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Carcinogenesis Advance Access originally published online on August 31, 2006
Carcinogenesis 2007 28(2):372-377; doi:10.1093/carcin/bgl153
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Association of p73 G4C14-to-A4T14 (GC/AT) polymorphism with breast cancer survival

Hongxia Li, Lihua Yao, Tao Ouyang, Jinfeng Li, Tianfeng Wang, Zhaoqing Fan, Tie Fan, Bin Dong1, Benyao Lin, Jiyou Li1 and Yuntao Xie*

Breast Center, Beijing Cancer Hospital Peking University School of Oncology, 100036, Beijing, P. R. China
1 Department of Pathology, Beijing Cancer Hospital Peking University School of Oncology, 100036, Beijing, P. R. China

*To whom correspondence should be addressed. Tel: +86 10 88196362; Fax: +86 10 88196362; Email: zlxyt2{at}bjmu.edu.cn


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
p73 gene shares structural and functional similarities to p53, and plays an important role in modulating cell-cycle arrest and apoptosis. A common non-coding polymorphism of exon 2 of the p73 gene (designated as GC/AT) may affect gene expression, thus, it may lead to functional significance. The correlation of this polymorphism with breast cancer survival has not been investigated. In this study, by using genomic DNA p73 GC/AT polymorphism was detected by PCR-SSCP in 526 breast cancer patients with a median follow-up of 7.3 years. Among the 526 breast cancer patients, 4% of the patients were homozygous for the AT/AT genotype, 39% were heterozygous GC/AT and 57% were homozygous for the GC/GC genotype. We found that patients with the GC/GC genotype had a significantly worse clinical outcome than did patients with the AT Variants (AT/AT or GC/AT genotype) (5-year disease-free survival, 74.2 versus 95.0 or 84.1%, P = 0.02; 5-year overall survival, 78.9 versus 95.0 or 87.5%, P = 0.01, respectively). As compared with the GC/AT and AT/AT genotypes, the GC/GC genotype remained an independent prognostic indicator of disease-free survival (HR 1.82, P = 0.003) and overall survival (HR 1.99, P = 0.004) in multivariate analysis. Our results suggest that the GC/GC genotype is significantly associated with poor prognosis in breast cancer and raise the possibility that analysis of p73 polymorphism may provide useful prognostic information for breast cancer patients. Additional independent studies are needed to confirm these findings.

Abbreviations: PCR-SSCP, polymerase chain reaction single-strand conformation polymorphism; ER, estrogen receptor; PR, progesterone receptor; DFS, disease-free survival; OS, overall survival


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
The incidence of breast cancer is currently increasing in China, particularly in large cities (1). Owing to the biological heterogeneity of breast cancer, individual patients belonging to the same stage of disease may exhibit completely different outcomes (2,3), hence, identifying factors in relation to breast cancer survival may have a great impact on the treatment for this disease.

p73, a member of p53 family, shares structural and functional similarities to p53 (4–6). It is located on chromosome 1p36, a region frequently deleted in a variety of tumors (7–9), indicating that p73 may be a potential tumor suppressor gene. Indeed, p73 is able to activate a set of p53-response genes and induce cell-cycle arrest or apoptosis in response to DNA damage (6,10).

The evidence that p73 knockout mice do not develop spontaneous tumor (11) and p73 gene is rarely mutated in a variety of tumors (<0.6%) (12), however, does not support the notion that p73 is a classical Knudson type tumor suppressor gene. Moreover, in contrast to p53, p73 gene gives rise to several different NH2-terminal isoforms that seem to play differential roles in tumorigenesis (5). The full-length p73 (TAp73), containing a (TA) transactivation domain capable of activating p53-response genes and inducing cell-cycle arrest or apoptosis, may act as a tumor suppressor gene (13–16). On the other hand the NH2-terminally truncated isoforms lack all or most of the transactivation domain generated by an aberrant splicing or an alternative promoter and are collectively called {Delta}TAp73 (p73{Delta}2exon, p73{Delta}2/3exon, {Delta}Np73, {Delta}'Np73) (14,17). {Delta}Np73 is the main isoform and functionally most important, studies suggest that {Delta}Np73 harbors an opposite function of TAp73 and seems likely to be an oncogene (15,16). Overexpression of {Delta}Np73 isoform is frequently found in a widely variety of tumors (18–20), including breast and female genital tract cancers (13).

