Two nonsynonymous polymorphisms (F31I and V57I) of the STK15 gene and breast cancer risk: A meta-analysis based on 5966 cases and 7609 controls

Abstract

Objectives

This meta-analysis examined the relationship between two nonsynonymous polymorphisms (F31I and V57I) of the aurora kinase A (STK15) gene and breast cancer risk.

Methods

A systematic search of the PubMed® and EMBASE™ databases was undertaken to identify case–control studies that investigated the relationship between STK15 gene polymorphisms and breast cancer risk.

Results

This meta-analysis included seven case–control studies (5966 breast cancer cases; 7609 controls). Combined results, based on all seven studies, showed that breast cancer cases had a significantly higher frequency of the 31 Ile/Ile genotype. In a subgroup analysis by race, breast cancer cases had a significantly higher frequency of the 31 Ile/Ile genotype in Asians and Caucasians. Combined results, based on four studies, suggested that the STK15 V57I gene polymorphism was unlikely to be associated with breast cancer risk in either Asians or Caucasians.

Conclusions

The present meta-analysis suggests that the STK15 F31I polymorphism is a strong predisposing risk factor for breast cancer, but no significant association existed between the STK15 V57I polymorphism and the risk of breast cancer.

Keywords

gene polymorphism breast cancer meta-analysis

Introduction

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer deaths among females, accounting for 23% of total cancer cases and 14% of cancer deaths, worldwide.¹ Breast cancer is now also the leading cause of cancer deaths among females in economically developing countries: a shift from the previous decade during which the most common cause of cancer deaths was cervical cancer.¹ The mechanism of breast carcinogenesis is still not fully understood, but breast cancers are generally considered to result from interactions between multiple environmental, dietary, hereditary, racial and socio-economic risk factors.²

Aurora kinase A, which is encoded by the STK15 gene (also known as BTAK), is involved in cell-cycle regulation, in particular the passage from G₂ to M, through the formation of mitotic spindles.³ Due to this regulatory function, the STK15 gene has been hypothesized to be a potential cancer susceptibility gene. ³ The STK15 gene is located on chromosome 20q13.2.⁴ Two nonsynonymous polymorphisms F31I (rs2273535) and V57I (rs1047972) have been identified in the STK15 gene.⁵ Both polymorphisms are located within two conserved motifs in the N-terminal region of the STK15 gene.^5,6 A thymine (T)/adenine (A) polymorphism located at nucleotide position 91 encodes a phenylalanine (Phe)-to-isoleucine (Ile) (F31I) substitution at amino acid position 31.^5,6 A guanine (G)/A polymorphism at nucleotide 169 encodes a valine (Val)-to-Ile (V57I) substitution at amino acid position 57.^5,6 STK15 gene polymorphisms have been reported to be associated with cancers of uterine,⁷ lung,⁸ oesophageal and ovarian tissue.^9,10

Studies have been performed to clarify the association between these two polymorphisms (F31I and V57I) of the STK15 gene and breast cancer risk,^11–17 but have reported conflicting results. The purpose of this current meta-analysis was to undertake a detailed investigation of the relationship between STK15 gene polymorphisms F31I and V57I and breast cancer risk.

Materials and methods

Literature search strategy

A systematic search of articles listed in electronic databases (PubMed® and EMBASE™), published between January 1950 and December 2012, was conducted using the following key words: ‘Aurora*’ or ‘STK15’ or ‘BTAK*’, ‘breast cancer’ or ‘breast carcinoma’, ‘polymorphism’ or ‘allele’ or ‘genetic variant’. No language restriction was used. Reference lists of the selected papers were screened by hand for potentially relevant new articles. If necessary, the corresponding authors of retrieved articles were contacted to acquire additional information. Furthermore, if more than one paper was published with an identical author using the same case series, the report with the larger sample size was selected. The list of articles was reviewed independently by two authors (K.Q. and C.W.).

Inclusion and exclusion criteria

The criteria employed to select studies for this systematic review were as follows: (i) independent epidemiological case–control studies (for humans only); (ii) a clear description of STK15 polymorphism in breast cancer cases and controls. The exclusion criteria were: (i) not an original paper (e.g. review or letter); (ii) duplicate publications; (iii) no control subjects.

Data extraction

Literature and eligible articles were searched by two authors (K.Q. and C.W.). The following data were extracted: the last name of the first author, publication year, country, study design, genotyping method, sample size and the results of the study. Methodological quality of the selected studies was independently assessed by two investigators (K.Q. and C.W.) using the nonrandomized study methodology quality assessment scale for nonrandomized trials.

