 1].
|Table 1: ERCC1 expression in colorectal normal, adenoma and carcinoma tissues|
Click here to view
|Figure 1: ERCC1 expression in colorectal adenoma and carcinoma subtypes (×200). (a) In adenoma (nuclear), (b) In conventional adenocarcinoma (nuclear), (c) In adenocarcinoma with mucinous component (nuclear, focal and faint), (d) In mucinous adenocarcinoma (nuclear), (e) In signet ring cell carcinoma (nuclear), (f) In conventional adenocarcinoma (cytoplasmic with some nuclear staining)|
Click here to view
ERCC1 and other MMR proteins expression in CRC
ERCC1 showed complete loss of expression in 17 cases (11.5%), intact nuclear expression in 104 cases (70.3%) and aberrant cytoplasmic expression in 27 cases (18.2%). NMA showed a significantly more frequent aberrant cytoplasmic expression (74.1%) than MA (25.9%), while MA showed a more frequent intact nuclear expression (54.8%) than NMA (45.2%) (P = 0.027) [Table 2] and [Figure 1]. Loss of nuclear expression was detected in 7 cases (4.7%) for MLH1, 23 cases (15.3%) for MSH2, 28 cases (18.7%) for MSH6 and 31 cases (21.5%) for PMS2. There were no significant differences between the NMA and MA groups in the expression of MMR proteins [Table 2] and [Figure 2].
|Figure 2: Nuclear MMR proteins expression in mucinous and non-mucinous colorectal carcinoma (×200)|
Click here to view
Relation of ERCC1 expression to CRC subtypes
Within NMA group, ERCC1 showed intact nuclear staining in 31 cases (66%) of CA, and 16 cases (57.1%) of AMC (P = 0.082). Similarly, ERCC1 showed intact nuclear staining in 41 cases (75.9%) of MA, and 16 cases (84.2%) of SRCC (P = 0.242). ERCC1 expression was not significantly associated with any of the CRC subtypes (data not shown) [Figure 1].
Relation of ERCC1 expression to other MMR proteins expression in CRC
In NMA cases, ERCC1 expression was significantly related to MMR status (P = 0.045). 74.5% of cases with preserved nuclear ERCC1 expression were MMR proficient (preserved nuclear MLH1, MSH2, MSH6, and PMS2 expressions), as well as 60% of cases with aberrant cytoplasmic ERCC1 expression. In addition, 71.4% of cases with negative ERCC1 expression were MMR deficient. ERCC1 expression either nuclear or cytoplasmic was significantly related to nuclear MSH6 (P = 0.011) and PMS2 (P = 0.048) expressions [Table 3].
|Table 3: Relation of ERCC1 expression to other MMR proteins expression in NMA|
Click here to view
In contrast, ERCC1 expression in MA cases was not significantly related to either MMR status or individual MMR proteins expression [Table 4].
|Table 4: Relation of ERCC1 expression to other MMR proteins expression in MA|
Click here to view
Relation of ERCC1 expression to clinicopathological and histological parameters in CRC
ERCC1 expression was not significantly associated with any of the tested clinicopathological and histological parameters (data not shown) except with the presence of lymphovascular emboli within the tumor, which were found in about 70% of cases with preserved nuclear ERCC1 expression (χ2 = 6.423, P = 0.040).
Relation of ERCC1 expression to survival of CRC cases
DFS and OS of all NMA and MA cases were previously reported. MA cases were significantly associated with worse DFS and OS than NMA cases (P < 0.001). To clarify the prognostic impact of ERCC1expression on survival of CRC cases, univariate and multivariate analyses were carried out for each group separately. Relation of ERCC1 expression to DFS and OS in NMA and MA cases was summarized at [Table 5]. In a univariate analysis, ERCC1 expression was not significantly related to DFS and OS in both NMA and MA groups [Table 5].
|Table 5: Univariate analysis of the relation of ERCC1 expression to survival in NMA and MA cases|
Click here to view
| Discussion|| |
In clinical practice, oncologists have started to require information on ERCC1 expression on CRC tumors since its overexpression strongly suggests resistance to platinum chemotherapy but also has a favorable prognosis. In addition, defining tumor subtypes of CRC based on pathway driven alterations has the potential to improve prognostication and guide targeted therapy.,
The current study presents a large dataset exploring the role of ERCC1 in colorectal adenoma-carcinoma sequence, expression of ERCC1 in CRC, its relation to clinicopathological, histological parameters, survival and to MMR proteins expression in of CRC cases, including various subtypes.
