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Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

The aim of the current study was to evaluate the relation between xeroderma pigmentosum complementation group C (XPC) polymorphisms and susceptibility to breast cancer (BC), the development and progression of disease, and response to different individualized drug treatments. We investigated two polymorphisms in XPC Ala499Val and Lys939Gln using PCR-RFLP assays including 618 cases and 622 controls. The frequency of the TT genotype of Ala499Val (adjusted odds ratio = 1.575; 95% confidence interval, 1.104–2.245; P = 0.012) and the AC genotype of Lys939Gln (adjusted odds ratio = 1.330; 95% confidence interval, 1.045–1.694; P = 0.020) were found to significantly increase the risk of developing BC. The CT+TT genotypes of Ala499Val were associated with estrogen receptor positive, and Her-2 and p53 negative status, and the AC+CC genotypes of Lys939Gln were associated with BRCA1 negative status. Moreover, a significantly increased chance of treatment with neoadjuvant anthracycline-based chemotherapy response was found in women carrying TT genotype of Ala499Val, or CC and AC genotypes of Lys939Gln. In addition, a significantly longer overall survival after chemotherapy was observed in patients who had XPC Lys939Gln AC+CC genotypes with estrogen receptor positive (log–rank test, = 0.086) and p53 negative (log–rank test, = 0.020). The current data suggested that XPC Ala499Val and Lys939Gln polymorphisms may contribute to the identification of patients with increased risk for BC. Moreover, the polymorphisms were associated with the prognosis of BC patients. (Cancer Sci 2012; 103: 1207–1214)

Breast cancer is the most common neoplasm among women. Similar to other cancers, breast cancer is the ultimate outcome of multiple hereditary and environmental factors, most likely including genetic mutations that are particularly important in DNA repair genes.[1] Polymorphisms in DNA repair genes have been reported that could lead to a deficiency in DNA repair capacity, subsequently contributing to genomic instability and an increase in an individual's susceptibility to cancer.[2-4] Several epidemiologic studies have identified some of single nucleotide polymorphisms (SNPs) in DNA repair genes as risk factors for cancers.[5-7]

As an important DNA damage recognition protein, xeroderma pigmentosum complementation group C (XPC) is involved in global genome DNA repair, a subclass of nucleotide excision repair (NER).[8] The XPC gene is localized at 3p25 and encodes a protein of 940 amino acids.[9] In the XPC gene, two common polymorphisms have been widely studied: (i) a substitution of alanine for valine in codon 499 (Ala499Val), with a C-to-T transition in exon 8, in the interaction domain of XPC with hHRAD23; and (ii) an A-to-C transition in exon 15 resulting in a lysine-to-glutamine transition at position 939 (Lys939Gln), located in the interaction domain with TFIIH. Previous studies have reported on the associations between SNPs in the XPC gene with risk of breast cancer,[10, 11, 4, 12-14] lung cancer,[15-21] bladder cancer,[22-25] and other cancers,[26-32] but the results were inconclusive. These findings suggested that the effects of these polymorphisms remained unclear, and further investigations were needed to resolve these discrepancies. Therefore, we investigated the association of the two SNPs with susceptibility to breast cancer (BC), the development and progression of disease, and patients’ responses to different individualized drug treatments.

In the present study, we carried out a case–control study of spontaneous BC patients and age/gender frequency-matched healthy controls to assess whether the two SNPs XPC Ala499Val and XPC Lys939Gln contributed to increased BC susceptibility. We further explored the association between the polymorphisms, the clinicopathological profile of BC, and therapeutic outcomes after adjuvant anthracycline-based chemotherapy.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Study subjects

The study was approved by the regional ethics committee at China Medical University (Shenyang, China). All breast cancer patients who participated in the study underwent surgery at the First Hospital of China Medical University between January 2005 and December 2010 and were of Han Chinese ethnicity, unrelated to each other, newly diagnosed, with pathologically confirmed disease, and previously untreated. The control subjects, women randomly selected from the same geographical region with no history of cancer, were frequency-matched to the cases in terms of age (±5 years) and ethnicity.

