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Carcinogenesis Advance Access originally published online on August 21, 2006
Carcinogenesis 2007 28(2):350-355; doi:10.1093/carcin/bgl149
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Polymorphisms of STK15 (Aurora-A) gene and lung cancer risk in Caucasians

Jian Gu, Yubo Gong, Maosheng Huang, Charles Lu1, Margaret R. Spitz and Xifeng Wu*

Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center Houston, TX 77030, USA
1 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center Houston, TX 77030, USA

*To whom correspondence should be addressed at: Department of Epidemiology, Unit 1340, The University of Texas M.D. Anderson Cancer Center, 1155 Pressler Blvd, Houston, TX 77030, USA. Tel: +1 713 745 2485; Fax: +1 713 792 4657; Email: xwu{at}mdanderson.org


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
STK15/Aurora-A is a centrosome-localized serine/threonine kinase that functions primarily in centrosome maturation and mitotic spindle assembly. In a large lung cancer case–control study of 1401 cases and 1397 controls including three ethnic groups, we examined the associations between two non-synonymous SNPs (Phe31Ile and Val57Ile) of the STK15 gene and lung cancer risk. There were statistically significant differences in the distribution of the genotypes (P < 0.0001) and haplotypes (P < 0.0001) by ethnicity for the Phe31Ile, but not the Val57Ile variant. Caucasians with the homozygous variant Phe31Ile genotype (Ile/Ile) were at a significantly reduced risk for lung cancer [odds ratio (OR) = 0.63, 95% confidence interval (CI) = 0.41–0.96]. The variant allele of Val57Ile was not associated with lung cancer risk overall. However, men with the homozygous variant genotype (Ile/Ile) had a reduced lung cancer risk as compared with men with the wild-type genotype (Val/Val) (OR = 0.42, 95% CI = 0.19–0.94). When we performed joint analysis of these two polymorphisms, compared with the reference group (TT + GG, 40.99% of controls), homozygous Ile31 allele/wild-type Val57 allele (AA + GG) carriers (5.45% of controls) exhibited a reduced lung cancer risk (OR = 0.78, 95% CI = 0.63–0.97). This is the first epidemiological study to report significant associations between STK15 polymorphisms and lung cancer risk.

Abbreviations: ESCC, esophageal squamous cell carcinoma; MGB, minor groove binder; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; SNPs, single nucleotide polymorphisms


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Genetic instability is a hallmark of human cancers, mostly occurring at the chromosome level and involving losses and gains of whole chromosomes or large portions thereof (1). In human cells, the faithful segregation of chromosomes is accomplished by an elaborate macromolecular machinery, the mitotic spindle, which allows all chromosomes to attach their kinetochores to opposite poles, and to segregate equally into two daughter cells. Centrosomes are the primary microtubule-organizing centers in human cells and play important roles in symmetric mitotic spindle formation. In addition, centrosomes are also required for cell-cycle progression in interphase and the completion of cytokinesis in mitosis (2). Given the role of centrosomes in ensuring chromosome integrity, it is not surprising that centrosome defects are a common feature of malignant tumors. Centrosome defects are found in essentially all aggressive human carcinomas (3,4). Moreover, centrosome abnormalities also occur in pre-invasive human carcinoma in situ, suggesting that centrosome defects may contribute to the earliest stages of cancer development (5,6).

Centrosome abnormalities encompass both numerical and structural alterations. Overexpression of centrosomal proteins is one of the major causes of centrosome abnormalities. STK15/Aurora-A is a centrosome-localized serine/threonine kinase. It localizes to the centrosome during interphase and to both spindle poles and spindle microtubules during early mitosis. STK15 is upregulated at the onset of mitosis and functions primarily in centrosome maturation and mitotic spindle assembly (7). Deregulation of STK15 gene, either by depletion or overexpression, leads to mitotic abnormalities, including centrosome separation and maturation defects, spindle aberrations, and missegragation of individual chromosomes (8,9).

