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Carcinogenesis Advance Access originally published online on June 13, 2006
Carcinogenesis 2006 27(11):2217-2222; doi:10.1093/carcin/bgl084
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Novel polymorphisms in the SUV39H2 histone methyltransferase and the risk of lung cancer

Kyong-Ah Yoon{dagger}, Bin Hwangbo{dagger}, Il-Jin Kim, Sohee Park, Hee Sun Kim, Hyun Jung Kee, Jong Eun Lee1, Yeun Kyu Jang, Jae-Gahb Park and Jin Soo Lee*

Research Institute and Hospital, National Cancer Center Goyang, Gyeonggi, Korea
1 Research Institute of Science for Aging, Yonsei University Seoul, Korea

*To whom correspondence should be addressed at: National Cancer Center, 809 Madu-dong, Ilsan-gu, Goyang, Gyeonggi 411-769, South Korea. Tel: +82 31 920 1601; Fax: +82 31 920 1520; Email: jinslee{at}ncc.re.kr


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Histone H3 lysine 9 (H3-K9) methylation and DNA methylation are important features of mammalian heterochromatin. Suppressor of variegation 3-9 homolog 2 (SUV39H2) is the histone methyltransferase that is required to methylate H3-K9, leading to transcriptional repression or silencing of target genes. In this study, we investigated the association of SUV39H2 polymorphisms and the risk of lung cancer. From the results of PCR direct sequencing, eight single nucleotide polymorphisms (SNPs) of SUV39H2 were identified in Korean population. In a hospital-based study of 346 lung cancer patients and 423 healthy controls, a novel SNP in the 3'-UTR of SUV39H2 (1624 G->C) was associated with a statistically significant increase in lung cancer risk. Compared to the G/G genotype, genotypes with 1624C allele (G/C + C/C) significantly increased the susceptibility to lung cancer with adjusted odds ratio (AOR) of 2.63 (95% confidence interval (CI)= 1.10–6.29) for ever-smokers, especially in the older age group (age ≥55 years). Specifically, the variant genotype of 1624SNP was significantly associated with an increased risk of squamous cell carcinoma (AOR, 3.52; 95% CI = 1.13–9.45) in the older age group, while no significant association was found in patients with other histology. This study provided the first evidence that a novel SUV39H2 polymorphism may be an important predictive marker for lung cancer susceptibility for the smokers.

Abbreviations: HP1, heterochromatin protein 1; MMP, matrix metalloproteinase; PCR–RFLP, polymerase chain reaction–restriction fragment length polymorphism; Suv39h1/2, suppressor of variegation 3-9 homolog 1/2; SNP, single nucleotide polymorphism


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Lung cancer is the leading cause of cancer deaths worldwide and also in Korea. Despite the strong association between cigarette smoking and lung cancer risk, not all smokers develop lung cancer and other factors play an important role in determining the ultimate outcome following the exposure to tobacco carcinogens. Individual susceptibility to lung cancer has been shown to vary with the presence of single nucleotide polymorphisms (SNPs) in a variety of critical genes (1,2). Polymorphisms in genes involved in the metabolic activation (cytochrome P450) and detoxification (glutathione S-transferase) of tobacco carcinogens as well as in the repair of DNA damage (8-oxoguanine DNA glycosylase 1) have all been associated with an increased risk of lung cancer in case–control studies (3–6). Recently, the polymorphism in matrix metalloproteinases (MMP-1, MMP-2 and MMP-7) that play a central role in degrading or breaking down extracellular matrix has also been reported to be associated with lung cancer susceptibility (7–9). However, few studies have reported on the possible association of lung cancer susceptibility with the genes that regulate the structure of the chromatin and histone methylation.

Higher-order chromatin that modulates gene expression and functional organization of chromosomes is modified by diverse post-translational modifications of histone amino termini, which include acetylation, phosphorylation, methylation and ubiquitination (10,11). The methylation of histone H3 lysine 9 was recently shown as the histone modification associated with transcriptional repression or silencing (12–14). One class of mammalian methyltransferase, suppressor of variegation 3-9 homolog 1 (suv39h1) and homolog 2 (suv39h2) were identified to have a site-specific histone H3-K9 methyltransferase activity (15–17). Suv39h-dependent methylation of lysine 9 in H3 generates a binding site for the heterochromatin protein 1 (HP1) (18,19). Suv39h methyltransferases are further implicated in cancer by virtue of its interaction with retinoblastoma (Rb), which plays a crucial role in cell-cycle control with cyclin E. Furthermore, Suv39h and HP1 are both involved in the repressive functions of the Rb protein (20,21). Suv39h-deficient mice display severely impaired viability and chromosomal instabilities that are associated with an increased tumor risk (22). It was also interesting to note that cancer cells from Suv39h double knockout mice resembled those in human slow-progressing non-Hodgkin's lymphomas. This raises the possibility that SUV39H1/2 could be important in the development of cancer. Methylation of H3-K9 by Suv39h was also reported as an important event for telomere length regulation in mammalian cells (23). These findings suggest that Suv39h has an important role in the regulation of normal cellular function as well as a role in tumor formation.

