ERCC1 Measurements in Clinical Oncology
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《新英格兰医药杂志》
Clinical oncology has struggled for decades with the predicament of the toxicity of chemotherapy for the treatment of malignant disease. For example, cisplatin and its analogues, carboplatin and oxaliplatin, are commonly used anticancer agents, but they are particularly toxic. Moreover, some patients benefit substantially from treatment with these drugs, whereas others suffer the toxic effects of the drugs without obtaining real benefit. The use of molecular markers to help identify who may benefit and who may not is one of the most exciting new areas of study in oncology.
The randomized International Adjuvant Lung Cancer Trial (IALT) found a modest benefit (4.1 percentage points) in 5-year survival among 1867 patients who were treated with adjuvant cisplatin-based chemotherapy.1 In this issue of the Journal, Olaussen and colleagues from the IALT Biology (IALT Bio) study report the assessment of a marker for the repair of cisplatin-induced DNA adducts in 761 specimens obtained before chemotherapy in the parent study.2 The results suggest that we may have a tool that can distinguish between patients who can benefit from platinum-based chemotherapy and those who cannot benefit from such treatment.
Cisplatin–DNA adducts are repaired by nucleotide excision repair, the DNA repair pathway that attends to DNA damage from polycyclic aromatic hydrocarbons and to DNA lesions caused by ultraviolet light and by exogenous chemicals that induce bulky DNA adducts, such as cisplatin and its analogues.3 The nucleotide excision repair proteins that recognize the damage and excise the adducts from the injured DNA strand differ from the proteins involved in mismatch repair, base excision repair, or double-strand break repair.3,4,5,6,7 Mismatch repair mends incorrect DNA base pairing and slipped intermediates and may link the persistence of DNA damage to apoptotic pathways. Base excision is a way of patching apurinic or apyrimidinic sites within DNA that result from oxidative damage or simple alkylations to DNA bases. Double-strand breaks can result from a range of severe insults to the cell.
ERCC1 (excision repair cross-complementation group 1) is 1 of 16 genes that encode the proteins of the nucleotide excision repair complex.6,7 This multiprotein complex also links the DNA repair process with other cellular processes, such as DNA transcription. Each protein within the complex has one or more specific functions. In excising DNA damage, ERCC1 forms a heterodimer with a protein called XPF. This heterodimer performs the 5' excision in the DNA strand, relative to the site of DNA damage, after all other excision substeps have been completed. This final step in the excision of damaged regions of DNA may limit the rate of the entire nucleotide excision repair process.
In Chinese hamster ovary cells, an ERCC1 defect causes the most severe DNA repair-deficiency phenotype yet found.6,7 In mice, ERCC1 is essential for normal aging, brain development, and immunoglobulin gene (isotype) switching, and it may contribute to homologous recombination in DNA and the repair of double-strand breaks in DNA. ERCC1 knockout mice die shortly after weaning. There is no reported case of a living human with an ERCC1 defect. This gene, or some form of it, exists in every organism above, and inclusive of, bacteria. It is thought to be essential for life.
Several groups have investigated the influence of ERCC1 on resistance to anticancer chemotherapy.4,5 Collectively, the data suggest that ERCC1 is a good marker for cellular or clinical resistance to cisplatin, carboplatin, and oxaliplatin. The ERCC1 gene has a number of complexities that appear to affect the cellular expression and function of the ERCC1 protein. These complexities include multiple variants of alternative splicing of the RNA translation product of ERCC1 and polymorphisms of the ERCC1 gene. These complexities influence resistance to platinum compounds. Factors that affect ERCC1 messenger RNA and expression of the ERCC1 protein include the transcriptional regulators activator protein 1 and extracellular signal-related kinase, which seem to up-regulate ERCC1 activity8,9; human myeloid zinc finger 1 and regulatory factor X1 may have inhibitory influences on the protein.10,11
Studies linking ERCC1 to resistance to platinum compounds have been conducted, for the most part, through analyses of RNA or DNA.4,5 A recent study in colorectal cancer, which assessed a polymorphism that reduces ERCC1 protein expression in cells, found a correlation between ERCC1 levels and clinical sensitivity to oxaliplatin12 — findings analogous to those of the IALT Bio study.2 Protein expression has been studied in a range of cell lines, and similar correlations with levels of ERCC1 and sensitivity to cisplatin have been reported. The IALT Bio study is the first large clinical study to use protein levels as the tool to assess ERCC1.
In the IALT Bio study, patients who had non–small-cell lung cancer with no detectable ERCC1 had longer disease-free survival after cisplatin-based chemotherapy than did patients with a tumor that contained ERCC1 (P<0.001). Also, in the group with no ERCC1 protein in the tumor, median overall survival was 14 months longer in those receiving chemotherapy than in those not receiving chemotherapy (P=0.002). In the group with ERCC1-positive tumors, there were no differences in survival between patients who received cisplatin chemotherapy and patients who did not receive the drug.