Two single polymorphisms at position 4 (G to A) and 14 (C to T) in the 5'-untranslated region (5'-UTR) of exon 2 of the p73 gene have been identified, the two polymorphisms are in complete linkage disequilibrium with one another and form a polymorphism so called the AT and GC alleles, respectively (4). This polymorphism lies upstream of the initiating AUG of exon 2, a region which may theoretically form a stem–loop structure that could potentially affect gene expression by through alteration of the efficiency of translation initiation (4), thus, it may lead to functional consequence.

The correlation of the p73 GC/AT polymorphism with cancer risk has been investigated in a variety of cancers (21–28). There are several studies indicating that subjects with the AT variants may have an increased risk of certain types of cancer (21,25,26), other studies, however, suggest that the AT variants possess a protective role against cancer development (23,28). On the other hand, the correlation between this polymorphism and breast cancer survival has not been investigated. Functional analysis implies that this common p73 polymorphism may contribute to cancer development and progression (4,21). Therefore, the purpose of this study was to investigate the association of this common p73 polymorphism with breast cancer survival in 526 breast cancer patients with a long-term follow-up.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Patients
A total of 608 consecutive patients with primary operable breast cancer were treated at Breast Center, Peking University School of Oncology from December 1994 to June 1998. The patients with axillary lymph-node samples unavailable were excluded in this study. Thus, 526 patients with primary operable breast cancer were included in this study. Pathological diagnosis was performed for all patients, the patients' ages ranged from 25 to 88 years, with a median of 49 years. Two hundred and sixty-seven patients were premenopausal, and 259 patients were postmenopausal. The stage of the tumors was classified according to the tumor-node-metastasis classification of the Union Internationale Contre Le Cancer. Tumor size was defined as the maximum tumor diameter measured on the mammogram and/or ultrasonogram at time of diagnosis. Patients received radical or modified radical mastectomy, the axillary lymph nodes were routinely dissected at least level I and II, and whether the lymph node metastasis or not was determined based on the histological examination. The majority of patients received adjuvant treatment, including chemotherapy, endocrine therapy, radiotherapy and combined treatment; the adjuvant treatment was summarized in Table I. Patients with positive lymph node status or negative-ER and -PR status received adjuvant chemotherapy (MCF, CAF or FEC regimen for 6 cycles), whereas patients with four or more lymph nodes involvement received additional radiotherapy, patients with positive-ER and/or -PR status received endocrine treatment (Tamoxifen, 20 mg/d for 5 years). The follow-up data were available for all patients, with a median follow-up time of 7.3 years (range, 0.3–10.1 years), during the follow-up period, one hundred and thirty-six patients had developed metastases or local recurrences, one hundred and five patients had died of breast cancer. This study was approved by the Research and Ethical Committee of Peking University School of Oncology.


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  		Table I Association between the genotypes of p73 polymorphism and patient's characteristics or adjuvant treatment

 
DNA extraction
The genomic DNA should be used for genotyping analysis (29,30). Thus, in this study, the genomic DNA from each patient was extracted from negative axillary lymph nodes (histological examination). Briefly, three to four sections of 10 µm thick, were cut from each sample, after xylene deparaffination and absolute ethanol washing, the sections were digested by proteinase K (0.1 mg/ml) in 200 µl of DNA extraction buffer at 56°C for overnight, following the phenol–chloroform extraction.