Recently, the association of a polymorphism of a histone H3-K4 methyltransferase and cancer was reported (24). The tandem repeats polymorphism of SMYD3 increased the risk of colorectal cancers, hepatocellular carcinomas and breast cancers. Therefore, we thought that polymorphism study of SUV39H1 and SUV39H2 was valuable to predict its relation to cancer. Here, we report eight polymorphisms of SUV39H2 and the association of 3'UTR SNP and lung cancer susceptibility in Korean population. This study suggested that a novel SUV39H2 polymorphism might be an important candidate for a predictive marker for lung cancer susceptibility among smokers.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Study population
This is a hospital-based case–control study. Eligible cases were the patients who came to the National Cancer Center, Korea, between May 2002 and July 2003 with the following criteria: (i) histologically confirmed lung cancer cases; (ii) received no previous chemotherapy or radiation therapy; and (iii) patients who were born after the year 1930. There were no recruitment restrictions on gender or cancer stage. A total of 346 eligible patients entered into this case–control study. Of the 346 lung cancer patients, 189 (54.6%) had adenocarcinomas, 84 (24.3%) had squamous cell carcinomas and 32 (9.3%) had small cell lung cancer. For a comparison, total 423 healthy control subjects without a prior history of cancer or other severe disease were recruited from the subjects who visited our institution either for cancer prevention and screening program or non-cancerous conditions, and volunteered to give their blood during the same period. By signing an informed consent, the study subjects voluntarily participated in the health questionnaire survey and provided the blood samples for genetic tests. Information on gender, age, smoking habit and family history of cancers was obtained from cancer patients and healthy controls by a personal interview that was administered by a trained personnel after a written informed consent was obtained. For smoking habit, the former and present smoking status, the number of cigarette smoked per day and the time of starting and quitting were inquired. Individuals who formerly or currently smoked ≥100 cigarettes for lifetime were defined as ever-smokers. Never-smokers were defined as subjects who smoked <100 cigarettes in lifetime. Genomic DNA was extracted from peripheral blood by using QIAamp DNA Blood Mini kit (Qiagen, Valencia, CA) following manufacturer's instruction.

Detection and genotyping SUV39H2 polymorphisms
To identify novel polymorphisms of SUV39H2, 29,760 bp of genomic DNA region were examined by PCR-direct sequencing. Variants were identified by comparison with the traces of the SUV39H2 sequence relative to the reference GenBank sequence (NM_024670 [GenBank] ) and confirmed by reamplification and resequencing.

The genotypes of four SNPs (–1481A->T, 109G->C, 228 + 32A->C, 900 + 128T->G) were determined by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) assay. Briefly, the PCR products that were amplified with two specific primers of each SNPs were digested with PstI (–1481SNP), CviAII (109SNP), BtsI (228 + 32SNP) and ApoI (900 + 128SNP) (New England BioLabs, Ipswich, MA), respectively. After digestion, the products were separated on a 1.5% agarose gel.

The genomic DNA fragment including –1290SNP and –1267SNP amplified by PCR (5'-GAAGTGGTGTTTCCCATCGT-3' and 5'-ACTGGAAATGAACGCAGACC) and then directly sequenced. The 1047 + 281SNP were also examined by PCR-direct sequencing using two primers (5'-TAAGCCTTAAAGGGCCTGGA-3' and 5'-ACGATGGGAAACACCACTTC-3').