A wealth of evidence has suggested that STK15 is involved in both cancer initiation and prognosis. STK15 gene is located at chromosomal locus 20q13.2, a region that is frequently amplified in human epithelial cancers (8,10–12). Several case–control studies have investigated the association between two non-synonymous single nucleotide polymorphisms (SNPs), T91A (Phe31Ile) and G169A (Val57Ile), of the STK15 gene and cancer risk (13–21). However, the results have not been consistent. Meta-analysis seems to support that the notion that homozygous variant Ile allele of the Phe31Ile SNP is associated with an increased breast cancer risk (17,18). Moreover, a recent meta-analysis of 9549 cases of 7 different cancer types suggested that the Ile/Ile genotype is a general cancer susceptibility factor for a variety of cancers [odds ratio (OR) = 1.50, 95% confidence interval (CI) = 1.14–1.99]. The only lung cancer study in this meta-analysis had 414 cases and 467 controls including both Caucasians and African-Americans and yielded an OR of 1.41 (95% CI = 0.74–2.71) for the homozygous Ile genotype. There have not been any single reports on the association of STK15 polymorphisms with lung cancer risk. However, chromosome 20q13 amplification has been identified as one of the most frequent genetic aberrations in lung cancer patients in both smokers and non-smokers, suggesting that STK15 may be involved in lung cancer initiation (22–26). In a large case–control analysis of ~1400 cases and 1400 controls, we evaluated the allele frequencies of these two SNPs of STK15 gene in Caucasians, African-Americans and Mexican-Americans, and further evaluated whether these SNPs are associated with altered lung cancer risk in Caucasians.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Study population and data collection
Case patients were newly diagnosed, histologically confirmed, and previously untreated (by radiotherapy or chemotherapy) lung cancer patients recruited from The University of Texas M.D. Anderson Cancer Center in Houston, TX, USA, during the period from August 1995 through July 2004. Over 60% of the cases included in this study were from Texas. Among the cases, 12.27% had below high school education (<12 years of education), 56.47% were high school graduates (12–15 years) and 31.26% had at least college degree (16 or more years of education). The histological diagnoses for the cases were as follows: 92.9% non-small cell lung cancer (NSCLC) (including 54.7% adenocarcinoma, 21.1% squamous cell carcinoma and 17.1% NSCLC unclassified); 6.1% small cell lung cancer (SCLC); and 0.97% others. The control subjects had no prior history of cancer (except non-melanoma skin cancer) and were selected from a contact database from the Kelsey-Seybold clinics, the largest multi-specialty physician group with 24 clinics in the Houston metropolitan area. The control subjects visited the clinics for annual checkups or treatment for a variety of diseases. The potential control subjects were first surveyed by a short questionnaire for willingness to participate in research studies and to provide preliminary demographic data for matching. A Kelsey-Seybold staff member provided the questionnaire to each potential control subject during clinical registration. The potential control subjects were contacted by telephone at a later date to confirm their willingness to participate and to schedule an interview appointment at a Kelsey-Seybold clinic convenient to the participant. The controls were matched with the case patients by age (±5 years), gender, ethnicity and smoking status (never-, former- or current-smokers). All subjects signed a consent form and were interviewed using a structured questionnaire regarding epidemiological data, including demographics, smoking history, alcohol consumption, family history of cancer, medical history and occupational history. At the end of the interview, 40 ml of peripheral blood was drawn into coded heparinized tubes. Six milliliters of blood was used to isolate DNA. The extra blood was retained for isolating lymphocytes and for other genetic susceptibility marker analyses. The study was approved by the institutional review boards of The University of Texas M.D. Anderson Cancer Center and the Kelsey-Seybold Foundation. To date, the overall response rate among both the cases and the controls has been ~75%.

STK15 genotyping
The STK15 genotyping was performed using the Taqman SNP assay. The probes were labeled fluorescently with either 6-FAM or VIC on the 5'-end and a non-fluorescent minor groove binder (MGB) quencher on the 3'-end (Applied Biosystems). The primer and probe sequences used were as follows: for Phe31Ile, 5'-CTGGCCACTATTTACAGGTAATGGA (forward primer), 5'-TGGAGGTCCAAAACGTGTTCTC (reverse primer), VIC-ACTCAGCAATTTCCTT-MGB (T allele for Phe), 6FAM-CTCAGCAAATTCCTT-MGB (A allele for Ile); for Val57Ile, 5'-CGGCTTGTGACTGGAGACA (forward primer), 5'-GGGTCTTGTGTCCTTCAAATTCTTC (reverse primer), 6FAM-CAGCGCGTTCCTT-MGB (G allele for Val), VIC-CAGCGCATTCCTT-MGB (A allele for Ile). Typical amplification mixes (5 µl) contained sample DNA (5 ng), 1x TaqMan buffer A, 200 µM dNTPs, 5 mM MgCl2, 0.65 units of AmpliTaq Gold, 900 nM each primer and 200 nM each probe. The reactions were carried out on the dual-384-well GeneAmp® PCR System 9700. The thermal conditions were 95° for 10 min followed by 50 cycles of 95°C for 15 s and 62°C (for Phe31Ile) or 60°C (for Val57Ile) for 1 min. The reacted plates were then read using the ABI Prism 7900HT Sequence Detection System. The analyzed fluorescence results were then auto-called into genotypes using the built-in software of the system. Water control, ample internal controls and 5% of the samples were randomly selected and run in duplicates with 100% concordance.