A clinical oncologist collected clinical and pathological characteristics and therapeutic response after chemotherapy retrospectively from medical records. Clinical data were collected from medical records including age at the time of diagnosis, menopause status, tumor size, tumor stage, tumor type, lymph node status, and estrogen receptor (ER), progesterone receptor, human epidermal growth factor receptor-2 (Her-2), tumor protein 53 (p53), breast cancer type 1 susceptibility protein (BRCA1), and BRCA2 status. Although patients received different types of chemotherapy, hormones, radiotherapy, or biological treatment, therapeutic outcome was evaluated only in those patients who received anthracycline-based (epirubicin [E] or doxorubicin [A]) chemotherapy. Anthracycline-based chemotherapy consists of cyclophosphamide (C), the anthracycline agent (E or A), and/or 5-fluorouracil (F), (CEF and CAF regimens) combined with radiotherapy.

According to Response Evaluation Criteria in Solid Tumors,[33] for patients with four times of the CEF/CAF program, the degree of sensitivity to chemotherapeutic drugs is divided into: (i) complete response (CR), the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; (ii) partial response (PR), at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; (iii) progressive disease (PD), at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also show an absolute increase of at least 5 mm; and (iv) stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Genotyping

DNA samples were obtained from stored blood samples using Qiagen standard protocols (Shanghai, China). Genotyping for XPC Ala499Val and Lys939Gln polymorphisms by PCR-RFLP assay was done following a modified method of Guo et al.[34] Primer sequences were: Ala499 Val, 5′-TAAGGACCCAAGCTTGCCCG-3′ (forward) and 5′-CCCACTTTTCCTCCTGCTCACAG-3′ (reverse); and Lys939Gln, 5′-ACCAGCTCTCAAGCAGAAGC-3′ (forward) and 5′-CTGCCTCAGTTTGCCTTCTC-3′ (reverse).

Polymerase chain reaction was carried out as follows: an initial melting step of 5 min at 94°C; 35 cycles of denaturation for 30 s at 94°C; annealing for 30 s at 63°C for Ala499Val, and 55°C for Lys939Gln; extension for 45 s at 72°C, followed by a 5 min final extension at 72°C. The PCR products were then digested with restriction endonucleases. For XPC Lys939Gln, the PCR products were digested with PvuII (New England BioLabs, Ipswich, MA, USA) overnight at 37°C. The variant C allele had a PvuII restriction site and after the digestion, two bands (150 and 131 bp) were generated; the wild-type A allele lacked this restriction site and a single band with a size of 281 bp was obtained. For XPC Ala499Val, the wild-type allele (C) produced two fragments of 131 and 21 bp and the polymorphic allele (T) produced a single 152 bp fragment.

For quality control, 10% of the two PCR-RFLP assays were randomly selected for sequencing. These results of the quality control analysis confirmed 100% concordance.

Statistical analysis

In order to match the groups of case and control in terms of several putative confounding factors, Pearson's 2 × 2 χ2-test (gender) and independent sample t-tests (mean age) were used for analysis of the differences of several qualitative and quantitative traits. To evaluate deviation from the Hardy–Weinberg equilibrium, the discrepancies between observed and expected genotype frequencies in patients and controls were compared using a χ2-test, with one degree of freedom. Genotypic risk of the two SNPs for BC, in terms of odds ratio (OR) and 95% confidence interval (CI), was derived from binary logistic regression analysis with SNP genotypes as the explainable variables. Overall survival (OS) was calculated as the time to progression or death without progression from the date of diagnosis. Survival distributions were estimated with the Kaplan–Meier method and compared with the log–rank test. Finally, the associations between individual epidemiologic risk factors, clinical characteristics, genotypes, and the time to the occurrence of BC were assessed using univariate and multivariate Cox regression analysis. In this study, the statistical analyses were carried out using spss version 13.0 statistical software (SPSS, Chicago, IL, USA). Statistical significance was set at < 0.05 and all tests were two-sided.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Subject characteristics

There were no significant differences in the distributions of age and menopausal state between cases and controls (P = 0.819 and P = 0.574), and the mean age was also matched for cases (range, 21–83 years; median, 45 years) and controls (range, 23–79 years; median, 47 years). Before statistical analysis, we also tested the two SNPs loci with the Hardy–Weinberg equilibrium. The SNPs in control populations did not significantly deviate from the Hardy–Weinberg equilibrium (data not shown). The demographics, risk exposure, clinical variables, and therapeutic outcome for all 618 BC patients are summarized in Table 1.