In this study, it was found that there was positive ERCC1 protein expression in 70.3% of CRC cases. Likewise, Gajjar et al. reported 72% positive ERCC1 immunoreactivity in patients with CRC. In another two studies, ERCC1 positivity was observed in 45% and 55% of Chinese patients with colorectal and stage III disease, respectively, [Supplementary [Table 1]. This heterogeneity may be due to several factors including antibody used, scoring technique, and preparation of the paraffin embedded tissue blocks. Another important explanation for this discrepancy is that the frequencies of ERCC1alleles were substantially different among patient populations with different ethnicity.
Most colorectal carcinomas are considered to arise from conventional adenoma based on the concept of the adenoma-carcinoma sequence. Investigating biological markers expression in colorectal adenomas and carcinomas help in better understanding of these pathogenic pathways involved in colorectal tumorigenesis. In the current study, ERCC1 expression was not significantly different between normal colonic mucosae, adenomas, and CRCs. In contrast, Sæbø et al. found that mRNA levels of ERCC1were up-regulated in both colorectal adenomas and carcinomas compared to corresponding normal colonic mucosa, indicating that increased expression of defense genes is an early event in the progression of colorectal adenomas to carcinomas. As the current study, they also reported that the level of ERCC1was not different between adenomas and CRC cases. The controversy from our results may be due to several factors including different methods of assessments and also the number of cases in their study was relatively small.
To the best of our knowledge, this study was the first to report the significant difference in ERCC1 immunohistochemical subcellular localization between NMA and MA subtypes. There was a wide discrepancy in the subcellular localization of ERCC1 in the literature. One study found that expression of ERCC1 protein was localized in the cytoplasm of epithelial cells of colon and rectum in 72% of cases. The primary antibody used was mouse monoclonal anti-ERCC1 (clone 4F9). Another study by Li et al. reported positive nuclear staining in 90.7% of CRC cases. The antibody used was mouse anti-human ERCC1 (clone OTI1A3). Also, Wang et al. observed nuclear ERCC1 expression in gastric cancer cells, but as in our study, they also detected its expression in the cytoplasm of some tumor cells. In non-small cell carcinoma cases, Olaussen et al. observed frequent cytoplasmic staining with FL297 and nuclear staining with 8F1 (the antibody used in the current study). Consequently, they believed that the 8F1 antibody is an acceptable tool to determine nuclear ERCC1 protein expression in tissues of solid tumors of epithelial origin, whereas FL297 leads to a puzzling cytoplasmic staining. Interestingly, we found cytoplasmic staining of ERCC1 as well using 8F1 antibody in about 18% of CRC cases, mainly of NMA histological type.
Universal assessment of immunohistochemical MMR staining is increasingly applied in colorectal cancer diagnostics in order to identify cases suspected of Lynch syndrome for further molecular diagnostics. In the current study, loss of nuclear expression for MMR protein was 34.6% of cases which is slightly higher than published incidence rate detected by Hall et al., (30.2%). Sylvester et al. and Kumar et al. reported MSI incidence rate of 27% and 19.8% respectively in a large samples of African-American colorectal cancer patients. Li et al. explained the low incidence of MMR mutation in his study (7.5%) as a significant proportion of CRC in China may follow tumorigenesis pathways distinct from the deficient MMR CRC progression sequence. The same explanation could be applied for the discrepancy in the incidence rates between different studies. Clearly, this possible heterogeneity could also have implications for CRC prognosis and the clinical management of disease.
In this study, no significant differences were found between the NMA and MA groups in the expression of MMR proteins. Our study showed that loss of nuclear expression was present in 36.1% of MA group. Similarly, Andrici et al. reported that loss of nuclear expression was present in 36.0% of mucinous colorectal cancer keeping with previous studies reporting ranges from 29 to 42%., In addition, Kaur et al. found a significant association between abnormal MMR proteins expression and mucinous, signet ring and poorly differentiated CRC in contrast to CA cases which showed normal MMR proteins expression. In contrast, in this study, 33.7% of NMC group showed loss of nuclear expression compared with only 14.1% on non-mucinous tumors reported by Andrici et al. and 18.5% reported by Vergouwe et al. This difference may be explained by multi-factorial etiology of CRC involving hereditary and racial causes, environmental factors, and somatogenetic changes during tumor progression.
