Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients

Abstract

Platinum agents cause DNA cross-linking. Nucleotide excision repair genes play a key role in DNA damage repair. This study aims to investigate whether polymorphisms in these genes are associated with tumor response and survival in cisplatin-treated osteosarcoma patients. Eight single nucleotide polymorphisms in ERCC2, XPC, XPA, ERCC1, ERCC4 and ERCC5 genes were analyzed in 91 patients diagnosed with osteosarcoma and treated with cisplatin. A significant association with tumor response, after correction for multiple testing, was found for the Lys751Gln polymorphism in the ERCC2 gene. We found that only 45% of patients with at least one polymorphic G allele responded compared with 80% of patients homozygous for the common T allele (odds ratio=4.9, 95% confidence interval=1.64–14.54, adjusted P-value=0.047). In addition, carrying at least one ERCC2 Lys751GlnG allele was significantly associated with shorter event-free survival (median=184 months, compared with 240 months for TT homozygotes; hazard ratio=5.76, 95% confidence interval=1.30–25.55; P-value=0.021). Although ototoxicity was only recorded in 32 patients, we found weak evidence of an association with the CC genotype of XPC Lys939Gln (P-value= 0.042). This is the first pharmacogenetic study focused on osteosarcoma treatment providing evidence that polymorphic variants in DNA repair genes could be useful predictors of response to cisplatin chemotherapy in osteosarcoma patients.

Introduction

Osteosarcoma is one of the most frequent bone tumors, occurring mainly in young patients.1 Standard treatment for osteosarcoma involves neoadjuvant therapy before surgical resection of the primary tumor, followed by post-operative chemotherapy.2

One of the most consistent prognostic factors for osteosarcoma is the histological response to pre-operative treatment,3 evaluated as the percentage of tumor necrosis; which correlates with event-free survival (EFS) and overall survival.4

Despite chemotherapy and surgery, some (about 30%) patients relapse or metastasize.5 As strategies such as the intensification of chemotherapy and the addition of other agents have not led to long-term benefits, many efforts are directed at identifying factors that could predict drug response and clinical outcome.

Cisplatin is one of the chemotherapeutic agents most used in osteosarcoma therapy, together with doxorubicin and methotrexate.2 Cisplatin causes DNA lesions by forming intra-strand and inter-strand cross-links that result in DNA distortion and inhibition of DNA replication.6 The nucleotide excision repair (NER) pathway is one of the major DNA repair systems involved in the removal of platinum adducts.7 The NER pathway is formed by a complex network of many proteins involved in lesion recognition, excision, DNA resynthesis and ligation.

Alterations in NER genes expression8 as well as the presence of single nucleotide polymorphisms (SNPs)9 are correlated with cisplatin resistance. SNPs in the ERCC1 and ERCC210 genes have been found to be associated with platinum response in different clinical studies. In particular, the ERCC2 Lys751Gln variant was associated with reduced survival and worse prognosis in platinum-treated non-small-cell lung cancer11 and colorectal cancer patients,12 respectively.

In this study we investigated the relationship of eight SNPs in six NER genes to cisplatin response and survival in osteosarcoma patients.

Associations between these SNPs and cisplatin-induced hearing impairment (ototoxicity) were also explored.

Results

Study population

The clinical features of the 91 osteosarcoma patients are summarized in Table 1. The median age at diagnosis was 15 years (range 4 to 34 years). Only 15 patients were older than 18 years at the time of recruitment and 51 (56%) were male. Most (59%) of the osteosarcoma were osteoblastic, whereas 17% were chondroblastic. The remainders (24%) were grouped together as ‘other’. At the time of diagnosis, 16% of the patients already presented metastasis, whereas 21% developed metastasis during follow-up. At the time of the final analysis on March 2007, the median follow-up was 91 months (range 10–272).

Table 1 Clinical characteristics of osteosarcoma patients (N=91)

Single nucleotide polymorphism frequencies

The genotypic frequencies of the eight SNPs are shown in Table 2. All of them are common SNPs with minor allele frequencies between 0.19 and 0.46. There was no evidence of departure from the Hardy–Weinberg equilibrium for any of them.