Table 1. Frequency distribution of selected variables in patients with breast cancer (n = 618)
CharacteristicCases (n = 618)
No.%
  1. †Contains cyclophosphamide, the anthracycline agent and/or 5-fluorouracil. ‡Treatments include docetaxel plus pirarubicin, surgery only, total parenteral nutrition, or traditional Chinese treatments. DIC, ductal invasive carcinoma; LIC, lobular invasive carcinoma.

Sex
Female618100
Age at diagnosis, years618 
≤4532552.6
>4529347.4
Menopausal status618 
Premenopausal33454.0
Postmenopausal28446.0
First-degree family history of breast cancer618 
No47276.4
Yes14623.6
Tumor size (cm)605 
≤2.025942.8
2.1–4.024540.5
4.1+10116.7
Lymph node metastasis410 
Node-negative21652.7
Node-positive19447.3
Histology618 
DIC53085.8
LIC6610.7
Others223.6
Therapeutic regimen
Anthracycline-based chemotherapy49179.4
Other chemotherapies or treatments12720.6

Genotypic association analysis of two SNPs between patients with BC and controls

Overall genotypes and allele frequencies for the XPC Ala499Val and Lys939Gln polymorphisms are shown in Table 2. We found a significant increase in the BC group (16.02%) compared with the control group (12.06%) in the frequency of the TT genotype of Ala499Val (= 0.012). Significantly different frequency was also observed for the CT+TT genotypes (= 0.030). For XPC Lys939Gln, the frequencies of the AC genotype were 51.94% and 46.92% for the BC and control group, respectively (= 0.020). Moreover, the AC+CC genotypes in the BC group (65.53%) has a higher frequency than the control group (58.84%) (= 0.015).

Table 2. Frequency distribution of XPC genotypes and their associations with risk of developing breast cancer
GenotypeCases (n = 618)Controls (n = 622)PAdjusted OR§ (95% CI)
No. (%)No. (%)
  1. †The observed genotype frequency among individuals in the control group was in agreement with Hardy–Weinberg equilibrium = 0.064 for XPC Ala499Val; = 0.659 for XPC Lys939Gln). ‡P-values were calculated from two-sided χ2-tests for either genotype distribution or allele frequency. §Odds ratio (OR) and 95% confidence interval (CI) values were calculated by unconditional logistic regression adjusted for age and menopausal status.

XPC Ala499Val
CC197 (31.88)235 (37.78) 1.00 (Ref.)
CT322 (52.10)312 (50.16)0.0961.231 (0.963–1.573)
TT99 (16.02)75 (12.06)0.0121.575 (1.104–2.245)
CT+TT421 (68.12)387 (62.22)0.0301.298 (1.027–1.640)
XPC Lys939Gln
AA213 (34.47)256 (41.2) 1.00 (Ref.)
AC321 (51.94)290 (46.6)0.0201.330 (1.045–1.694)
CC84 (13.59)76 (12.2)0.1211.328 (0.927–1.903)
AC+CC405 (65.53)366 (58.8)0.0151.330 (1.056–1.674)

Next, we used adjusted the OR values and 95% CI to predict risk of breast cancer using logistic regression analysis. The results showed that the CT+TT genotypes of XPC Ala499Val had a higher risk of BC (adjusted OR = 1.298; 95% CI, 1.027–1.640; P = 0.030). Patients with the TT genotype had a 1.58-fold increased risk of developing BC (adjusted OR = 1.575; 95% CI, 1.104–2.245; P = 0.012). In addition, the AC genotype (adjusted OR = 1.330; 95% CI, 1.045–1.694; P = 0.020) and the AC+CC genotypes (adjusted OR = 1.330; 95% CI, 1.056–1.674; P = 0.015) of Lys939Gln both have increased the risk of BC (Table 2).

Relation between genotype distribution and clinicopathologic characteristics

To investigate the effects of the two SNPs on the clinicopathological features of BC patients, we used the χ2-test and unconditional logistic regression adjusted by age and menopausal state. Clinical and pathological characteristics of the patients differentiated according to XPC genotypes are shown in Table 3.

Table 3. Correlations between clinicopathologic parameters and XPC Ala499Val and Lys939Gln polymorphisms in patients with breast cancer (n = 618)
Features

Total

no.