Genotyping
p73 GC/AT polymorphism was detected using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) assay as described previously (23). A nested-PCR was applied for amplification of genomic DNA from the axillary lymph node. In brief, PCR was composed of 100 ng of genomic DNA, 2 µl 10x PCR buffer, 0.8 mM dNTP, 2.5 mM MgCl2, 0.5 µM each of outer specific sense and antisense primers (forward: 5'-CCAAGCGCACTCACAGA-3' and reverse: 5'-TCACAGGAGGACAGAGCA-3'), and 1 U AmpliTaq DNA polymerase (Promega, WI) in a total volume of 20 µl. The reaction condition was first 94°C for 2 min to activate Taq DNA polymerase, followed by denaturation at 94°C for 30 s, annealing 54°C for 45 s and extension 72°C for 45 s. The first-round PCR was run for 32 cycles and finally elongated for 10 min. The second round of PCR, using inter primers (forward: 5'-AGGGTGCTCAGGTGTCATTCC-3' and reverse: 5'-GCTCCAGAGGTGCTCAAACG-3') and 1 µl of first-round PCR product, was performed under the same conditions except that the cycles was reduced to 30 cycles and annealing temperature was 56°C. The PCR product was 127 bp.

For the SSCP analysis, 12 µl of PCR product was mixed with 6 µl of loading buffer (95% formamide, 20 mM EDTA, 0.05% xylene cyanol and 0.05% bromphenol blue). This mixture was denatured at 98°C for 10 min, then immediately put on ice and loaded on the 10% nondenaturing polyacrylamide (29:1 acrylamide–biasacrylamide) gel. The gel was electrophoresed in 1x Tris–borate–EDTA buffer at 125 V for ~150 min on ice and subsequently stained with 0.5% ethidium bromide and visualized by using AlphaImager 2200 system, thus, the p73 GC/AT genotypes were easily discriminated each other (Figure 1, upper panel).


Figure 1
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  		Fig. 1 (A) Detection of the p73 G4C14-to-A4T14 (GC/AT) polymorphism by PCR-SSCP. M, 100 bp ladder; Lane 1, the AT/AT genotype; Lanes 3, 5, 6, the GC/AT heterozygotes; Lanes 2, 4, 7, 8, the GC/GC genotype; Lane 9, Negative control. (B) Sequencing analysis for genotypes of the p73 G4C14 to A4T14. The three charts represent the GC/GC, GC/AT and AT/AT genotypes, respectively.

 
In order to avoid the potential contamination, each set of PCR (eight samples) contains a negative and two positive controls, a negative control without DNA template and two positive controls (known GC/GC or GC/AT genotype, respectively) were performed simultaneously. A total of 75% of the cases were genotyped in duplicates and results were fully concordant. Furthermore, to verify the PCR-SSCP results, we randomly selected six PCR products from the three genotypes analyzed by PCR-SSCP for DNA sequencing analysis as described previously (23). The genotypes were confirmed by the DNA sequencing analysis (Figure 1, lower panel).

Detection of estrogen receptor (ER) and progesterone receptor (PR)
An enzyme immunoassay was performed to detect ER and PR protein levels in the fresh breast tumor tissues, the cut-off value for both ER and PR was 10 fmol/mg protein.

Statistical analysis
The correlation between the genotype variants and clinicopathologic characteristics or adjuvant treatment was determined using Pearson's {chi}2 test. Two-sided P-values less than 0.05 were considered as statistically significant. Disease-free survival or overall survival curves were estimated with the Kaplan–Meier method, the endpoint was the date of relapse or death, or the last point of follow-up, and comparisons between survival curves were performed using the log rank test. A Cox regression model was applied to determine whether a factor was independent predictor of disease-free survival or overall survival in multivariate analysis, factors involved in the univariate analysis were included in the multivariate analysis, a backward stepwise selection was performed, with an inclusion criterion of P ≤ 0.05 and an exclusion of P > 0.05 (31). All statistical analyses were performed using SPSS 10.0 software.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
The correlation between the p73 GC/AT genotypes and clinicopathologic characteristics or adjuvant treatment
The p73 GC/AT polymorphism was analyzed in the 526 breast cancer patients, 4% (20 of 526) of the patients were homozygous for the AT/AT genotype, 39% (208 of 526) were heterozygous GC/AT and 57% (298 of 526) were homozygous for the GC/GC genotype. The frequencies of genotypes conformed to Hardy–Weinberg equilibrium. The p73 GC/AT genotypes were neither correlated with age, nor with ER or PR status. Furthermore, there was no significant correlation between the genotypes and tumor size (Table I). Although the tumor size was evenly distributed among the genotypes prior to treatment, we found, however, the GC/GC genotype was significantly associated with lymph node status or clinical stage, patients with the GC/GC genotype were more likely than those with the GC/AT or AT/AT genotype to be a positive lymph node status or advanced stages (Table I). On the other hand, the adjuvant treatment, i.e. chemotherapy, endocrine therapy, radiotherapy, alone or combined, was evenly distributed among the three genotypes, no statistically significant difference was observed between the genotype groups (P = 0.88, Table I). Importantly, the different clinical outcome seen among the genotypes, therefore, was not due to the potential effects of different adjuvant treatment (Table I).