The genotypes of 1624G->C were determined by the TaqMan assay and direct sequencing. Genotyping using Taqman 5' nuclease assay for allelic discrimination was carried out on the 384-well ABI 7900HT Sequence Detection System (applied biosystems, Foster City, CA). Probes for Taqman assay of 1624G->C SNP were designed by ‘Assays-by-Design’ (Applied Biosystems, CA). PCR primers for 1624G->C polymorphism were forward: 5'-GCFCGTAGTGTTTGAAAGCGTTAAGCT-3' and reverse: 5'-GCRTGAGGTGTATGGCAAGTTGAATCTT-3'. The fluorescent probes were VIC-ATCTCTCAGCAGTTGTT and FAM-ATCTCTCAGGAGTTGTT. The reactions were carried out in 384-well microtiter plates. PCR reactions were carried out in a volume of 5 µl containing 1 µl of 10 ng genomic DNA, 2.5 µl of 2x TaqMan Universal PCR Master Mix (Applied Biosystems, Foster City, CA), 0.13 µl of 40x `Assay-by-Design' solution and 1.37 µl of distilled water. The PCR was performed as 10 min at 95°C (denaturation) and 40 cycles of 15 s at 95°C and 1 min at an annealing temperature of 60°C. The genotyping was analyzed using allele discrimination plots using the SDS 2.1 program (version 5.0, Applied Biosystems). PCR primers for direct sequencing (5'-CCAAACTAATGGAAGGCAGAC-3' and 5'-TTTATCATTGAGGTGCCAAT-3') were designed to amplify a fragment of 3'UTR encompassing the 1624G->C polymorphism.

Statistical analysis
Descriptive analyses were carried out by reporting median and range for continuous variables and by two-way contingency tables for categorical variables. As age and pack-years had skewed distribution, the comparison between cases and controls for these variables were performed using a non-parametric test (Wilcoxon's rank sum test). For categorical variables, Pearson's {chi}2-test was used. Hardy–Weinberg equilibrium of alleles was tested with a goodness-of-fit {chi}2-test. Linkage disequilibrium coefficients (|D'| and r2) were computed using the software Haploview (http://www.broad.mit.edu/mpg/haploview/). Haplotype of each individual were estimated from genotype data using PHASE v.2.1 (http://www.stat.washington.edu/stephens/software.html) (25,26). Unconditional logistic regression models were used to estimate the lung cancer risk associated with genotype or haplotype, by adjusting for potential confounders such as gender, age (continuous) and pack-years (continuous value). A significance level of 5% ({alpha} = 0.05) was considered significant for all statistic analyses. Formal interaction tests for the effect of age and genotype, and smoking and genotype were performed with the likelihood ratio test by comparing two models with and without these interaction terms. Although not significant at the 0.05 level, when there was a trend in the interaction terms, we performed the subset analyses by age and smoking status. All reported P-values were two-sided. Statistical analyses were performed using SAS software version 9.0 (SAS Institute Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Identification of SUV39H2 polymorphisms
By direct DNA sequencing analysis, we identified eight genetic variants within the 29 kb full genome including –3000 bp promoter region of SUV39H2: three in 5' region (–1481A->T), one in exon 1 (109G->C), three in introns (228 + 32A->C, 900 + 128T->G, 1047 + 281C->T) and one in exon 5 (1624G->C) (Figure 1A). Two polymorphisms (–1482 SNP and 1047 + 281SNP) were identical with registered SNPs (rs2400103 and rs10430783) in the NCBI dbSNP database. No non-synonymous SNPs were found in any regions of SUV39H2. Haplotypes of SUV39H2 were estimated from the genotype data of eight polymorphisms. There were seven haplotypes in SUV39H2 showing frequencies of >1% among the 12 haplotypes observed (Figure 1B). Linkage disequilibrium coefficients (|D'| and r2) among eight SNPs revealed that two sets of SNPs (–1481SNP and –1290SNP; 1624SNP and 900 + 128SNP) were in absolute LD (|D'| = 1 and r2 = 1) (Figure 1C).


Figure 1
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  		Fig. 1 SNPs and haplotypes of the SUV39H2 gene. (A) SNPs identified in SUV39H2. Black boxes indicated the coding regions and white indicated 5' and 3' UTR. SNPs were named according to their location when the first base of the transcription start site was denoted as nucleotide +1. The frequencies of minor allele were indicated in parentheses. (B) Haplotypes of SUV39H2 gene. (C) LD coefficients (|D'| and r2) among SUV39H2 polymorphisms.