XPC Ala499ValXPC Lys939Gln

CC

No. (%)

CT+TT

No. (%)

POR (95% CI)§

AA

No. (%)

AC+CC

No. (%)

POR (95% CI)§
  1. †Median age was 45 years. ‡P- values were calculated from two-sided χ2-tests or Fisher's exact test. §Odds ratio (OR) and 95% confidence interval (CI) values were calculated by unconditional logistic regression adjusted for age and menopausal status. BRCA1, breast cancer type 1 susceptibility protein; BRCA2, breast cancer type 2 susceptibility protein; ER, estrogen receptor; DIC, ductal invasive carcinoma; LIC, lobular invasive carcinoma; Her-2, human epidermal growth factor receptor-2; NA, not applicable; p53, tumor protein 53; PR, progesterone receptor; ref., reference.

Age at diagnosis, years618  0.438   0.672 
≤45 99 (16.0)226 (36.6) 1.0 (ref.)115 (18.6)210 (34.0) 1.0 (ref.)
>45 98 (15.9)195 (31.6) 0.872 (0.621–1.223)98 (15.9)195 (31.6) 1.090 (0.781–1.520)
Menopausal status618  0.603   0.309 
Premenopausal 103 (16.7)231 (37.4) 1.0 (ref.)109 (17.6)225 (36.4) 1.00 (ref.)
Postmenopausal 94 (15.2)190 (30.7) 0.901 (0.642–1.265)104 (16.8)180 (29.1) 0.838 (0.601–1.169)
First-degree family history of breast cancer618  0.839   0.274 
No 149 (24.1)323 (52.3) 1.0 (ref.)157 (25.4)315 (51.0) 1.00 (ref.)
Yes 48 (7.8)98 (15.9) 0.942 (0.634–1.400)56 (9.1)90 (14.6) 0.801 (0.545–1.177)
Tumor size (cm)605  0.199   0.352 
≤2.0 78 (12.9)181 (29.9) NA83 (13.7)176 (29.1) NA
2.1–4.0 75 (12.4)170 (28.1) NA93 (15.4)152 (25.1) NA
≥4.1 40 (6.6)61 (10.1) NA33 (5.5)68 (11.2) NA
Lymph node metastasis410  0.916   0.079 
Node-negative 69 (16.8)147 (35.8) 1.0 (ref.)85 (20.7)131 (32.0) 1.0 (ref.)
Node-positive 63 (15.4)131 (32.0) 0.976 (0.645–1.478)60 (14.6)134 (32.7) 1.449 (0.963–2.181)
Histology618  0.507   0.732 
DIC 166 (26.9)364 (58.9) NA185 (29.9)345 (55.8) NA
LIC 25 (4.0)41 (6.6) NA22 (3.6)44 (7.1) NA
Others 6 (1.0)16 (2.6) NA6 (1.0)16 (2.6) NA
ER status610  0.011   0.438 
Negative 98 (16.1)160 (26.2) 1.0 (ref.)84 (13.8)174 (28.5) 1.0 (ref.)
Positive 99 (16.2)253 (41.5) 1.565 (1.112–2.204)126 (20.7)226 (37.0) 0.866 (0.617–1.216)
PR status609  0.078   0.795 
Negative 90 (14.8)157 (25.8) 1.0 (ref.)87 (14.3)160 (26.3) 1.0 (ref.)
Positive 107 (17.6)255 (41.9) 1.366 (0.969–1.926)123 (20.2)239 (39.2) 1.057 (0.752–1.484)
Her-2 status600  0.019   0.384 
Negative 41 (6.8)121 (20.2) 1.0 (ref.)60 (10.0)102 (17.0) 1.0 (ref.)
Positive 155 (25.8)283 (47.2) 0.619 (0.413–0.927)145 (24.2)293 (18.8) 1.189 (0.816–1.731)
p53 status598  0.010   0.546 
Negative 71 (11.9)197 (33.0) 1.0 (ref.)97 (16.2)171 (28.6) 1.0 (ref.)
Positive 120 (20.1)209 (35.0) 0.628 (0.441–0.893)111 (18.6)218 (36.5) 1.114 (0.794–1.562)
BRCA1 status587  0.823   <0.001 
Negative 38 (6.5)77 (13.1) 1.0 (ref.)19 (3.2)96 (16.4) 1.0 (ref)
Positive 149 (25.4)323 (55.0) 1.070 (0.693–1.652)186 (31.7)286 (48.7) 0.304 (0.180–0.515)
BRCA2 status574  0.235   0.789 
Negative 79 (13.8)149 (26.0) 1.0 (ref.)78 (13.6)150 (26.2) 1.0 (ref.)
Positive 103 (18.0)242 (42.2) 1.246 (0.872–1.780)122 (21.3)223 (38.9) 0.950 (0.669–1.351)