Table 2 Genotype distribution, logistic regression and Cox regression analyses assessing associations of polymorphisms with tumor response and event-free survival

Tumor response

Forty-two (60%) of the 70 patients for whom necrosis data were available were classified as good responders. The results of tumor response to treatment by genotype are shown in Table 2. A significant association was detected for the presence of at least one polymorphic allele of each of Lys751Gln in ERCC2 and Lys939Gln in XPC. In particular, the polymorphic G allele of Lys751Gln was associated with a poor response: the estimated odds ratio (OR) under a dominant model was 4.89 (95% confidence interval (CI)=1.64–14.54) (P-value=0.004). We found that only 45% (18 of 40) of patients with at least one G allele were good responders compared with 80% (24 of 30) of patients homozygous for the T allele. On the contrary, the polymorphic C allele of XPC Lys939Gln was significantly associated with good response (OR=0.34, 95% CI=0.12–0.91, P-value=0.032). For this SNP, 71% (29 of 41) of carriers of at least C allele responded to therapy compared with 45% (13 of 29) of patients homozygous for the A allele. No substantial changes were observed in these ORs after adjustment for each of cisplatin doses, tumor location and metastasis at diagnosis as covariates. Only the association with ERCC2 Lys751Gln polymorphism was maintained after correction for multiple testing (adjusted P-value=0.047). No evidence of association was found for the other polymorphisms in the NER genes considered.

Event-free survival

The polymorphic G allele of Lys751Gln was significantly associated with shorter EFS (hazard ratio under a dominant model=5.76, 95% CI=1.30–25.55, P-value =0.021) (Table 2 and Figure 1). The median EFS of patients that carried the GG genotype was 141 months compared with 240 months for TT homozygotes.

Figure 1
figure1

Kaplan–Meier curves for event-free survival (EFS) of osteosarcoma patients treated with platinum-based therapy. Analysis for ERCC2 Lys751Gln (X2=6.82, P-value=0.009).

No substantial changes were observed in this hazard ratio reported above after adjustment for each of cisplatin doses, tumor location, metastasis at diagnosis and tumor necrosis as covariates.

Association with ototoxicity

Data on ototoxicity were available for 32 patients. We detected a marginally significant association between this specific type of toxicity and rs2228001 (XPC) (Table 3). Ototoxicity was observed in 27% in patients with the AA genotype compared with 80% in patients with the CC genotype (OR=17.16, 95% CI=1.10–266.8, P-value=0.042). The frequencies of the AA, AC and CC genotypes in this SNP were 20, 53 and 27%, respectively in 15 patients with ototoxicity, and 47, 47 and 6%, respectively in the 17 patients without hearing impairment. Sixty-seven percent of the patients with ototoxicity were good responders.

Table 3 Logistic regression analysis for association of XPC Lys939Gln polymorphism with ototoxicity

Discussion

The identification of molecular markers capable of predicting response to treatment is essential for osteosarcoma, as there are few alternative treatments for patients who relapse.13 The only prognostic factors available are the presence of metastasis, tumor necrosis after neoadjuvant chemotherapy, tumor location and tumor volume.2 Many studies are now focused on the identification of molecular prognostic markers, and molecular tumor profiling in particular, in order to improve the treatment of these tumors. To date, some pathways, such as CXCR4, survivin, MMP2 and MMP9, have been related to osteosarcoma patient outcome.14 Nevertheless, the genetic profile of the patients may also play a role in treatment response, so it would be of great interest also to explore the genetic variations in patients with osteosarcoma. Cisplatin is one of the most effective chemotherapeutic agents used for osteosarcoma treatment. As the NER pathway is responsible for the removal of DNA adducts induced by platinum compounds,6 we analyzed the association between treatment response and polymorphisms in the NER genes ERCC2, XPC, ERCC1, ERCC4, ERCC5 and XPA in osteosarcoma patients treated with cisplatin.

In our study, carrying at least one G allele in ERCC2 Lys751Gln conferred an estimated fivefold risk of poor tumor response in osteosarcoma patients treated with cisplatin. This result was consistent with that observed for survival, with nearly fivefold increased risk of relapse or death.

The association between the ERCC2 Lys751Gln polymorphism and platinum response has already been described.10, 12, 15

On the contrary, some reports in lung cancer didn't find an association between this polymorphism and cisplatin response;16, 17, 18 further studies to elucidate the real role of ERCC2 Lys751Gln polymorphism on cisplatin response are warranted. Regarding the other variant in the ERCC2 gene, the ERCC2 Asp312Asn polymorphism, we observed a trend of an increased risk of poor tumor response and reduced EFS, but without reaching the statistical significance.

Ruzzo et al.12 also studied ERCC2 Asp312Asn, and found that the association with platinum response seemed to be weaker than for Lys751Gln, located 12 kb downstream. In our patient series, we have observed a similar trend of a weaker effect for Asp312Asn polymorphism. This finding could be explained by the fact that these two SNPs are in incomplete linkage disequilibrium (D′=0.66) in our sample. Therefore, our result suggests that the ERCC2 Lys751Gln polymorphism could be a better predictive marker for both clinical response and survival.