Protein expression is the desirable end point for any gene for which biologic significance is sought. In the IALT Bio study, ERCC1 protein was assessed in stored tumor specimens. With such specimens, finely tuned measurements of protein levels or assessments of the function of a protein are not possible. ERCC1-negative tumors would be expected to have low DNA repair efficiency; ERCC1-positive tumors should have high DNA repair efficiency, but such evidence could not be adduced from the IALT Bio study. For this reason, we can only assume that the resistance to cisplatin found in both the IALT studies was indeed associated with high DNA repair activity in ERCC1-positive tumors.
The results of the IALT Bio study do not imply that ERCC1 is a marker for resistance to all types of chemotherapy. Nor should these results be taken to imply that ERCC1 is the only marker that is appropriate for cisplatin resistance. However, this study does confirm the findings of many other smaller studies that suggest that ERCC1 expression (RNA or protein) is the most useful marker of resistance to cisplatin and its analogues. Now the question is whether this information can be used prospectively.
No potential conflict of interest relevant to this article was reported.
The views presented do not necessarily reflect the official view of the Centers for Disease Control and Prevention.
Source Information
From the Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta.
References
The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004;350:351-360.
Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006;355:983-991.
Reed E. Cisplatin, carboplatin, and oxaliplatin. In: Chabner BA, Longo DL, eds. Cancer chemotherapy and biotherapy: principles and practice. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2006:332-43.
Reed E. ERCC1 and clinical resistance to platinum-based therapy. Clin Cancer Res 2005;11:6100-6102.
Reed E. Nucleotide excision repair and anti-cancer chemotherapy. Cytotechnology 1998;27:187-201.
Sancar A, Reardon JT. Nucleotide excision repair in E. coli and man. Adv Protein Chem 2004;69:43-71.
Mitchell JR, Hoeijmakers JH, Niedernhofer LJ. Divide and conquer: nucleotide excision repair battles cancer and ageing. Curr Opin Cell Biol 2003;15:232-240.
Li Q, Gardner K, Zhang L, Tsang B, Bostick-Bruton F, Reed E. Cisplatin induction of ERCC-1 mRNA expression in A2780/CP70 human ovarian cancer cells. J Biol Chem 1998;273:23419-23425.
Li Q, Ding L, Yu JJ, et al. Cisplatin and phorbol ester independently induce ERCC-1 protein in human ovarian carcinoma cells. Int J Oncol 1998;13:987-992.
Yan Q-W, Reed E, Zhong X-S, Thornton K, Guo Y, Yu JJ. MZF1 possesses a repressively regulatory function in ERCC1 expression. Biochem Pharmacol 2006;71:761-771.
Yu JJ, Thornton K, Guo Y, Kotz H Reed E. An ERCC1 splicing variant involving the 5'-UTR of the mRNA may have a transcriptional modulatory function. Oncogene 2001;20:7694-7698.
Viguier J, Boige V, Miquel C, 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;11:6212-6217.(Eddie Reed, M.D.)
The randomized International Adjuvant Lung Cancer Trial (IALT) found a modest benefit (4.1 percentage points) in 5-year survival among 1867 patients who were treated with adjuvant cisplatin-based chemotherapy.1 In this issue of the Journal, Olaussen and colleagues from the IALT Biology (IALT Bio) study report the assessment of a marker for the repair of cisplatin-induced DNA adducts in 761 specimens obtained before chemotherapy in the parent study.2 The results suggest that we may have a tool that can distinguish between patients who can benefit from platinum-based chemotherapy and those who cannot benefit from such treatment.
Cisplatin–DNA adducts are repaired by nucleotide excision repair, the DNA repair pathway that attends to DNA damage from polycyclic aromatic hydrocarbons and to DNA lesions caused by ultraviolet light and by exogenous chemicals that induce bulky DNA adducts, such as cisplatin and its analogues.3 The nucleotide excision repair proteins that recognize the damage and excise the adducts from the injured DNA strand differ from the proteins involved in mismatch repair, base excision repair, or double-strand break repair.3,4,5,6,7 Mismatch repair mends incorrect DNA base pairing and slipped intermediates and may link the persistence of DNA damage to apoptotic pathways. Base excision is a way of patching apurinic or apyrimidinic sites within DNA that result from oxidative damage or simple alkylations to DNA bases. Double-strand breaks can result from a range of severe insults to the cell.
ERCC1 (excision repair cross-complementation group 1) is 1 of 16 genes that encode the proteins of the nucleotide excision repair complex.6,7 This multiprotein complex also links the DNA repair process with other cellular processes, such as DNA transcription. Each protein within the complex has one or more specific functions. In excising DNA damage, ERCC1 forms a heterodimer with a protein called XPF. This heterodimer performs the 5' excision in the DNA strand, relative to the site of DNA damage, after all other excision substeps have been completed. This final step in the excision of damaged regions of DNA may limit the rate of the entire nucleotide excision repair process.
In Chinese hamster ovary cells, an ERCC1 defect causes the most severe DNA repair-deficiency phenotype yet found.6,7 In mice, ERCC1 is essential for normal aging, brain development, and immunoglobulin gene (isotype) switching, and it may contribute to homologous recombination in DNA and the repair of double-strand breaks in DNA. ERCC1 knockout mice die shortly after weaning. There is no reported case of a living human with an ERCC1 defect. This gene, or some form of it, exists in every organism above, and inclusive of, bacteria. It is thought to be essential for life.
