Year : 2019 | Volume
: 62 | Issue : 3 | Page : 366--367
Biomarker for colorectal carcinoma -ERCC1-New kid on the block
Department of Histopathology, SRL Ltd Fortis Escort Heart Institute [FEHI], Okhla, New Delhi, India
Department of Histopathology, SRL Ltd Fortis Escort Heart Institute [FEHI], Okhla, New Delhi
|How to cite this article:|
Bansal N. Biomarker for colorectal carcinoma -ERCC1-New kid on the block.Indian J Pathol Microbiol 2019;62:366-367
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Bansal N. Biomarker for colorectal carcinoma -ERCC1-New kid on the block. Indian J Pathol Microbiol [serial online] 2019 [cited 2019 Aug 19 ];62:366-367
Available from: http://www.ijpmonline.org/text.asp?2019/62/3/366/263504
DNA damage that occurs during cellular replication is repaired by several pathways that protect cellular DNA such as nucleotide excision repair (NER), mismatch repair (MMR), double-strand break repair (DSBR), base excision repair (BER), and direct repair.
Of these varied repair pathways, two have gained importance in recent past because of their vast application in tumor pathogenesis and guiding cancer therapies, these are MMR proteins and NER pathways.
MMR defects are produced from germline mutations in any one of the MLH1, MSH2, MSH6, or PMS2 genes. 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). Role of MSI has been established in colon carcinomas by several studies. dMMR (deficient MMR) is known to be associated with a special subset of colon carcinoma patients known as hereditary nonpolyposis colorectal cancer or Lynch syndrome. Therapeutic role of MMR status in colon carcinoma is studied by Boland et al. who stated 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.
Excision repair cross-complementing group 1 (ERCC1) is a rate-limiting molecule in the NER pathway of DNA repair. This gene repairs DNA adducts induced by platinum drugs. In patients where ERCC1 pathway is deficient, the damaged DNA formed by platinum-based chemotherapeutic drugs cannot be repaired and thus the tumor cells will be damaged and therapeutic response will be good.
Oncologists have always been searching for diagnostic tools that can predict which first-line chemotherapy option is best for an individual patient. Choice of first-line therapy is of great importance especially in mCRC as it has been shown that patients who respond to first-line therapy have longer overall survival.
The utility of ERCC1 to predict response to platinum-based chemotherapy has led to development of immunohistochemical markers to diagnose its status in cancer patients. 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.
However, the type of clone used for ERCC1 antibody also affects the immunohistochemical staining within the cells. Anti-ERCC1 clone 4F9 and FL297 usually stains cytoplasm, whereas clones OTI1A3 and 8F1 result in nuclear staining., Clone 8F1 is usually considered acceptable tool to determine nuclear ERCC1 protein expression in tissues of solid tumors of epithelial origin.
As both ERCC1 and MMR proteins are involved in DNA repair, several authors have tried to extrapolate if there is any association between expression of MMR and ERCC1 in CRC. Li et al. showed that patients with retained expression of MMR tended to have positive ERCC1 expression. Tóth et al. reported that loss of MLH1 and MSH2 was associated with lower expression or loss of ERCC1 in colorectal liver metastasis. The difference in expression levels of ERCC1 in various CRC subgroups is reported by Shimamoto et al. who found that the lowest levels of expression of ERCC1 were observed in patients with mucinous adenocarcinoma, whereas the highest level of expression was observed in patients with poorly differentiated adenocarcinoma.
Owing to the well-known genetic differences between mucinous and nonmucinous colorectal carcinomas, it is important to study the association between ERCC1 and MMR expression separately in these subgroups.
Thus, although the expression of ERCC1 and MMR proteins are being utilized for guiding therapies and predicting prognosis, further research about the relation between various DNA repair pathways is needed. Development of a diagnostic tool that measures the repair capacity of the cell as a whole inclusive of all repair pathways will give better insight in this area. Also, different CRC subgroups should be evaluated separately for expression of these genes.
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Conflicts of interest
There are no conflicts of interest.
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