The mechanisms by which this polymorphism affects platinum response are not fully clear. The ERCC2 gene encodes a DNA helicase that is an essential component of the NER pathway. The effect of this polymorphism on DNA repair has been evaluated by functional studies with controversial results. Lunn et al.19 showed that carriers of the common T allele had a suboptimal DNA repair activity, whereas Spitz et al.20 reported that the polymorphic G variant was associated with lower DNA repair activity. On the other hand, some reports didn't find any evidence of association between this polymorphism and DNA repair activity.21, 22 The discrepancies observed between these studies could be because of the different assays used to measure DNA repair. As they measure different parameters, such as X-ray-induced chromatic aberrations and the host cell reactivation assay, they may not be appropriate for the evaluation of the effect of this polymorphism on DNA repair. Another possible explanation is that this polymorphism is not causal itself, but rather is in linkage disequilibrium with a functional polymorphism involved in cisplatin response. ERCC2 Lys751Gln is a coding SNP located in the last exon, close to the 3′UTR region. Variation in this region could affect the stability of mRNA or even the regulation of protein translation.

Although after conservative multiple testing correction the significant association is lost, our results suggest a possible role of XPC in platinum response. This gene encodes a protein of 940 amino acids that recognizes DNA damage, and XPC polymorphisms have earlier been related to cancer risk.23, 24 Additionally, the minor allele of XPC Lys939Gln could be associated with higher risk of ototoxicity, although the limited number of patients included in the analysis does not permit definitive conclusions. Although a recent paper25 has reported an association of polymorphisms in the drug metabolism gene, GSTP1, with ototoxicity in testicular cancer survivors,25 no studies relating XPC variation with hearing impairment have been published to date. A possible explanation for our observed association could be that Lys939Gln may reduce the activity of XPC, and thus its DNA repair capacity. This decrease in DNA repair capacity could enhance apoptosis in response to platinum in both tumor cells, increasing the cisplatin response, as well as in the normal outer hair cells of the organ of Corti, explaining the associated ototoxicity. Unfortunately, functional studies for this polymorphism have also yielded inconsistent results.26, 27 Additional studies are required to evaluate the role of XPC variations in cisplatin response and ototoxicity.

Despite the earlier published data reporting an association between ERCC1 SNPs and platinum response,28, 29 there was no strong evidence of this effect in our patients. We only observed a tendency towards an increased risk of poor tumor response and reduced EFS in patients carriers of the polymorphic alleles for ERCC1 Lys504Gln and ERCC1 Asn118Asn polymorphisms, but without reaching the statistical significance in none of the cases. The rest of variants analyzed in XPA, ERCC5 and ERCC4 genes were included in this study since previously described as cancer risk related variants24, 30, 31 that could be an indication of the implication of these variants in DNA repair efficiency. Despite so, we have not found any evidence of association with cisplatin response.

We have to highlight that because of the multidrug neoadyuvant therapy, the response and the outcome of the patients may be the result of the combination of all these drugs, and we cannot exclude the fact that the polymorphisms could be relevant to the response to some of the other agents.

However, to date, there is no clear evidence in the literature of an association between NER and sensitivity to the other drugs used in combination with cisplatin in osteosarcoma. In fact, the NER pathway removes cisplatin-induced DNA adducts7 and, to date, doesn't seem to be related to the damage induced by these other drugs. Therefore, the association found in our study with NER gene polymorphisms could be attributed to cisplatin drug administration in particular.

In conclusion, to our knowledge, this is the first study showing the involvement of polymorphisms in DNA repair genes in the response of osteosarcoma patients to chemotherapy. We found that polymorphisms in the ERCC2 gene, specifically ERCC2 Lys751Gln, could be a marker for predicting the tumor response and clinical outcome of osteosarcoma patients. Furthermore, for the first time we have found a possible evidence of a role of XPC in platinum response. However, further studies with larger number of patients are required to confirm our findings. Functional analyses for these associated SNPs are also required to elucidate their role in DNA repair activity.

Patients and methods

Patients, treatments and clinical variables

This retrospective study included 91 patients diagnosed with osteosarcoma and treated at the University Clinic of Navarra, Pamplona, Spain between 1986 and 2007. The study was approved by the ethics committee of the University Clinic.

Patients were treated preoperatively with intravenous (i.v.) adriamycin (three courses at 25–30 mg m–2 per day for 3 days), i.v. methotrexate (four courses of up to 14 g m–2 per day for 1 day) and intra-arterial cisplatin (three courses at 35 mg m–2 per day for 3 days) and, after surgery, the adjuvant chemotherapy included methotrexate (10 g m–2 per day for 1 day) and alternate cycles of i.v. cisplatin/adriamycin or i.v. actinomycin D (0.45 mg m–2 per day for 3 days), cyclophosfamide (500 mg m–2 per day for 3 days) and vincristine (1.5 mg m–2 per day for 1 day) up to 48 weeks of treatment.