Statistical analyses

Statistical analyses were performed using Stata® software (version 11.0; Stata Corp., College Station, TX, USA). The Mantel–Haenszel method was used for fixed effects and the method of DerSimonian and Laird was used for random effects to estimate the pooled odds ratio (OR) and corresponding 95% confidence interval (CI). A fixed-effects method was used if the result of the Q-statistic test was not significant; otherwise, the pooled estimates and confidence intervals were calculated based on a random-effects model. Publication bias was assessed by visual inspection of funnel plots, the Begg’s rank correlation method and the Egger’s weighted regression method. Subgroup analyses were performed on the basis of race. A P-value < 0.05 was considered statistically significant and all statistical tests were two sided.

Results

The initial database search identified 168 publications. After screening the titles and abstracts, 146 articles were excluded (86 did not study polymorphisms, 44 were not case–control studies, and 16 were not conducted in humans), which left 22 articles for a full publication review. Of these, a further 15 articles were excluded (13 were not case–control studies and two did not report useable data), leaving seven studies that met the inclusion criteria and were included in this current meta-analysis.^11–17 These seven studies included 5966 breast cancer cases and 7609 control subjects:^11–17 four were population-based case–control studies;^11,12,16,17 three were hospital-based case–control studies.^13–15 Studies were conducted in the USA, UK and China (Table 1).

Table 1.

Principal characteristics of seven studies included in a meta-analysis to investigate the relationship between aurora kinase A (STK15) gene polymorphisms F31I and V57I and breast cancer risk^11–17.

Study	Design	Study period	Population/ country	Genotyping method	Cases, n	Controls, n	Polymorphisms
Dai et al. 2004^{1 7}	PCC	1996–1998	Asians/China	PCR	1132	1222	F31I, V57I
Egan et al. 2004^{1 6}	PCC	1998–1999	Caucasians/USA	PCR	941	830	F31I, V57I
Sun et al. 2004^{1 5}	HCC	1997–2002	Asians/China	PCR–RFLP	520	520	F31I
Ewart-Toland et al. 2005^{1 4}	HCC	NR	Caucasians/USA	PCR–RFLP	898	448	F31I
Lo et al. 2005^{1 3}	HCC	2002–2003	Asians/China	PCR	709	1972	F31I, V57I
Cox et al. 2006^{1 2}	PCC	1989–2000	Caucasians/USA	PCR	1259	1742	F31I, V57I
Fletcher et al. 2006¹¹	PCC	NR	Caucasians/UK	PCR–RFLP	507	875	F31I

PCC, population-based case–control; PCR, polymerase chain reaction; HCC, hospital-based case–control; RFLP, restriction fragment length polymorphism; NR, data not reported.

Genotyping results for the seven studies that reported on the association between STK15 F31I gene polymorphisms and breast cancer are presented in Table 2.^11–17 Combined results (based on all seven studies) showed that breast cancer cases had a significantly higher frequency of the 31 Ile/Ile genotype genotype (OR [recessive model] 1.18, 95% CI 1.07, 1.30; OR [codominant model] 1.23, 95% CI 1.07, 1.41) (Table 3) (Figure 1). In the subgroup analysis by race, breast cancer cases had a significantly higher frequency of the 31 Ile/Ile genotype, not only in Asians (OR [recessive model] 1.16, 95% CI 1.05, 1.30; OR [codominant model] 1.21, 95% CI 1.01, 1.45) but also in Caucasians (OR [recessive model] 1.26, 95% CI 1.01, 1.56; OR [codominant model] 1.26, 95% CI 1.01, 1.57) (Table 3). Statistical heterogeneity was found by using the Q- statistic (P = 0.003). Publication bias was not found by the Begg’s rank correlation method or Egger’s weighted regression method.

Figure 1.

Meta-analysis of the association between the aurora kinase A (STK15) F31I gene polymorphism and risk of breast cancer.^11–17 ID, identity; OR, odds ratio; CI, confidence interval.

Table 2.

Genotype counts of the aurora kinase A (STK15) gene polymorphisms (F31I and V57I) reported by seven studies included in a meta-analysis to investigate the relationship between STK15 gene polymorphisms and breast cancer risk^11–17.