The p73 GC/AT polymorphism and breast cancer survival
The 5-year disease-free survival (DFS) and 5-year overall survival (OS) in the whole population (526 cases) were 77.9 and 81.9%, respectively. The correlation of the clinicopathologic factors or the p73 GC/AT genotypes with 5-year DFS or 5-year OS was investigated in this cohort. As shown in Table II, the p73 GC/AT polymorphism was significantly associated with clinical outcome, patients with the GC/GC genotype had worse 5-year DFS (74.2 versus 95.0 or 84.1%, P = 0.02) and worse 5-year OS (78.9 versus 95.0 or 87.5%, P = 0.01) than did patients with the AT Variants (AT/AT or GC/AT) (Table II and Figure 2). As expected, tumor size, clinical stage, lymph node status and PR, were found to be significantly associated with both DFS and OS (Table II). In contrast, age, ER were not significantly associated with DFS or OS in this cohort (Table II).


Figure 2
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  		Fig. 2 Kaplan–Meier analyses of disease-free survival (A) and overall survival (B) for all 526 breast cancer patients. Patients with GC/GC genotype were significantly associated with worse disease-free or overall survival than those with the AT variants (AT/AT or GC/AT genotype).

 


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  		Table II Association between the genotypes of p73 polymorphism, clinicopathologic characteristics and survival in 526 breast cancer patients

 
In the multivariate analysis, the GC/GC genotype remained an independent prognostic marker of DFS (HR 1.82, 95% CI 1.23–2.70, P = 0.003) and OS (HR, 1.99, 95% CI 1.25–3.16, P = 0.004) after adjusting for clinical stage, age, tumor size, lymph node status, and ER or PR status (Table III). The GC/GC genotype still retained an independent prognostic marker even adjusting for adjuvant treatment (data not shown). Although, impact of the GC/GC genotype was less evident than clinical stage III (HR, 4.06, 95% CI 2.54–6.50, P < 0.001) or positive lymph node status (HR, 3.52, 95% CI 1.97–6.30, P < 0.001), the risk of patients with the GC/GC genotype died from the disease was almost two times higher than the risk for patients with the AT/AT or GC/AT genotype (Table III).


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  		Table III Results of multivariate analysis of independent prognostic factors in 526 breast cancer patients

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Although p73 shows significant homology to p53 and largely mimics p53 functions (4–6), however, p73 gene harbors some unique functions that fundamentally differ from p53. Indeed, the precise roles of p73 gene in breast tumorigenesis remain to be elucidated.

In the present study, we investigated the prognostic value of the p73 GC/AT polymorphism in a large series of breast cancer. We showed here for the first time that the GC/GC genotype was significantly associated with poor prognosis in breast cancer.

Although, the role of the p73 GC/AT polymorphism in cancer risk has been investigated extensively in a variety of cancers, the results are inconsistent (21–28). Some studies even fail to find any correlation between this polymorphism and risk of several types of cancer (24,32,33), including breast cancer (32). However, we found Chinese women with the GC/GC genotype had an increased risk of developing breast cancer than those with the GC/AT or AT/AT genotype (unpublished data). With respect to prognostic study, there is only one study with a relatively small sample size (n = 179) evaluating the correlation of the p73 GC/AT polymorphism with overall survival in colorectal cancer from a Swedish population (21), Pfeifer et al. reported that patients with the GC/GC genotype had worse outcome than did those with the AT variants (AT/AT + GC/AT) (21). By extending their findings we were able to demonstrate the GC/GC genotype was strongly associated with an unfavorable disease-free survival or overall survival in this large series of breast cancer patients. Furthermore, although the tumor size was evenly balanced among three genotypes before treatment, the GC/GC genotype, however, was associated with a positive lymph-node status, suggesting that patients with the GC/GC genotype had a more aggressive phenotype. More importantly, the GC/GC genotype remained an independent prognostic marker after adjusting for lymph node involvement, ER or PR status, clinical stage and tumor size. Thus, our findings may have potential clinical implications.