Statistical analysis
STATA software was used to perform all the described statistical analyses. In the first step of analysis, Pearson's {chi}2 test was used to compare the distribution of select demographic variables including age, gender, ethnicity, smoking status and the STK15 genotypes between lung cancer cases and controls. Hardy–Weinberg equilibrium was tested using the goodness-of-fit {chi}2 test to compare the observed allele frequencies with the expected frequencies in control subjects. Student's t-test was used to compare mean age and mean pack-years between cases and control subjects. All the subjects were stratified into three categories of smoking: never-, former- and current-smoker. A never-smoker was defined as one who had never smoked or had smoked fewer than 100 cigarettes in his/her lifetime. A former-smoker was defined as one who had a history of smoking but had stopped at least 1 year before being diagnosed (or at least 1 year before enrollment into the study, for control subjects). Pack-years were calculated using the following formula: pack-years = (number of cigarettes smoked per day/20 cigarettes) x number of years smoked. Each study subject with a history of smoking was further classified as a light smoker or a heavy smoker; the mean number of pack-years for the control group (37.5 pack-years) was used as the threshold to distinguish between light and heavy smokers. In the second step of analysis, ORs and 95% CI were used to estimate risk associated with the STK15 genotypes using both univariate and unconditional multivariate logistic regression models; and in the latter model, confounding factors such as age, gender and smoking status or pack-years were adjusted where appropriate. Tests for genotype–smoking interactions were performed by the likelihood ratio test to compare goodness of fit of the model with the interaction term, to the reduced model including the main effects of genotype and smoking. Haplotypes were analyzed using the EM algorithm-based HelixTree Genetics Analysis Software (version 4.1.0, Golden Helix, Bozeman, MT, USA). P-values <0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Distribution of genotypes among different ethnic groups
We first determined the allele frequencies of Phe31Ile and Val57Ile in different ethnic groups. Among the 1397 controls with genotyping data for both SNPs, there were 1027 Caucasians (73.51%), 120 Hispanics (8.59%) and 250 African-Americans (17.90%). For Phe31Ile, Hispanics had the highest variant allele frequency (0.325), Caucasians had intermediate value (0.216) and African-Americans had the lowest variant allele frequency (0.128). There were statistically significant differences in the distribution of the genotypes among the ethnic group for Phe31Ile (P < 0.0001), but not for Val57Ile (P = 0.894). Since 78% of cases and 74% of controls were Caucasians, and there were significant differences in genotype distribution among different ethnic groups for Phe31Ile, we report our subsequent observations for Caucasians.

Characteristics of study population in Caucasians
Table I shows selected characteristics of Caucasian cases and controls. There were a total of 1165 cases and 1095 controls. The cases and controls were matched well on age and gender. The cases and controls were also matched on smoking status by study design and there was a similar percentage of ever smokers in the cases and the controls (83.6 and 83.8%, respectively) (P = 0.882). However, among ever smokers, the cases had a higher percentage of current-smokers (40.0%) than controls (34.8%) (P = 0.029). In addition, ever smokers in cases had a heavier smoking history than controls (mean pack-years: 53.12 versus 43.15, P < 0.0001).