Several groups have investigated the influence of ERCC1 on resistance to anticancer chemotherapy.4,5 Collectively, the data suggest that ERCC1 is a good marker for cellular or clinical resistance to cisplatin, carboplatin, and oxaliplatin. The ERCC1 gene has a number of complexities that appear to affect the cellular expression and function of the ERCC1 protein. These complexities include multiple variants of alternative splicing of the RNA translation product of ERCC1 and polymorphisms of the ERCC1 gene. These complexities influence resistance to platinum compounds. Factors that affect ERCC1 messenger RNA and expression of the ERCC1 protein include the transcriptional regulators activator protein 1 and extracellular signal-related kinase, which seem to up-regulate ERCC1 activity8,9; human myeloid zinc finger 1 and regulatory factor X1 may have inhibitory influences on the protein.10,11
Studies linking ERCC1 to resistance to platinum compounds have been conducted, for the most part, through analyses of RNA or DNA.4,5 A recent study in colorectal cancer, which assessed a polymorphism that reduces ERCC1 protein expression in cells, found a correlation between ERCC1 levels and clinical sensitivity to oxaliplatin12 — findings analogous to those of the IALT Bio study.2 Protein expression has been studied in a range of cell lines, and similar correlations with levels of ERCC1 and sensitivity to cisplatin have been reported. The IALT Bio study is the first large clinical study to use protein levels as the tool to assess ERCC1.
In the IALT Bio study, patients who had non–small-cell lung cancer with no detectable ERCC1 had longer disease-free survival after cisplatin-based chemotherapy than did patients with a tumor that contained ERCC1 (P<0.001). Also, in the group with no ERCC1 protein in the tumor, median overall survival was 14 months longer in those receiving chemotherapy than in those not receiving chemotherapy (P=0.002). In the group with ERCC1-positive tumors, there were no differences in survival between patients who received cisplatin chemotherapy and patients who did not receive the drug.
Protein expression is the desirable end point for any gene for which biologic significance is sought. In the IALT Bio study, ERCC1 protein was assessed in stored tumor specimens. With such specimens, finely tuned measurements of protein levels or assessments of the function of a protein are not possible. ERCC1-negative tumors would be expected to have low DNA repair efficiency; ERCC1-positive tumors should have high DNA repair efficiency, but such evidence could not be adduced from the IALT Bio study. For this reason, we can only assume that the resistance to cisplatin found in both the IALT studies was indeed associated with high DNA repair activity in ERCC1-positive tumors.
The results of the IALT Bio study do not imply that ERCC1 is a marker for resistance to all types of chemotherapy. Nor should these results be taken to imply that ERCC1 is the only marker that is appropriate for cisplatin resistance. However, this study does confirm the findings of many other smaller studies that suggest that ERCC1 expression (RNA or protein) is the most useful marker of resistance to cisplatin and its analogues. Now the question is whether this information can be used prospectively.
No potential conflict of interest relevant to this article was reported.
The views presented do not necessarily reflect the official view of the Centers for Disease Control and Prevention.
Source Information
From the Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta.
References
The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004;350:351-360.
Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006;355:983-991.
Reed E. Cisplatin, carboplatin, and oxaliplatin. In: Chabner BA, Longo DL, eds. Cancer chemotherapy and biotherapy: principles and practice. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2006:332-43.
Reed E. ERCC1 and clinical resistance to platinum-based therapy. Clin Cancer Res 2005;11:6100-6102.
Reed E. Nucleotide excision repair and anti-cancer chemotherapy. Cytotechnology 1998;27:187-201.
Sancar A, Reardon JT. Nucleotide excision repair in E. coli and man. Adv Protein Chem 2004;69:43-71.
Mitchell JR, Hoeijmakers JH, Niedernhofer LJ. Divide and conquer: nucleotide excision repair battles cancer and ageing. Curr Opin Cell Biol 2003;15:232-240.
Li Q, Gardner K, Zhang L, Tsang B, Bostick-Bruton F, Reed E. Cisplatin induction of ERCC-1 mRNA expression in A2780/CP70 human ovarian cancer cells. J Biol Chem 1998;273:23419-23425.
Li Q, Ding L, Yu JJ, et al. Cisplatin and phorbol ester independently induce ERCC-1 protein in human ovarian carcinoma cells. Int J Oncol 1998;13:987-992.
Yan Q-W, Reed E, Zhong X-S, Thornton K, Guo Y, Yu JJ. MZF1 possesses a repressively regulatory function in ERCC1 expression. Biochem Pharmacol 2006;71:761-771.
Yu JJ, Thornton K, Guo Y, Kotz H Reed E. An ERCC1 splicing variant involving the 5'-UTR of the mRNA may have a transcriptional modulatory function. Oncogene 2001;20:7694-7698.
Viguier J, Boige V, Miquel C, 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;11:6212-6217.(Eddie Reed, M.D.)