The underlying mechanisms how p73 GC/AT polymorphism influences breast cancer development and progression is currently unknown. The patterns of p73 allele expression may be associated with breast tumorigenesis. Previous studies suggested that monoallelic or biallelic p73 expression is largely depended on tumor types (34–37). Ahomadegbe et al. (8) reported that monoallelic p73 expression is very frequently observed in breast cancer, in their study tumor RNA was reversed to cDNA and cDNA was subsequently digested with StyI, they found the GC allele is exclusively expressed in the majority of tumors, and this phenomena is more marked in inflammatory breast cancer, an aggressive form of breast tumor. In contrast, biallelic expression (both AT and GC alleles) was found in their matched normal breast tissues (8). These data strongly suggest that selecting GC allele expression in parallel with AT allele silencing is obligatory for breast cancer development and progression. In the present study, the finding that the GC/GC genotype was associated with poor outcome in breast cancer was, at least in part, in consistent with these observations.

Another possibility is that the GC to AT change may lead to formation of a stem–loop structure and therefore may alter the translation efficiency or splicing variants of p73 protein (4), but we cannot exclude the possibility that the stem–loop structure may lead to the AT allele silencing or low expression. The p73 gene has two distinct promoters which allows the formation of two protein isoforms with functionally different properties (5). The transactivation proficient isoform TAp73 shows pro-apoptotic effects, while the NH2-terminally truncated isoform {Delta}Np73 has anti-apoptotic function (15,16). In colorectal cancer it has been shown that patients with the AT/AT genotype exhibited a slightly lower p73 expression in their tumors than those with the GC/GC genotype, but the difference did not reach statistical significance, moreover, the antibody used cannot discriminate TAp73 or {Delta}Np73 (21).

Zaika et al. (13) reported that {Delta}Np73 is frequently overexpressed in breast cancer but not in matched normal tissues. In a series of 52 breast cancers, 31% of tumors was dramatically overexpressed {Delta}Np73, suggesting that {Delta}Np73 might selectively be up-regulated during breast cancer tumorigenesis (13). Although the prognostic significance of {Delta}Np73 in breast cancer is currently lacking, it has been shown that overexpression of {Delta}Np73 is significantly associated with poor outcome in lung cancer and neuroblastoma (18,20).

A more recent study suggests that the disruption of the balance between TAp73 and {Delta}Np73 protein confers resistance to chemotherapy and associates with poor prognosis in hepatocellular carcinoma (13,38). Therefore, it would be of great interest to explore whether the GC/GC genotype was associated with the expression of TAp73 and/or {Delta}Np73, such analysis may provide additional information to elucidate the functional consequences of this important polymorphism.

In conclusion, in the present study we found that the GC/GC genotype is strongly associated with poor clinical outcome in breast cancer, and the GC/GC genotype remains an independent prognostic indicator in multivariate analysis. Thus, analysis of p73 polymorphism may be useful in identifying the breast cancer patients that have a high risk of relapse and are most likely to benefit from the adjuvant treatment. Nevertheless, our present findings are needed to confirm in other tumor types and different populations.


   Footnotes
 
Correspondence may also be addressed to Jiyou Li. Email: lijiyou{at}263.net


   Acknowledgments
 
This study was supported by a grant from the Ministry of Personnel, P. R. China (to Dr Y.X.) and a grant H020920030390 from the Beijing Science and Technology Commission (to Dr J.L.).


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received May 8, 2006; revised July 24, 2006; accepted August 18, 2006.


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