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  		Table I Select characteristics among Caucasian cases and controls

 
Risk estimate of STK15 Phe31Ile polymorphism in Caucasians
The risk estimates for individuals with variant alleles of Phe31Ile are shown in Table II. Compared with individuals with the wild-type TT genotypes (Phe/Phe), Caucasians with the homozygous variant AA genotype (Ile/Ile) were at a significantly reduced risk for lung cancer, with an adjusted OR of 0.63 (95% CI = 0.41–0.96). There was no association for the heterozygous genotype (adjusted OR = 1.04, 95% CI = 0.86–1.25), nor was there a significant association of combined variant alleles (AT + TT) with lung cancer risk (adjusted OR = 0.98, 95% CI = 0.82–1.17). Caucasians were further stratified by gender, age and smoking status. The protective effect of the Ile/Ile allele appeared to be stronger in younger than in older subjects with adjusted ORs of 0.54 (95% CI = 0.27–1.09) and 0.71 (95% CI = 0.41–1.24), respectively. In terms of smoking status, when we used median pack-years (37.5) of controls as a cutoff point, the adjusted ORs for never-smokers, light smokers (<37.5 pack-years) and heavy smokers (≥37.5 pack-years) were 0.38 (95% CI = 0.11–1.29), 0.48 (95% CI = 0.22–1.05), and 0.78 (95% CI = 0.43–1.40), respectively. The protective effect of the homozygous variant genotype was more apparent in never-smokers and light smokers, although none of the risk estimates reached statistical significance. However, when we combined never-smokers and light smokers, the homozygous variant alleles conferred a protective effect in this group (adjusted OR = 0.47, 95% CI = 0.24–0.91). There was no statistically significant interaction between smoking and Phe31Ile in modulating lung cancer risk (P for interaction = 0.93).


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  		Table II Risk estimates for Phe31Ile SNP in Caucasian cases and controls

 
Risk estimate of STK15 Val57Ile polymorphism in Caucasians
The risk estimates for individuals with variant alleles of Val57Ile are shown in Table III. Compared with individuals with the wild-type GG genotypes (Val/Val), the adjusted ORs for Caucasians with the heterozygous (AG, Val/Ile) and homozygous variant genotype (AA, Ile/Ile) were 1.01 (0.83–1.23) and 0.72 (95% CI = 0.41–1.26), respectively. However, when stratified by gender, men with the Ile/Ile genotype had a significantly reduced lung cancer risk (adjusted OR = 0.42, 95% CI = 0.19–0.94). When stratified by smoking status, never-smokers with at least one variant allele had a borderline significant protective effect on lung cancer risk (OR = 0.66, 95% CI = 0.41–1.04). The ORs for homozygous Ile/Ile genotype in never-smokers, light smokers and heavy smokers were 0.49 (95% CI = 0.11–2.11), 0.70 (95% CI = 0.21–2.36) and 0.73 (95% CI = 0.36–1.48), respectively, similar to the pattern for Phe31Ile SNP. We did not find statistically significant interaction between smoking and Val57Ile in modulating lung cancer risk (P for interaction = 0.32).


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  		Table III Risk estimates for Val57Ile SNP in Caucasian cases and controls

 
Risk estimate for STK15 haptotypes in Caucasians
We also estimated the risk of lung cancer associated with the haplotypes inferred from these two SNPs. The most common haplotype (T–G) showed a frequency of 66% and 68% in controls and cases, respectively. There was no association between any minor haplotypes and lung cancer risk using the most common haplotype as the reference group (Table IV).


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  		Table IV Risk estimates for STK15 haptolypes in Caucasians

 
Risk estimate for combined STK15 polymorphisms in Caucasians
We next determined the risk of lung cancer when combining the two STK15 polymorphisms (Table V). The reference group was the most common genotype combination (TT + GG, 40.99% of controls). Homozygous Ile31 allele/wild-type Val57 allele (AA + GG) carriers had a reduced lung cancer risk (OR = 0.78, 95% CI = 0.63–0.97). None of the other groups were significantly associated with lung cancer risk. Since the homozygous Ile31 alone carried a stronger protective effect (OR = 0.63, 95% CI = 0.41–0.96, Table II), it appeared that the Val57Ile did not contribute to the effect of the Phe31Ile genotype.