 
Genotyping of SNPs
The distribution of demographic characteristics of lung cancer patients and healthy controls are presented in Table I. The lung cancer cases were more likely to be males, older and ever-smokers than controls (P-values <0.01)


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  		Table I Demographic characteristics among lung cancer cases and cancer-free controls

 
The genotyping results of six SNPs in 346 lung cancer patients and 423 healthy controls are shown in Table II. There were no statistically significant difference in the polymorphism distribution for the genotypes of –1290SNP, –1267SNP and 1047 + 281SNP between lung cancer cases and controls. There were some frequency differences in the distribution of variant alleles of 109SNP (109C) (2.9% in lung cancer patients and 1.5% in healthy controls, P = 0.07) and the minor allelic frequency of 228 + 32SNP (11.8% in lung cancer group and 9% in healthy control group, P = 0.08), although these differences did not reach a statistical significance.


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  		Table II Genotype distribution of the SUV39H2 polymorphisms in lung cancer cases and cancer-free controls

 
For the 1624SNP, the frequency of variant allele (1624C) was 9.8% in lung cancer group and 7.1% in the control group (P = 0.05). The frequencies of the 1624G/G, 1624G/C and 1624C/C genotypes were 80.9, 18.5 and 0.6% in the cases and 86.3, 13.2 and 0.5% in the controls, respectively. Since frequency of the C/C genotype was very low in both of the lung cancer and the control groups, G/C and C/C genotypes were combined to analyze the effect of the 1624SNP on the risk of lung cancer. Although lung cancer patients and healthy controls were not adequately matched in age and gender, the genotype distribution of 1624SNP was not different between females and males as well as older group and younger group (Table III).


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  		Table III The genotype distribution of 1624SNP in lung cancer cases and cancer-free controls, by gender, age and smoking

 
As there was a hint of interaction effect of age (age ≥55 years) and genotype (SNP1624) with adjusted odds ratio (AOR) for interaction term of 1.44, although not statistically significant (P > 0.05), we performed the subset analyses for the main effect of SNP1624 by age groups. Similarly, the analyses were also stratified by smoking status. As shown in Table IV, among the older age group (age ≥55 years), the variant genotype of 1624SNP (G/C + C/C) was associated with the increased risk of lung cancer [AOR = 1.77, 95% confidence intervals (CI) = 0.97–3.23], especially for the ever-smokers (AOR = 2.63, 95% CI = 1.10–6.29). Since the smoking history is a well-known risk factor for lung cancer, the association between the 1624SNP and the risk of lung cancer was analyzed controlling for the pack-years of ever-smokers as a continuous variable.


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  		Table IV Association analysis among 1624SNP genotype, smoking status, age and histologic cell type in lung cancer patients

 
We further analyzed the data by different histologic cell types of adenocarcinoma, squamous cell carcinoma, SCLC and others. Among patients with squamous cell carcinoma, the variant genotype was associated with an increased risk of developing lung cancer, especially in the older age group (AOR = 3.52, 95% CI = 1.31–9.45; P = 0.01) and in the older ever-smoker group (AOR = 3.64, 95% CI = 1.32–10.06; P = 0.01).

Haplotype analysis of SUV39H2
The genotype data of six polymorphisms in SUV39H2 were used to estimate the haplotype of individual. –1481SNP and 900 + 128SNP were excluded from the haplotype analysis because their genotype results were identical with –1290SNP and 1624SNP, respectively. Among 12 estimated haplotypes, 3 common haplotypes with frequency >5% were found with an accumulated frequency of 90%. Other rare haplotypes were grouped together in the analyses as shown in Table V. Ht1 represented all SNPs carrying the wild-type allele and Ht2 showed only one variant allele of 1047 + 281SNP. Subjects carrying one copy of variant Ht3 had a 1.3-fold increased risk of lung cancer but did not reach the statistical significance. In case of minor haplotypes that exclude Ht1 and Ht2, individuals carrying one copy showed a 1.42-fold increased risk of lung cancer (95% CI = 1.00–2.01).


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  		Table V Association analysis between SUV39H2 haplotypes and the risk of lung cancer

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Since histone H3 methylation is an important modification of mammalian heterochromatin, it is not surprising to note the association of the histone-modifying enzymes, SUV39H2 polymorphism and lung cancer risk. The histone methyltransferases that contain a conserved methyltransferase domain termed as a SET (Su9var3-9, Enhancer-of-zeste, Trithorax) domain appear to be intimately involved in carcinogenesis (27,28). SUV39H1 and SUV39H2 are also known as SET domain-containing proteins that are required for methylation of H3-K9 in heterochromatic regions and SET domain-dependent regulation of transcriptional silencing and growth control has been reported (29,30). Recently, genetic polymorphism in the SET domain-containing histone methyltransferase has been shown to affect cancer susceptibility. The common variable number of tandem repeats polymorphism in SMYD3 H3-K4 histone methyltransferase was reported as a risk factor for such human cancers as colorectal cancer, hepatocellular carcinoma and breast cancer (24).