The cumulative dose of platinum relative to the total body surface was recorded for each patient, considering both intra-arterial neoadjuvant and i.v. adjuvant treatment with cisplatin. Cisplatin was given at a dose ranging from 120 to 1131 mg m–2 for intra-arterial treatment and from 83 to 948 mg m–2 for i.v. treatment.

Treatment response was determined histologically by the percentage of necrosis induced in the tumor after neoadjuvant chemotherapy. Patients with <90% necrosis were classified as poor responders and those with 90% necrosis or higher, as good responders.32

Of the 91 osteosarcoma patients, 16 were excluded because the neoadyuvant regimen did not include cisplatin, and a further five lacked tumor response information. Therefore, a total of 70 were considered in the analysis of response to treatment.

Event-free survival was considered from tumor diagnosis to the first of disease recurrence, development of lung or bone metastases and/or death. Patients who were alive and free of disease at the last follow-up evaluation (March 2007) were censored at that time. Data for EFS were available for all the 91 patients included in the study.

Ototoxicity was evaluated using objective audiometric tests at the otorhynolaryngology consultation.

Other clinical data, including age, sex, tumor location, metastatic events (both at diagnostic or at follow-up) and relapses (disease recurrence in the same bone) were systematically recorded from the clinical records. Only conventional high-grade osteosarcomas were included, regardless of metastatic stage at diagnosis.

DNA extraction and genotyping

The peripheral blood samples were collected from patients in remission, with their informed consent, and data were encrypted, anonymized and linked to their clinical data. All blood samples were chemonaïve, as they were obtained either at the time of first consultation before chemotherapy or at long-term remission. Only in one case the sample was collected after the first cycle of chemotherapy.

Genomic DNA was extracted from the peripheral blood lymphocytes, using standard protocols of phenol–chloroform extraction. DNA was quantified using PicoGreen (Invitrogen Corp., Carlsbad, CA, USA) and diluted to a final concentration of 5 ng μl–1 for genotyping. A total of 10 ng of DNA were used for each genotyping reaction.

Eight SNPs located in six DNA repair genes were analyzed: Lys751Gln (rs13181) and Asp312Asn (rs1799793) in ERCC2 (excision repair group 2), Lys939Gln (rs2228001) in XPC (xeroderma pigmentosum group C), Lys504Gln (rs3212986) and Asn118Asn (rs11615) in ERCC1 (excision repair group 1), rs744154 in ERCC4 (excision repair group 4) intron 1, His46His (rs1047768) in ERCC5 (excision repair group 5) and rs1800975 in XPA 5′UTR (xeroderma pigmentosum group A) genes. All these SNPs have been related to platinum and radiotherapy response and/or risk of cancer in other type of tumors.9, 10, 11, 12, 24, 30, 31 Genotypes were determined by TaqMan SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) for all SNPs, except rs1800975 (or which the KASPar SNP genotyping system was used (KBioscience, Hoddesdon, UK). Allelic discrimination was carried out using the ABI PRISM 7900 Sequence Detection System (Applied Biosystems). Duplicate samples were genotyped as a quality control.

Statistical analysis

Associations between SNPs and platinum response were assessed using logistic regression analysis,33 comparing genotype frequencies in good responders and poor responders, and estimating odds ratios. Homozygotes for the most frequent allele were used as the reference group. In addition to the model comparing the genotypes separately (co-dominant model), we considered dominant and recessive models, the best fitting model determined by parsimony. P-values were corrected for multiple comparisons using a permutation test. We randomly assigned the status of responder/non-responder, and recorded the minimum P-value from co-dominant, dominant and recessive models among all SNPs considered. This was repeated 10 000 times to generate the empirical distribution of minimum values, and the proportion less than a given observed P-value was considered the corresponding adjusted P-value.

Single nucleotide polymorphisms showing evidence of an association with tumor response were then assessed in relation to event-free survival using Cox regression analysis.34

Tumor location (femur, tibia, arm and central), cisplatin cumulative dose (continuous) and metastasis at diagnosis were included as covariates in multivariable logistic regression and Cox regression analyses.

The SPSS software (version.13.0, SPSS Inc., Chicago, IL, USA) was used for all analyses, and P-values <0.05 were considered statistically significant.

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Acknowledgements

The work was funded by FIS EC07/90305 and the Genome Spain Foundation

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Correspondence to A González-Neira.

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The authors declare no conflict of interest.

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Caronia, D., Patiño-García, A., Milne, R. et al. Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients. Pharmacogenomics J 9, 347–353 (2009). https://doi.org/10.1038/tpj.2009.19

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Keywords

  • cisplatin
  • single nucleotide polymorphisms
  • tumor response
  • osteosarcoma

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