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  		Table V Risk estimates for combined genotypes of Phe31Ile and Val57Ile in Caucasians

 
Linkage disequilibrium analysis
Finally, we examined the linkage between these two loci. The {chi}2 test for linkage disequilibrium analysis was statistically significant for both cases ({chi}2 = 14.19, P = 6.42 x 10–15, D' = 0.994) and controls ({chi}2 = 15.20, P = 6.32 x 10–16, D' = 0.995).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
To our knowledge, this is the first epidemiological study addressing the association between STK15 polymorphisms and lung cancer risk. The major finding of this study is that the homozygous variant allele of the Phe31Ile is associated with significantly reduced lung cancer risk. In addition, the homozygous variant allele of the Val57Ile polymorphism confers a reduced risk for lung cancer in men. These two polymorphisms are in strong linkage disequilibrium in Caucasians. We also showed that the distribution of allele frequencies of Phe31Ile vary significantly among different ethnic groups.

Compelling evidences have linked STK15 to tumorigenesis, including its amplification and overexpression in a variety of human cancers, such as colon, bladder, breast, ovarian, liver, gastric and pancreatic cancers (27); the transforming ability of the STK15 gene; and the association of the Ile31 variant allele with colon cancer. There have not been any reports of STK15 amplification and overexpression in lung cancer. However, several studies have pinpointed chromosome 20q13 amplification as one of the most frequent genetic aberrations in lung cancer patients in both smokers and non-smokers, suggesting that STK15 may be involved in lung cancer initiation and/or prognosis (22–26). The key issue is how STK15 contributes to tumorigenesis. STK15 has been reported to interact and phosphorylate several critical proteins, such as p53, BRCA1 and CDC25B, and play important physiological functions. The aberrant expression of STK15 leading to deregulated function of these proteins could conceivably mediate its role in malignant transformation. For example, the most prominent substrate of STK15 is p53. Overexpression of STK15 leads to diminished transcriptional activity and increased degradation of p53, causing check-points defects and genetic instability and facilitating oncogenic transformation (28,29). In light of the oncogenic roles of STK15 in a variety of human cancers, there have been several studies evaluating the associations between polymorphisms in STK15 gene and cancer risk. The Phe31Ile SNP is of special interest since Ewart-Toland et al. (12) found that the variant allele (Ile) was more oncogenic than the wild-type Phe allele in vitro and that the Ile allele was preferentially amplified and associated with aneuploidy in human colon tumors. Several case–control studies have been published on the association of Phe31Ile with breast cancer risk (13–18,30). For the homozygous variant (Ile/Ile) genotype, Sun et al. (13) found a significantly increased risk (OR = 1.76, 95% CI = 1.16–2.66); two studies found borderline increased risks (OR = 1.54, 95% CI = 0.96–2.47; and OR = 1.43, 95% CI = 0.99–2.06, respectively) (14,17); and two studies did not find significant associations (15,16). A meta-analysis of the above five breast cancer studies produced an overall OR of 1.29 (95% CI = 1.08–1.53) for the Ile/Ile genotype (17). However, the most recent study published during the revision of our manuscript suggested that the association between the Ile/Ile genotype and the risk of breast cancer was negligible or protective in English women (30). The authors further performed a meta-analysis of six published breast cancer case–control studies and found significant heterogeneity in the OR estimates (P < 0.001), which may be due to population-specific linkage disequilibrium with another functional variant or artifacts such as population stratification and publication bias (30). Three additional studies were published in other cancers. Two Asian studies on esophageal cancer reported somewhat contradictory results. Miao et al. (19) reported a significantly elevated risk for the Ile/Ile genotype in esophageal squamous cell carcinoma (ESCC) (OR = 1.97, 95% CI = 1.36–2.85), whereas a Japanese study reported an OR of 1.93 (95% CI = 0.90–4.15) for the Phe/Phe in ESCC (20). The third study was based on three population-based ovarian cancer case–control studies from the UK, US and Denmark, which did not find overall a significant association between the homozygous Ile/Ile genotype and ovarian cancer risk, although the Phe/Ile heterozygotes (OR = 1.17, 95% CI = 1.01–1.36) and the Ile31 allele carriers (OR = 1.17, 95% CI = 1.02–1.35) exhibited modestly increased ovarian cancer risk in the combined group (21). Our study is the first lung cancer study. It is evident from this study and other published reports that the genotype and haplotype frequencies of Phe31Ile were different by ethnicity. The variant allele (Ile) frequency and homozygous variant genotype (Ile/Ile) frequency in our Caucasian controls were 21.62 and 5.45%, respectively, which were very similar to other Caucasian studies (M-allele frequency, ~20%, and Ile/Ile frequency, ~5%) (14,17,18,21). In Asians, however, the Ile allele is the major allele with an allele frequency of ~65% and the homozygous Ile/Ile frequency is ~45% (13,15,16,18,19). Given such a dramatic difference in genotype distributions among different ethnic groups, it is likely that the Ile31 allele may play different roles in modifying cancer risk in different populations. In addition, the role of Ile31 in modifying cancer risk may also depend on specific cancer types. Ewart-Toland et al. (18) performed a meta-analysis of 15 case–control studies (5 published and 10 unpublished) for a total of 9549 cases of 7 different cancer types and suggested that the Ile/Ile genotype is a general cancer susceptibility factor for all cancers (OR = 1.50, 95% CI = 1.14–1.99). The cases and controls in this meta-analysis included all ethnicities. The only unpublished lung cancer study included in this analysis had 414 cases (72.9% Caucasians and 27.1% African-American) and 467 controls (from two different sources, 62.7% Caucasians and 37.3% African-Americans) and produced an OR of 1.41 (95% CI = 0.74–2.71). The analysis was not limited to Caucasians and there were no information on age, gender and smoking status. Since the allele distribution of Phe31Ile was dramatically different across ethnicities, race-specific analysis may be more appropriate. Further studies are warranted to confirm our results in lung cancer and determine whether the Phe31Ile SNP is a general or a cancer type-specific susceptibility factor.

