Abstract
Purpose
The mismatch repair (MMR) system is a DNA repair mechanism that corrects mispaired bases during DNA replication errors. Cancer cells deficient in the MMR proteins have a 102 –103-fold increase in the mutation rate. Single nucleotide polymorphisms (SNPs) of MMR genes have been shown to cause a reduction in DNA repair activity. We hypothesized that mismatch repair gene polymorphism could be a risk factor for prostate cancer (PC) and that p53 Pro/Pro genotype carriers could influence MSH3 and MSH6 polymorphisms.
Material and Methods
DNA samples from 110 cases of prostate cancer and healthy controls (n=110) were analyzed by SSCP and PCR-RFLP to determine the genotypic frequency of five different polymorphic loci on two MMR genes (MSH3 and MSH6) and p53 codon72. The chi-square test was applied to compare the genotype frequency between patients and controls.
Results
A significant increase in the G/A+A/A genotype of MSH3 Pro222Pro was observed in patients compared to controls (OR, 1.87; 95% CI, 1.0–3.5). The frequency of A/G + G/G genotypes of MSH3 exon23 Thr1036Ala also tended to increase in patients (OR, 1.57; 95% CI, 0.92–2.72). Among p53 codon72 Arg/Pro + Pro/Pro carriers, the frequency of the AG + GG genotype of MSH3 exon23 was significantly increased in patients compared to controls (OR = 2.1, 95% CI; 1.05–4.34).
Conclusion
This is the first report on the association of MSH3 gene polymorphisms in prostate cancer. These results suggest that the MSH3 polymorphism may be a risk factor for prostate cancer.
Keywords: Polymorphism, mismatch repair gene, prostate cancer, p53
INTRODUCTION
Prostate cancer (PC) is one of the most common malignancies in United States males.1 Generally speaking, Japanese men have a lower incidence of prostate cancer than Americans. However recently, the prostate cancer incidence is increasing. 1 The etiology of prostate cancer is largely unknown, although several risk factors such as ethnicity, family history, and age are associated with the disease. 2 Also several dietary constituents have been linked to prostate cancer risk and prevention. 3 The mismatch repair (MMR) system is one of several DNA repair mechanisms that correct mispaired bases during DNA replication errors. Cancer cells deficient in MMR proteins have a 102–103 fold increase in their mutation rate. In the MMR system, there are seven mismatch repair genes including MSH2, MSH3, MSH6, MLH1, PMS1, PMS2, and MLH3.4 The heterodimers formed by MSH2–MSH6 (MutSα) and MSH2–MSH3 (MutSβ) proteins detect mispaired bases. The MutSα complex functions to repair base-base and insertion/deletion mispairs, whereas MutSβ is associated only with the repair of insertion/deletion mispairs.4 MutSα also associates with another heterodimer of MLH1 and PMS2 (MutLα).4 Loss of MMR gene activity causes replication errors and thus microsatellite instability (MSI). HNPCC (hereditary non-polyposis colorectal carcinoma) is a hereditary cancer syndrome caused by MMR gene mutations and more than 90% of the HNPCC shows MSI.5 Among the MMR genes, germ-line mutations of MLH1, MSH2, and MSH6 have been reported in the majority of HNPCC.5 The MSH6 gene is on chromosome 2 and mutation of this gene has been detected in atypical HNPCC families, where the age of onset of cancer is higher than those in the usual HNPCC families.6
The MSH3 gene is located on chromosome 5q11-13 and was first described in 1989.7 The MSH2 gene located on chromosome 2, encodes a 105 kD protein and plays a central role in mismatch recognition. Some MSH2 SNPs are associated with a significantly increased cancer risk in endometrial, and lung cancer.8, 9 The function of MSH3 and MSH6 overlap and apparently do not play a significant role in MMR compared to the other genes.4
Recently, Song et al. investigated MMR polymorphisms in ovarian cancer.10 They found evidence for an increased ovarian cancer risk with SNPs in MSH6 and MSH3.10 In a previous study we showed that decreased MMR activity was associated with low expression of MMR proteins.11 Several studies have been published associating with gastrointestinal cancer, although there have been few reports about MMR gene polymorphisms in prostate cancer. p53 is a tumor suppressor gene that initiates apoptosis in response to severe DNA damage. A p53 polymorphism at amino acid 72 (Arg/Pro; G/C) is very common and in an in vitro study, the p53 Arg/Arg genotype induced apoptosis more efficiently than the Pro/Pro genotype.12 It has been thought that this genotype may be linked to decreased p53 function. Talseth et al reported an association between the p53 polymorphism and colorectal cancer characteristics in HNPCC patients.13 They found no association between p53 SNPs and disease development in HNPCC patient, although there was some evidence of an effect when MLH1 and MSH2 mutation status was included.13 Namely, the p53 SNP was over-represented in a Polish MSH2 mutation population.13
We hypothesized that polymorphisms of mismatch repair genes could be a risk factor for prostate cancer (PC) and that p53 Pro/Pro genotype carriers could influence MSH3 and MSH6 polymorphisms. To test this hypothesis, we examined whether polymorphisms in MSH3 and MSH6 genes are associated with PC, and investigated the additional effect of p53 Pro/Pro on MSH3 and MSH6 gene polymorphisms.