Scarce studies had assessed ERCC1 expression in different pathological types of CRC by immunohistochemistry. We found that ERCC1 showed intact nuclear staining in 66% of CA, 57.1% of AMC, 75.9% of MA, and 84.2% of SRCC without significant association with any of the CRC subtypes. Similarly, Li et al. found that most of cases of CA (90.7%), MA (88.4%) and SRCC (85.7%) showed positive ERCC1 nuclear staining but without statistical difference. However, they did not differentiate between CA and AMC as many of the studies did. To the best of our knowledge, this study was the first to assess ERCC1 expression in AMC. In contrast to our results, Shimamoto et al. found that the lowest levels of expression of ERCC1 were observed in patients with mucinous adenocarcinoma, while the highest level of expression was observed in patients with poorly differentiated adenocarcinoma.
Li et al. large dataset showed that CRC patients with retained expression of MMR tended to have positive ERCC1 expression, suggesting a collaboration of these two DNA repair pathways in maintaining cell integrity and normalcy. MMR proteins are responsible for correcting mismatched nucleotides and insertion-deletion loops in DNA caused by polymerase errors, chemical modifications, and recombination between heterologous DNA sequences, while ERCC1 is a key molecule in the NER pathway, which is responsible for repairing DNA adducts induced by platinum drugs., The underlying mechanisms of these potential interactions between these DNA repair proteins still needs to be elucidated to gain a better understanding of CRC pathogenesis and its prognosis. Similarly, Tóth et al. reported that loss of MLH1 and MSH2 was associated with lower expression or loss of ERCC1 in colorectal liver metastasis. In the study of Zhang et al., they have examined MSI level and ERCC1 polymorphisms of CRC patients before receiving adjuvant chemotherapy and they found no significant correlation was found between MSI status and ERCC1 polymorphisms. However, we believe that it is not feasible to investigate the relationship between both DNA repair pathways in a large group of CRC cases involving multiple subgroups, especially MA which is well known to have specific pathogenic pathways and prognosis. To the best of our knowledge, the current study is the first to assess the relation of ERCC1 expression to MMR proteins expression in NMA and MA cases. This specification can explain the discrepancy found in previous studies. Only in NMA cases, ERCC1 expression was significantly related to MMR status, as reported by Li et al. In contrast to Tóth et al., we found that ERCC1 expression either nuclear or cytoplasmic was significantly related to nuclear MSH6 and PMS2 expressions. This can be explained by the known genetic dissimilarity between primary tumors and their metastases. In addition, ERCC1 expression in MA cases in our study was not significantly related to either MMR status or individual MMR proteins expression.
Similar to the study of Li, et al., ERCC1 expression in this study was not significantly associated with any of the clinicopathological and histological parameters. However, we could demonstrate significant relation between the presence of lymphovascular emboli within the tumor and preserved nuclear ERCC1 expression. In contrast, Kim et al. and Shimamoto et al. reported no significant difference between lymphovascular emboli and ERCC1 expression.
Some studies reported that patients with low levels of ERCC1 expression have an improved response and a longer OS in gastrointestinal tumors treated with FOLFOX. One of the suggested explanations of this relation is the identification of several common and putatively functional single nucleotide polymorphisms (SNPs) of ERCC1. The rs11615 T allele of ERCC1polymorphism was found to be associated with high mRNA expression of the corresponding gene. Patients carrying the ERCC1rs11615 T may have higher DNArepair capacity that could effectively reduce the anticancer effect of oxaliplatin, leading topoor prognosis of these patients. Thus, inter-individual difference in the NER capacity may influence clinical outcomes of the treated cancer patients.,,,,,,,,,,,,,,,,,,,,,,,,,, Notably, Yin et al. confirmed the existence of ethnical difference in the estimates for the ERCC1allele. Although the underlying mechanisms are not clear, numerous factors may have played a role, such as gene-gene interaction from different genetic background, and gene environmental interaction from different lifestyles. These points can explain the lack of association between enzyme expression and survival in the present study. One more point is that the current study is the first to investigate OS and DFS in CRC subtypes (NMA and MA). Nevertheless, multivariate analysis of Kwon et al. revealed that ERCC1 expression is significantly related to OS which indicates that immunohistochemical staining for ERCC1 may be useful for predicting the clinical outcomes of advanced gastric cancer patients treated with 5-FU and oxaliplatin. However, it is well known that immunohistochemical staining has many limitations attributable to its semi-quantitative nature, the staining technique, the enzyme antibody used, and inter-observer variation.