In this study, eight SNPs were identified in the SUV39H2 gene based on the results of direct sequencing of whole genomic region among Koreans. From the genotyping results of SNPs, LD analysis showed that two sets of SNPs were in absolute LDs. The frequency of variant alleles for –1290, –1267, 109, 228 + 32 and 1047 + 281SNPs was not significantly different between lung cancer patients and healthy controls. However, the variant genotype of 1624SNP was associated with increased risk of developing lung cancer, especially in older age group.

In older age group, the ever-smokers with variant 1624SNP genotype had a statistically significantly higher risk of lung cancer than did non-carriers. Additionally, the variant genotype increased the lung cancer risk by 3.5-fold among patients with squamous cell carcinoma especially in the older age group. However, when compared with the never-smokers with wild-type, the ever-smokers with the variant 1624SNP genotypes (G/C + C/C) showed >3.9 times increased risk of lung cancer (P = 0.0004), although the formal gene–environment interaction did not reach statistical significance at 0.05 level.

Furthermore, the analysis of frequent haplotypes of SUV39H2 did not show significant association with lung cancer risk. In case of minor haplotypes that exclude Ht1 and Ht2, individuals carrying one copy showed a 1.42-fold increased risk of lung cancer.

Since the 1624 SNP was significantly associated with the lung cancer risk from the result of genotyping study, we were interested to demonstrate the effect of 1624SNP on the expression of SUV39H2 and its functional significance. The luciferase activity of the luciferase construct containing the fragment of SUV39H2 3'UTR with 1624C allele was 2-fold higher than the construct containing the 1624G allele in the HEK 293 cell line (data not shown). However, we could not confirm the same result in human lung cancer cell lines. Further studies are needed to elucidate the role of SUV39H2 variants in the expression level of SUV39H2 in lung cancer patients and the function of the histone methyltransferase.

This study has several limitations. First, this is a hospital-based case–control study, where the controls were selected from the persons that visited the hospital for other medical health checkups (but with no previous cancer or severe disease history). Since no matching was done, our controls, being healthier group, were younger and more likely to be non-smokers. However, our major explanatory variable of interest was the genetic polymorphism. And the bias the estimate of stratum-specific odds ratio owing to a specific gene (or haplotype) with strata defined by levels of measured confounders and effect modifiers (such as smoking, etc.) will only occur if, within these strata, the subset of controls is more likely than other types of controls to have a particular allele or alleles of genotype under study, and this is an unlikely scenario. Although we did not match individually our controls to cases on age, gender or smoking variables, we did adjust for these variables in the statistical analyses.

Second, this study only considers the Korean population. Hence, it needs further investigation to apply these findings to other ethnic population.

In conclusion, this is the first study to show that a novel polymorphism in 3'UTR of SUV39H2 was significantly associated with the risk of lung cancer, particularly squamous cell carcinoma. These results suggest that the polymorphism of SUV39H2 could be used as an important marker of genetic susceptibility to lung cancer although additional studies are required to confirm our findings with larger sample sizes. The importance of SUV39H2 gene in regulation of histone methylation and gene expression makes it attractive for further study in other cancers and as a useful marker for epidemiological study.


   Footnotes
 
{dagger}These authors contributed equally to this work. Back


   Acknowledgments
 
We thank Yeun Ho Choi and Jin Hee Kim (National Cancer Center) for their excellent technical assistance. This work was supported by the National Cancer Center Research Grant (0410110-1) (P.I. J.S.L.).

Conflict of Interest Statement: None declared.


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received December 30, 2005; revised April 26, 2006; accepted May 19, 2006.


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K.-A. Yoon, S. Park, B. Hwangbo, H. D. Shin, H. S. Cheong, H.-R. Shin, and J. S. Lee
Genetic polymorphisms in the Rb-binding zinc finger gene RIZ and the risk of lung cancer
Carcinogenesis, September 1, 2007; 28(9): 1971 - 1977.
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A. Miremadi, M. Z. Oestergaard, P. D.P. Pharoah, and C. Caldas
Cancer genetics of epigenetic genes
Hum. Mol. Genet., April 15, 2007; 16(R1): R28 - R49.
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