MATERIALS AND METHODS
Samples
A total of 110 patients with pathologically confirmed prostate cancer (PC), and 110 age-matched control individuals were enrolled in this study. The mean ages and standard deviation of the patient and control groups were 68 ± 5 and 68 ± 14 years, respectively (Table 1, p = 0.60). Genomic DNA was obtained from the peripheral blood of healthy controls and patients. All of the patients tested were diagnosed with prostate cancer on the basis of histopathological findings from radical prostatectomy. They were classified according to the WHO criteria and staged according to the tumor-node-metastasis (TNM) classification and the Gleason grading system. Healthy controls consisted of volunteers with no apparent abnormal findings upon medical examination at Shimane University Hospital.
Table 1.
Characteristics of PC patients and controls
| Cases (n=110) | Controls (n=110) | |
|---|---|---|
| Age(mean ± S.D.)a | 68±5 | 68±15 |
| pT | ||
| 1 | 0 (0%) | |
| 2 | 67 (61%) | |
| 3 | 39 (35%) | |
| 4 | 4 (4%) | |
| Gleason sum | ||
| <7 | 71 (64%) | |
| 7 | 23 (21%) | |
| >7 | 16 (15%) | |
| Preoperative serum PSA | ||
| <4 | 18 (16%) | |
| 4–10 | 53 (48%) | |
| >10 | 36 (36%) | |
| Smoking status | ||
| Yes (current and former smokers) | 48 (44%) | |
| No (never smokers) | 62 (56%) | |
Cases versus controls, P = 0.60
Regarding body mass index (BMI), the frequency of more than 23 kg/m2 was 60% and 58% in PC cases and controls, respectively. There was no statistical difference between the two groups (p=0.89). The smoking statuses were investigated through interviews with doctors or nurses. Current smokers were defined as those who smoked within 12 months of tumor development. Former smokers were those who had quit smoking more than 12 months before tumor development. None of these patients had received androgen deprivation therapy before radical prostatectomy. There were no significant differences between patients and control groups with regard to family history of cancer.
Genotyping
Polymorphisms were analyzed by SSCP (Single Strand Conformational Polymorphism) or PCR-RFLP. Primer sets and annealing temperatures used for SSCP and RFLP are shown in Table 2. PCR products were digested with BstuI (New England Biolabs, Beverly, MA) for p53. The restricted products were analyzed in a 2% agarose gel containing ethidium bromide. SSCP was performed using non-radioactive method. To confirm the genotype ascribed by SSCP or RFLP, the PCR products were subjected to direct sequencing. The reaction products were analyzed using an ABI PRISM 377 DNA sequencer (Applied Biosystems).
Table 2.
Primer sequence and annealing temperature
| primer sequence | annealing T(C) | PCR product | genotyping | |
|---|---|---|---|---|
| MSH3 codon222 | S 5 -AAAACTTTATACATCTTTTGGTTGC -3′ | 53 | 178 bp | SSCP |
| rs1805355 | AS 5 -ACTGCATCTTTGTGCTGCTG -3′ | |||
| MSH3 codon1036 | S 5 -TTTCAGCTTTCAGGCACAGTT -3′ | 57 | 200 bP | SSCP |
| rs26279 | AS 5 -CCTTCCAGCTCTTTTGACTTG -3′ | |||
| MSH6 codon39 | S 5 -AGCTTCTTCCCCAAGTCTCC -3′ | 56 | 205 bp | SSCP |
| rs1042821 | AS 5 -CCCTCCGTTGAGGTTCTTC -3′ | |||
| MSH6 intron 2 | S 5 -TTGTTTAAGCGACCCTTTCC -3′ | 56 | 176 bp | SSCP |
| rs3136245 | AS 5 -ATACACCCGTTTGGTTTGGA -3 | |||
| p53 codon72 | S 5 -TTGCCGTCCCAAGCAATGGATGA -3′ | 56 | 199 bp | RFLP (BstU I) |
| AS 5 -TCTGGGAAGGGACAGAAGATGAC -3 |
Statistical analysis
Hardy-Weinberg equilibrium was evaluated using SNPAlyze version 2.2 (DYNACOM Co. Ltd., Tokyo, Japan). The strength of associations between PC patients and MMR gene polymorphisms were measured as odds ratios (ORs). The ORs were obtained with unconditional logistic regression analysis. Crude ORs and those adjusted for age were calculated. All statistical analyses were performed using StatView (version 5; SAS Institute Inc., NC). A p-value of less than 0.05 was regarded as statistically significant.