In conclusion, this study is the first to investigate the relation between MMR status and ERCC1 expression in mucinous and non-mucinous colorectal carcinoma. ERCC1 expression was significantly related to MMR status only in NMA cases. In contrast, ERCC1 expression in MA cases was not significantly related to MMR status or individual MMR proteins expression. Hence, the current study emphasizes that further research about the relation between various DNA repair pathways is needed. Owing to the well-known genetic differences between MA and NMA CRC, we emphasize that these relations should be investigated in each subgroup separately.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Haggar FA, Boushey RP. Colorectal cancer epidemiology: Incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg 2009;22:191-7.
Metzger R, Bollschweiler E, Hölscher AH, Warnecke-Eberz U. ERCC1: Impact in multimodality treatment of upper gastrointestinal cancer. Future Oncol 2010;6:1735-49.
Kheirelseid EAH, Miller N, Chang KH, Curran C, Hennessey E, Sheehan M, et al.
Mismatch repair protein expression in colorectal cancer. J Gastrointest Onco 2013;l4:397-408.
Gossage L, Madhusudan S. Cancer pharmacogenomics: Role of DNA repair genetic polymorphisms in individualizing cancer therapy. Mol Diagn Ther 2007;11:361-80.
Cheng L, Sturgis EM, Eicher SA, Spitz MR, Wei Q. Expression of nucleotide excision repair genes and the risk for squamous cell carcinoma of the head and neck. Cancer 2002;94:393-7.
Vogel U, Nexø BA, Tjønneland A, Wallin H, Hertel O, Raaschou-Nielsen O. ERCC1, XPD and RAI mRNA levels in lymphocytes are not associated with lung cancer risk in a prospective study of Danes. Mutat Res 2006;593:88-96.
Roth JA, Carlson JJ. Prognostic role of ERCC1 in advanced non-small-cell lung cancer: A systematic review and meta-analysis. Clin Lung Cancer 2011;12:393-401.
Hamilton SR, Bosman FT, Boffetta P, Ilyas M, Morreau H, Nakamura SI, et al.
Tumours of the colon and rectum. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO Classification of Tumours of the Digestive System. Lyon: IARC Press; 2010.
Altman DG, McShane LM, Sauerbrei W, Taube SE. Reporting recommendations for tumor marker prognostic studies (REMARK): Explanation and elaboration. PLoS Med 2012;9:e1001216.
Foda AA. No-cost manual method for preparation of tissue microarrays having high quality comparable to semiautomated methods. Appl Immunohistochem Mol Morphol 2013;21:271-4.
Olaussen KA, Soria JC. Validation of ERCC1-XPF immunodetection-letter. Cancer Res 2010;70:3851-2.
Mehra R, Zhu F, Yang DH, Cai KQ, Weaver J, Singh MK, et al.
Quantification of excision repair cross-complementing group 1 and survival in p16-negative squamous cell head and neck cancers. Clin Cancer Res 2013;19:6633-43.
Foda AA, El-Hawary AK, Abdel-Aziz A. Differential expression of matrix metalloproteinase 13 in mucinous and nonmucinous colorectal carcinomas. Ann Diagn Pathol 2013;17:347-51.
Foda AA, El-Hawary AK, Abdel Aziz A, Hosni A, Zalata KR, Gado AL. Rare mucinous colorectal adenocarcinoma: Analysis of the epidemiological factors in relation to survival in Egyptian patients. AJCEP2014;2:10-9.
Gray SW, Kim B, Sholl L, Cronin A, Parikh AR, Klabunde CN, et al.