This is the first study to show a protective role for Ile31 in cancer. Ewart-Toland et al. (12) showed that the Ile31 allele is preferentially amplified in colon cancer and individuals with one Ile31 allele develop more highly aneuploid tumors, which might be more relevant to a role for STK15 in tumor progression. Overexpression of the Ile31 variant transforms rodent cells more potently than the more common Phe31 allele; however, under physiological conditions, the functional impact of this variation is unclear. Interestingly, the E2 ubiquitin-conjugating enzyme UBE2N binds preferentially to the weak Phe31 variant in human cells and co-localizes to the centrosomes. The outcome of this interaction under physiological conditions, which may lead to either activation of STK15 or inactivation and degradation of STK15, is currently unknown and awaits further elucidation of other partners of the UBE2N–STK15 complex. Since either depletion or overexpression of STK15 leads to mitotic defects, it is likely that more UBE2N–STK15 complex due to strong association of STK15 with the Phe31variant may provide growth advantage to potential pre-malignant cells; therefore, individuals with Phe31 allele have higher lung cancer risk than those with Ile31 allele.

Several previous studies of Val57Ile polymorphism and cancer risk did not find significant associations (14,15,17,20,21). In the current study, we found that Ile/Ile homozygotes exhibited a reduced lung cancer risk only in men (OR = 0.42, 95% CI = 0.19–0.94), but not in females. The functional impact of this SNP is not clear. The frequency of this polymorphism is similar across ethnicities, including Caucasians and Asians. In our study, we observed that this polymorphism is in strong linkage disequilibrium with Phe31Ile in Caucasians, and the protective effect might be attributed to the Phe31Ile polymorphism.

The strengths of our study include the relatively large sample size and the power to detect reasonably small risks. All lung cancer cases were histologically confirmed. By limiting our analysis to Caucasians, we also reduce the risk of confounding by population stratification. The limitations of our study include the hospital-based study design with which we could not exclude the possibility of selection bias and the fact that our controls are not population based. In addition, even though our study is of fairly large size, it may still have been underpowered for some stratified analyses and gene–smoking interactions. Further studies are needed to confirm these observations and to determine the mechanism by which Phe31Ile variants modify cancer risk differentially.

In summary, we found that the homozygous Ile31 variant has a protective effect against lung cancer, and homozygous Ile57 variant confers a reduced lung cancer risk only in male subjects. This is the first reported lung cancer case–control study to evaluate the association between STK15 polymorphisms and lung cancer risk. This is also the first study to suggest that the homozygous Ile31 genotype is a protective factor against a type of cancer. This study suggests that the Phe31Ile SNP of STK15 may modify cancer risk in a cancer type-specific manner.


   Acknowledgments
 
We thank Dr Allan Balmain for help in initiating this study and for thoughtful discussions. This study was supported by the following grants: NCI CA 111646, CA 55769, CA 70907, DAMD17-02-1-0706 and Flight Attendant Medical Research Institute.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received March 20, 2006; revised July 28, 2006; accepted August 4, 2006.


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