Study	Polymorphisms	Genotypes of cases^a			Genotypes of controls^a			HWE
Study	Polymorphisms	XX	Xx	xx	XX	Xx	xx	HWE
Dai et al. 2004^{1 7}	F31I	121	491	490	149	503	534	0.07
Dai et al. 2004^{1 7}	V57I	805	281	16	908	263	17	0.68
Egan et al. 2004^{1 6}	F31I	559	331	50	516	283	31	0.31
Egan et al. 2004^{1 6}	V57I	637	245	23	542	225	21	0.68
Sun et al. 2004^{1 5}	F31I	50	214	256	66	262	192	0.11
Ewart-Toland et al. 2005^{1 4}	F31I	533	303	62	279	148	21	0.81
Lo et al. 2005^{1 3}	F31I	71	288	348	196	887	886	0.23
Lo et al. 2005^{1 3}	V57I	543	146	15	1506	414	30	0.80
Cox et al. 2006^{1 2}	F31I	774	401	66	1075	571	65	0.31
Cox et al. 2006^{1 2}	V57I	870	342	28	1215	462	47	0.70
Fletcher et al. 2006¹¹	F31I	335	154	18	547	280	48	0.13

Data presented as the number of cases or control subjects; note that the exact number for each polymorphism is often less than the total number of cases or controls included in the studies.

For the F31I polymorphism: XX, phenylalanine/phenylalanine; Xx, phenylalanine/isoleucine; xx, isoleucine/isoleucine; for the V57I polymorphism: XX, valine/valine; Xx,valine/isoleucine; xx, isoleucine/isoleucine.

HWE, Hardy–Weinberg equilibrium.

Table 3.

Meta-analysis of aurora kinase A (STK15) gene polymorphisms F31I and V57I, and breast cancer risk^11–17.

Polymorphism	Studies, n	OR (95% CI) Recessive model xx versus [Xx + XX]^a	Statistical significance of OR	Statistical significance of heterogeneity	OR (95% CI) Codominant model xx versus XX^a	Statistical significance of OR	Statistical significance of heterogeneity	OR (95% CI) Codominant model Xx versus XX^a	Statistical significance of OR	Statistical significance of heterogeneity
F31I	7	1.18 (1.07, 1.30)	P = 0.001	P = 0.003	1.23 (1.07, 1.41)	P = 0.004	P = 0.06	1.02 (0.93, 1.11)	NS	NS
Asians	3	1.16 (1.05, 1.30)	P = 0.006	P = 0.002	1.21 (1.01, 1.45)	P = 0.04	NS	1.06 (0.88, 1.27)	NS	NS
Caucasians	4	1.26 (1.01, 1.56)	P = 0.04	P = 0.07	1.26 (1.01, 1.57)	P = 0.04	NS	1.00 (0.91, 1.11)	NS	NS
V57I	4	0.98 (0.74, 1.32)	NS	NS	0.99 (0.74, 1.33)	NS	NS	1.04 (0.94, 1.14)	NS	NS
Asians	2	1.20 (0.75, 1.91)	NS	NS	1.22 (0.77, 1.96)	NS	NS	1.10 (0.95, 1.26)	NS	NS
Caucasians	2	0.87 (0.60, 1.26)	NS	NS	0.87 (0.60, 1.26)	NS	NS	0.99 (0.87, 1.13)	NS	NS

OR, odds ratio; CI, confidence interval; NS, not statistically significant (P ≥ 0.05).

Four studies reported on the association between STK15 V57I gene polymorphism and breast cancer (Table 2).^12,13,16,17 Combined results, based on all four studies, suggested that the STK15 V57I gene polymorphism was unlikely to be associated with breast cancer risk (Table 3). In the subgroup analysis by race, results demonstrated that the STK15 V57I gene polymorphism was unlikely to be associated with breast cancer risk in either Asian or Caucasian subjects. Statistical heterogeneity was not found by using the Q-statistic.

Discussion

This current meta-analysis of seven studies involving 5966 breast cancer cases and 7609 control subjects was conducted in order to make a more precise estimation of the association between two nonsynonymous polymorphisms (F31I and V57I) of the STK15 gene and breast cancer risk. Breast cancer cases had a significantly higher frequency of the 31 Ile/Ile genotype, not only in Asians but also in Caucasians. However, no significant association existed between the STK15 V57I polymorphism and the risk of breast cancer.