Medical oncologists experiences in using genomic testing for lung and colorectal cancer care. J Oncol Pract 2017;13:e185-96.
Foda AA, El-Hawary AK, Aziz AA. Colorectal adenocarcinoma with mucinous component: Relation of MMP-13, EGFR, and E-cadherin expressions to clinicopathological features and prognosis. APMIS 2015;123:502-8.
Foda AAM, Aziz AA, Mohamed MA. Colorectal signet ring cell carcinoma: Influence of EGFR, E-cadherin and MMP-13 expression on clinicopathological features and prognosis. Ann Diagn Pathol 2018;32:41-6.
Gajjar KK, Yadav DK, Kobawala TP, Trivedi TI, Vora HH, Ghosh NR. ERCC1 expression in patients with colorectal cancer: A pilot study. J Cancer Metastasis Treat 2016;2:471-6.
Chang PM, Tzeng CH, Chen PM, Lin JK, Lin TC, Chen WS, et al.
ERCC1codon 118 C→T polymorphism associated with ERCC1 expression and outcome of FOLFOX-4 treatment in Asian patients with metastatic colorectal carcinoma. Cancer Sci 2009;100:278-83
Li Y, Liu Z, Liu H, Wang LE, Tan D, Ajani JA, et al.
ERCC1 and ERCC2 variants predict survival in gastric cancer patients. PLoS 2013;One8:e71994.
Yin M, Yan J, Martinez-Balibrea E, Graziano F, Lenz HJ, Kim HJ, et al.
ERCC1 and ERCC2 Polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectalcancer: A systemic review and meta-analysis. Clin Cancer Res 2011;17:1632-40.
Foda AA, El-Hawary AK, Abdel-Aziz A. Matrix metalloproteinase-13 expression in the colorectal adenoma and carcinoma. Tumour Biol 2014;35:5653-8.
Sæbø M, Skjelbred CF, Nexø BA, Wallin H, Hansteen IL, Vogel U, et al.
Increased mRNA expression levels of ERCC1, OGG1 and RAI in colorectal adenomas and carcinomas. BMC Cancer 2006;6:208.
Li P, Xiao Z, Braciak TA, Ou Q, Chen G, Oduncu FS. Systematic immunohistochemical screening for mismatch repair and ERCC1 gene expression from colorectal cancers in China: Clinicopathological characteristics and effects on survival. PLoS One 2017;12:e0181615.
Wang J, Zhou XQ, Li JY, Cheng JF, Zeng XN, Li X, et al.
Prognostic significance of ERCC1 expression in postoperative patients with gastric cancer. Chin J Cancer Res 2014;26:323-30.
Moreira L, Balaguer F, Lindor N, de la Chapelle A, Hampel H, Aaltonen LA, et al.
Identification of Lynch syndrome among patients with colorectal cancer. JAMA 2012;308:1555-65.
Hall G, Clarkson A, Shi A, Langford E, Leung H, Eckstein RP, et al.
Immunohistochemistry for PMS2 and MSH6 alone can replace a four antibody panel for mismatch repair deficiency screening in colorectal adenocarcinoma. Pathology 2010;42:409-13.
Sylvester BE, Huo D, Khramtsov A, Zhang J, Smalling RV, Olugbile S, et al.
Molecular analysis of colorectal tumors within a diverse patient cohort at a single institution. Clin Cancer Res 2012;18:350-9.
Kumar K, Brim H, Giardiello F, Smoot DT, Nouraie M, Lee EL, et al.
Distinct BRAF (V600E) and KRAS mutations in high microsatellite instability sporadic colorectal cancer in African Americans. Clin Cancer Res 2009;15:1155-61.
Li W, Zhi W, Zou S, Qiu T, Ling Y, Shan L, et al.
Distinct clinicopathological patterns of mismatch repair status in colorectal cancer stratified by KRAS Mutations. PLoS ONE 2015;10:e0128202.
Andrici J, Farzin M, Sioson L, Clarkson A, Watson N, Toon CW, et al.
Mismatch repair deficiency as a prognostic factor in mucinous colorectal cancer. Mod Pathol 2016;29:266-74.
Yoon YS, Kim J, Hong SM, Lee JL, Kim CW, Park IJ, et al.