We observed that the distribution frequency of the CT+TT genotypes of XPC Ala499Val were associated with the patients who had ER positive status rather than the CC genotype (adjusted OR = 1.565; 95% CI, 1.112–2.204; = 0.011). The CT+TT genotypes were associated with Her-2 (adjusted OR = 0.619; 95% CI, 0.143–0.927; = 0.019) and p53 negative status (adjusted OR = 0.628; 95% CI, 0.441–0.893; = 0.010) (Table 3). For Lys939Gln, the AC+CC genotypes were associated with BRCA1 negative status (adjusted OR = 0.304; 95% CI, 0.180–0.515; < 0.001). There were no statistically significant correlations between genotype distributions and age at diagnosis, menopausal state, first-degree family history of breast cancer, tumor size, histology, clinical stage, or lymph node metastasis.

Association between genotypes and response to neoadjuvant chemotherapy

Neoadjuvant chemotherapy treatment is given to patients with the aim of reducing the size of the primary tumor to increase the likelihood of breast conservation and to abolish occult systemic metastases. In our study, only 72 patients received neoadjuvant anthracycline-based chemotherapy before surgical operation and 36 of them were CR and PR. For XPC Ala499Val, the TT genotype had a significantly higher response rate (73.3%; 11 responders among 15 patients). Statistical analysis showed a significantly increased chance of treatment response in women carrying the TT genotype (OR = 0.218; 95% CI, 0.053–0.895; P = 0.029). In addition, there were statistically significant associations between polymorphism of Lys939Gln and successful treatment with neoadjuvant anthracycline-based chemotherapy for the CC genotype (P = 0.013), the AC genotype (= 0.049), and the AC+CC genotypes (= 0.020) (Table 4). The results suggested that the polymorphisms of XPC may increase the sensitivity of neoadjuvant anthracycline-based chemotherapy and improve the effects of treatment of BC patients.

Table 4. Association of XPC polymorphisms with therapeutic response to neoadjuvant chemotherapy in breast cancer patients
VariableNo.RECIST P OR (95% CI)‡
CR and PR (%)SD and PD (%)
  1. P-values were calculated from χ2-tests or Fisher's exact test. ‡Odds ratio (OR) and 95% confidence interval (CI) values were calculated by unconditional logistic regression adjusted for age and menopausal status. CR, complete response; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; ref., reference; SD, stable disease.

XPC Ala499Val72    
CC249 (37.5)15 (62.5) 1.00 (ref.)
CT3316 (48.5)17 (51.5)0.4090.637 (0.218-1.862)
TT1511 (73.3)4 (26.7)0.0290.218 (0.053-0.895)
CT+TT4827 (58.3)21 (41.7)0.1370.467 (0.171-1.274)
XPC Lys939Gln72    
AA216 (28.6)15 (71.4) 1.00 (ref.)
AC4223 (54.8)19 (45.2)0.0490.330 (0.107-1.018)
CC97 (77.8)2 (22.2)0.0130.114 (0.018-0.716)
AC+CC5130 (58.8)21 (41.2)0.0200.280 (0.093-0.840)

Genotypic difference and therapeutic regimen, prognosis

In our study, OS was evaluated using the Kaplan–Meier method in BC patients (n = 618). But we did not find an association between the polymorphisms of Ala499Val (Fig. 1A) or Lys939Gln (Fig. 1B) and OS.

image

Figure 1. Kaplan–Meier curves illustrating the overall survival of breast cancer patients with XPC Ala499Val (A) and XPC Lys939Gln (B) polymorphisms.