Studies investigating the association between genetic polymorphisms and breast cancer risk are being reported with rapidly increasing frequency. For example, a systematic review and pooled analysis of 10 studies, including 4644 cases and 5485 controls, suggested that rs1137101 and rs1137100 polymorphisms of the leptin receptor gene were significantly correlated with breast cancer risk; this study also found that the A allele of the rs1137101 variant and the G allele of the rs1137100 variant were low-penetrant risk factors for developing breast cancer.¹⁸ A meta-analysis of nine studies, involving 2597 cases and 2618 controls, suggested that the matrix metalloproteinase-2-1306 cytosine (C)/T polymorphism may contribute to breast cancer susceptibility.¹⁹ Another meta-analysis of 14 case–control studies (12 183 cases and 10 183 controls) suggested that the RAD51 variant 135C homozygote was associated with elevated breast cancer risk among carriers of the breast cancer type 2 susceptibility protein gene mutation.²⁰ A meta-analysis of 17 case–control studies (12 153 cases and 10 245 controls) suggested that the RAD51 G135C polymorphism was a low-penetrant risk factor for developing breast cancer.²¹ The findings of a meta-analysis of 11 studies, including 5090 cases and 5214 controls, suggested that the xeroderma pigmentosum complementation group C PAT+/− polymorphism allele may be a low-penetrant risk factor for developing breast cancer.²² Rare alleles at the v-Ha-ras Harvey rat sarcoma viral oncogene homologue–variable number tandem repeats locus were identified as possibly contributing to breast cancer susceptibility in a meta-analysis of 13 studies (1926 cases and 2800 controls).²³ A meta-analysis of seven studies (3177 cases and 4038 controls) suggested that the nicotinamide adenine dinucleotide phosphate hydrogen quinone oxidoreductase 1 proline187serine polymorphism may contribute to breast cancer development in Caucasians.²⁴ A thymidylate synthase (TYMS) gene enhancer region polymorphism may increase susceptibility to breast cancer in the Caucasian population, and a TYMS gene 3′-untranslated region polymorphism may be a genetic determinant for developing breast cancer in the Asian population, as demonstrated by a meta-analysis of 10 eligible studies.²⁵ A meta-analysis of 16 studies (involving 23 445 subjects) suggested that the sulphotransferase 1A1 codon 213 polymorphism may be associated with breast cancer susceptibility, based on data from hospital-based studies.²⁶ A meta-analysis of 13 case–control studies (10 236 cases and 13 143 controls) indicated that the tumour necrosis factor-α 308 A allele may be an important protective factor for breast cancer in European individuals.²⁷ Another meta-analysis of 30 case–control studies (15901 cases and 18 757 controls) suggested that the glutathione S-transferase pi gene Ile105Val polymorphism may increase susceptibility to breast cancer in the Asian population.²⁸ A meta-analysis of seven case–control studies, including 26 015 cases and 33 962 controls, suggested that the mitogen-activated protein kinase kinase kinase 1 rs889312 C allele was a low-penetrant risk factor for developing breast cancer.²⁹

The mechanism by which the STK15 F31I polymorphism affects breast cancer risk is unclear. The F31I polymorphism is located within a conserved motif in the N-terminal region of the STK15 gene.^5,6 This motif could be related to ubiquitin-dependent degradation in early G₁ that is dependent on the C-terminal degradation box domain; it might also serve as a localization domain to target the protein to the centrosome in a microtubule-dependent manner.^30,31 The Ile31 variant transforms rat1 cells more potently than the more common Phe31 variant.⁶ The STK15 31 Ile/Ile genotype has been associated with a significantly increased risk of uterine and ovarian cancer.^7,10

The present meta-analysis had several limitations that should be mentioned. First, relatively small sample sizes and significant heterogeneity were observed in the meta-analysis of STK15 F31I gene polymorphisms and breast cancer. Secondly, because many environmental factors may affect breast cancer susceptibility, all of our current findings might be due to interactions between the genetic background and multiple environmental factors. Thirdly, because of the lack of individual patient data, it was not possible to perform an adjustment estimate. Finally, this meta-analysis pooled genetic association studies published between 2004 and 2006; all of these studies were conducted before the ‘Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE Statement’ was published.³² Therefore, the studies included in this current meta-analysis did not fulfil all of the STROBE checklist items.

Despite these limitations, this current meta-analysis also had some advantages. First, a comprehensive search strategy based on computer-assisted and manual searching allowed all eligible studies to be included. Secondly, no publication bias was found, which would suggest a robust result.

In conclusion, the findings of this present meta-analysis suggest that the STK15 F31I polymorphism is a strong predisposing risk factor for breast cancer. Furthermore, no significant association existed between the STK15 V57I polymorphism and the risk of breast cancer.

Footnotes

Declaration of conflicting interest

The authors declare that there are no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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