Clinical implications of mucinous components correlated with microsatellite instability in patients with colorectal cancer. Colorectal Dis 2015;17:O161-7.
Leopoldo S, Lorena B, Cinzia A, Gabriella DC, Angela Luciana B, Renato C, et al.
Two subtypes of mucinous adenocarcinoma of the colorectum: Clinicopathological and genetic features. Ann Surg Oncol 2008;15:1429-39.
Kaur G, Masoud A, Raihan N, Radzi M, Khamizar W, Kam LS. Mismatch repair genes expression defects & association with clinicopathological characteristics in colorectal carcinoma. Indian J Med Res 2011;134:186-92.
] [Full text]
Vergouwe F, Boutall A, Stupart D, Algar U, Govender D, van der Linde GD, et al.
Mismatch repair deficiency in colorectal cancer patients in a low-incidence area. S Afr J Surg 2013;51:16-21.
Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996;87:159-70.
Shimamoto Y, Nukatsuka M, Takechi T, Fukushima U. Association between mRNA expression of chemotherapy-relatedgenes and clinicopathological features in colorectal cancer: A large-scale population analysis. Int J Mol Med2016;37:319-28.
Lanza G, Gafa R, Santini A, Maestri I, Guerzoni L, Cavazzini L. Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol 2006;24:2359-67.
Viguier J, Boige V, Miquel C, Pocard M, Giraudeau B, Sabourin JC, et al.
ERCC1 codon 118 polymorphism is a predictive factor for the tumor response to oxaliplatin/5-fluorouracil combination chemotherapy in patients with advanced colorectal cancer. Clin Cancer Res 2005;11:6212-7.
Nishina T, Takano Y, Denda T, Yasui H, Takeda K, Ura T, et al.
A phase II clinical study of mFOLFOX6 plus bevacizumab as first-line therapy for Japanese advanced/recurrent colorectal cancer patients. Jpn J Clin Oncol 2013;43:1080-6.
Tóth C, Sükösd F, Valicse KE, Herpel E, Schirmacher P, Renner M, et al.
Expression of ERCC1, RRM1, TUBB3 in correlation with apoptosis repressor ARC, DNA mismatch repair proteins and p53 in liver metastasis of colorectal cancer. Int J Mol Med 2017;40:1457-65.
Zhang L, Zhao J, Yu B, Song X, Sun G, Han L, et al.
Correlations between microsatellite instability, ERCC1/XRCC1 polymorphism and clinical characteristics, and FOLFOX adjuvant chemotherapy effect of colorectal cancer patients. Cancer Genet 2017;51:218-9.
Zalata KR, Elshal MF, Foda AA, Shoma A. Genetic dissimilarity between primary colorectal carcinomas and their lymph node metastases: Ploidy, p53, bcl-2, and c-myc expression-a pilot study. Tumour Biol 2015;36:6579-84.
Kim CY, Seo SH, An MS, Kim KH, Bae KB, Hwang JW, et al.
ERCC1 as a predictive marker for FOLFOX chemotherapy in an adjuvant setting. Ann Coloproctol 2015;31:92-7.
Shirota Y, Stoehlmacher J, Brabender J, Xiong YP, Uetake H, Danenberg KD, et al.
ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 2001;19:4298-304.
Vilmar A, Sorensen JB. Excision repair cross-complementation group 1 (ERCC1) in platinum based treatment of non-small cell lung cancer with special emphasis on carboplatin: A review of current literature. Lung Cancer 2009;64:131-9.
Park DJ, Zhang W, Stoehlmacher J, Tsao-Wei D, Groshen S, Gil J, et al.
ERCC1 gene polymorphism as a predictor for clinical outcome in advanced colorectal cancer patients treated with platinum-based chemotherapy. Clin Adv Hematol Oncol 2003;1:162-6.
Kwon HC, Roh MS, Oh SY, Kim SH, Kim MC, Kim JS, et al.
Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S
-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer. Ann Oncol2007;18:504-9.
Abd AlRahman Mohammad Foda
Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura - 35516
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
| Article Access Statistics|
| Viewed||63 |
| Printed||4 |
| Emailed||0 |
| PDF Downloaded||24 |
| Comments ||[Add] |