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It is well established that anthracycline-based chemotherapy influences the outcome for BC patients, and it has been shown to be effective in the treatment of BC. Next, we further studied the hierarchical factors ER, progesterone receptor, Her-2, and p53 status in patients with BC who received anthracycline-based neoadjuvant and/or adjuvant chemotherapy. We found that the Lys939Gln polymorphism had the extended trend of OS for patients treated with anthracycline-based chemotherapy (log–rank test, P = 0.187) (Fig. 2A). Moreover, this trend was also found in patients with ER positive status who received anthracycline-based chemotherapy (log–rank test, P = 0.086) (Fig. 2B). The estimated median OS for patients with ER positive status who had the AA of XPC Lys939Gln genotype was 37.834 months (95%CI, 31.029–44.639) and for those with the AC+CC genotypes, 43.968 months (95% CI, 37.981–49.956). In addition, patients with p53 negative status with Lys939Gln AC+CC genotypes showed significantly longer OS (log–rank test, P = 0.020) (Fig. 2C). The estimated median OS for patients with p53 negative status who had the AA genotype and the AC+CC genotypes of XPC Lys939Gln was 34.883 months (95% CI, 29.748–40.018) and 42.569 months (95% CI, 37.844–47.294), respectively. However, for patients with p53 positive status, there was no statistically significant differences (log−rank test, P = 0.752) (Fig. 2D). And there was no statistically significant differences for Her-2 negative (log–rank test, P = 0.213) (Fig. 2E) and Her-2 positive status (log–rank test, P = 0.385) (Fig. 2F).

image

Figure 2. Kaplan–Meier curves illustrating the overall survival of breast cancer patients who received anthracycline-based neoadjuvant and/or adjuvant chemotherapy (A), patients with estrogen receptor (ER) positive status (B), p53 negative status (C), p53 positive status (D), Her-2 negative status (E), and Her-2 positive status (F).

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To estimate the independent impact of each variable on OS, a descriptive Cox proportional hazard model was carried out. Univariate analysis identified that the genotypes AC+CC of XPC Lys939Gln showed longer OS for the anthracycline-based chemotherapy patients with p53 negative status. Finally, multivariate Cox regression analysis also identified that XPC Lys939Gln (OR = 0.620, 95% CI, 0.389–0.987; = 0.044) was predictive of OS for patients (Table 5).

Table 5. Hazard ratios for overall survival (OS) in the breast cancer patients with anthracycline-based chemotherapy
VariableUnivariate P MultivariateP
HR (95% CI)HR (95% CI)
  1. P-values, odds ratios (OR), and 95% confidence intervals (CI) were assessed using univariate Cox regression analysis. ‡BRCA1, breast cancer type 1 susceptibility protein; BRCA2, breast cancer type 2 susceptibility protein; Her-2, human epidermal growth factor receptor; DIC, ductal invasive carcinoma; ER, estrogen receptor; HR, hazards ratio; LIC, lobular invasive carcinoma; p53, tumor protein 53; PR, progesterone receptor.

Age (≥45 years vs <45 years)1.003 (0.764–1.316)0.983  
Menopausal status (postmenopausal vs premenopausal)0.870 (0.662–1.143)0.318  
XPC Ala499Val (CT+TT vs CC)1.227 (0.922–1.633)0.160  
XPC Lys939Gln (AC+CC vs AA)0.717 (0.536–0.960)0.0250.620 (0.389–0.987)0.044
First-degree family history of breast cancer (yes vs no)1.064 (0.778–1.454)0.699  
Tumor size (>4 cm vs ≤4 cm)0.818 (0.667–1.002)0.053  
Histology (DIC/LIC vs others)1.064 (0.778–1.454)0.699  
Lymph node metastases (metastases vs non-metastases)1.441 (1.013–2.049)0.0421.585 (1.013–2.475)0.043
ER status (positive vs negative)0.966 (0.734–1.272)0.805  
PR status (positive vs negative)1.074 (0.815–1.414)0.613  
Her-2 status (positive vs negative)0.920 (0.692–1.221)0.562  
BRCA1 status (positive vs negative)0.997 (0.728–1.365)0.983  
BRCA2 status (positive vs negative)0.899 (0.674–1.199)0.469  

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Recently, the associations between XPC polymorphisms and the risk of BC have been widely studied, but the results were inconclusive. Smith et al.,[10] and Jorgensen et al.,[4] did not find the genotypes distribution of XPC Ala499Val and Lys939Gln in the USA. Försti A et al.[12] found that significant findings among Finnish were associations to XPC Lys939Gln, but these findings were not repeated in the Polish series. A meta-analysis[13] that involved a total of 11 studies including 2258 (44.36%) Caucasian, 1798 (35.32%) mixed, 814 (16.00%) African, and only 220 (4.32%) Asian BC cases (Zhang et al.[14]) reported that there was no significant association between the XPC Ala499Val or Lys939Gln polymorphisms and BC risk. However, they did not indicate an association between the polymorphisms and clinicopathological parameters or therapeutic outcome. Therefore, we investigated 618 BC cases to assess whether XPC Ala499Val and Lys939Gln polymorphisms contribute to increased susceptibility to BC, and we evaluated the association between the SNPs and the development and progression of disease, and response to different individualized drug treatments. We found that patients with the AC genotype of XPC Lys939Gln had a higher risk of BC (OR = 1.330), which agreed with the results of Zhang et al. and assessed many more BC cases in Asian women. Moreover, we found a significant increase in the frequency of the TT genotype of Ala499Val for the BC group, and the patients had increased risk of developing BC (OR = 1.575). It is suggested the XPC Ala499Val and Lys939Gln polymorphisms were both closely related to the development of BC in Chinese patients. It may be because the XPC protein binds with HR23B to form the heterodimeric complex, which is the first NER factor to detect a lesion and recruit the rest of the repair machinery to the damaged site.[35, 36] The specific binding of XPC–HR23B is an important molecular process, based on detection by the NER machinery of a wide variety of lesions that vary in terms of chemical structure during DNA repair.[8] The XPC gene polymorphisms, particularly nsSNP, may alter an individual's capacity to repair damaged DNA, possibly leading to genetic instability and carcinogenesis.

The XPC polymorphisms may cause instability in the DNA of tumor cells and promote tumor cell DNA damage, further increasing the efficacy of DNA-damaging agents. Topoisomerase II is an important ribozyme involved in DNA repair and replication processes. Anthracycline-based chemotherapy is currently one of the most commonly used chemotherapy regimens for BC patients and the main mechanism for it is the inhibition of DNA topoisomerase II. As an anticancer drug target, it combines to form stable drug–topoisomerase II–DNA complexes that cause the DNA breakage and lead to the death of tumor cells.[37] Therefore, this study examined XPC gene polymorphisms on the clinical efficacy of a DNA damage agent. We first reported that XPC polymorphisms were associated with the prognosis of anthracycline-based chemotherapy patients. Our study analyzed the therapeutic response to neoadjuvant anthracycline-based chemotherapy in BC patients in relation to XPC gene polymorphisms and found that the TT genotype of XPC Ala499Val had a significantly higher response rate. Patients with the Lys939Gln polymorphism were also more likely to be successfully treated with neoadjuvant anthracycline-based chemotherapy. In addition, we found that the Lys939Gln polymorphism has an extended trend of OS for anthracycline-based chemotherapy patients, and anthracycline-based chemotherapy patients with ER positive status. The result was consistent with Fleming et al.[38] who indicated that SNPs in the XPC gene may represent novel markers of ovarian cancer response to platinum-based chemotherapy. Notably, the patients with p53 negative status and Lys939Gln GC+CC genotypes showed significantly longer OS, suggesting that the GC+CC genotypes might increase the effects of anthracycline-based chemotherapy. The tumor suppressor p53 mainly induced apoptosis in the DNA damage response and p53 negative expression could cause instability of genome function.[39, 40] If p53 negative status was associated with the mutation of DNA repair gene XPC, it may decrease the ability to repair DNA, further increase the DNA double-strand breakages, and induce more tumor cell to death by anthracycline. Therefore, the effects of anthracycline-based chemotherapy could be more sensitive and have a longer OS in our study.

Moreover, our study analyzed the association between XPC polymorphisms and clinicopathological parameters. The results showed that the polymorphisms of XPC Ala499Val and Lys939Gln were associated with p53 and BRCA1 negative status, respectively. The results imply that XPC gene mutation can reduce the p53 and BRCA1 tumor suppressor role and further enhance the risk of cancer. In addition, the distribution frequencies of the XPC Ala499Val CT+TT genotypes were associated with patients who were ER positive. It showed us that XPC gene polymorphisms might be able to increase the ER level, and improve the efficiency of target and endocrine therapy, and the prognosis of BC patients further.

In conclusion, this hospital-based case–control study showed that XPC Ala499Val and Lys939Gln are associated with BC risk in this Chinese population. The two SNPs may have an effect on preoperative diagnosis and postoperative treatment, and we hope these accompanying predictive and prognostic biomarker tests will help to improve the efficacy of treatment.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

This work was supported by grants from the Fund of the National Natural Science Foundation of the Republic of China (Grant Nos. 30873097 and 30973559), the study on the cooperation of major disease control techniques in Liaoning province (Grant No. 2010225001), and Colleges and Universities Doctoral Programs Specifically Research Fund (Grant No. 20092104110020).

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References