Results
Characteristics of pc patients and controls
Table 1 shows the mean age, pT, Gleason sum, preoperative serum PSA, and smoking status of individual PC patients. Two-tailed Student’s t-tests were used to compare the age distribution between patients and control subjects. There was no significant difference of mean age between cases and controls (Table 1). In the 110 prostate cancer cases, 67 (61%) were organ confined and 71 (64%) had a Gleason sum (GS) of less than 7.
Hardy-Weinberg equilibrium
The genotype frequencies of the four polymorphisms in total samples (n = 220), PC patients (n = 110) and healthy controls (n = 110) were consistent with the Hardy-Weinberg equilibrium distribution (p-value > 0.05).
MSH3 and MSH6 gene polymorphism and pc
Table 3 shows the genotype distribution of the MSH3 Pro222Pro (rs1805355), MSH3 Thr1036Ala (rs26279), MSH6 rs1042821, MSH6 rs3136245 polymorphisms in PC cases and healthy controls. A significant increase in the G/A + A/A genotypes of MSH3 Pro222Pro was observed in patients compared to controls (OR, 1.87; 95%CI, 1.0–3.5; p = 0.04) (Table 3). The frequency of A/G + G/G genotypes of MSH3 exon 23 Thr1036Ala also tended to increase in patients (OR, 1.57; 95%CI, 0.92–2.72; p = 0.09). There was no statistical difference in the genotypes of the MSH6 rs1042821 and MSH6 rs3136245 polymorphisms between cases and controls. The frequencies of the variant alleles between cases and controls were as follows: MSH3 Pro222Pro (45%, 38%), MSH3 Thr1036Ala (26%, 20%) MSH6 rs1042821 (35%, 34%) and MSH6 rs3136245 (54%, 55%) (Table 3).
Table 3.
Distribution of MSH3 and MSH6 gene polymorphisms in PC patients and controls
| Gene | Genotype | Cases (n=110) (%) | Controls (n=110) (%) | Age adjusted OR | 95%CI | P-value |
|---|---|---|---|---|---|---|
| MSH3 | ||||||
| exon4 (G/A) | G/G | 21 (19) | 34 (31) | |||
| G/A | 78 (72) | 69 (63) | ||||
| A/A | 11 (10) | 7 (6) | 1.63 | 0.61–4.39 | 0.44 | |
| G/A + A/A | 89 (81) | 76 (69) | 1.87 | 1.00–3.50 | 0.04 | |
| G allele | 120 (55 %) | 137 (62 %) | ||||
| A allele | 100 (45 %) | 83 (38 %) | 1.33 | 0.76–2.34 | ||
| MSH3 | ||||||
| exon23 (A/G) | A/A | 60 (55) | 72 (65) | |||
| A/G | 43 (39) | 31 (28) | ||||
| G/G | 7 (6) | 7 (6) | 1.00 | 0.34–2.95 | ||
| A/G + G/G | 50 (45) | 38 (34) | 1.57 | 0.92–2.72 | 0.09 | |
| A allele | 163 (74 %) | 175 (80 %) | ||||
| G allele | 57 (26 %) | 45 (20 %) | 1.34 | 0.86–2.10 | ||
| MSH6 | ||||||
| exon1 (G/A) | G/G | 44 (40) | 46 (42) | |||
| G/A | 55 (50) | 54 (49) | ||||
| A/A | 11 (10) | 10 (9) | 1.11 | 0.45–2.73 | 0.82 | |
| G/A + A/A | 66 (60) | 64 (58) | 1.10 | 0.63–1.85 | 0.78 | |
| G allele | 143 (65 %) | 146 (66 %) | ||||
| A allele | 77 (35 %) | 74 (34 %) | 1.06 | 0.72–1.57 | ||
| MSH6 | ||||||
| Intron 2 (C/T) | C/C | 16 (15) | 20 (18) | |||
| C/T | 69 (62) | 59 (54) | ||||
| T/T | 25 (23) | 31 (28) | 0.75 | 0.41–1.38 | 0.35 | |
| T/T + C/T | 94 (85) | 90 (82) | 1.31 | 0.64–2.67 | 0.46 | |
| C allele | 101 (46 %) | 99 (45 %) | ||||
| T allele | 119 (54 %) | 121 (55 %) | 0.96 | 0.66–1.40 | ||
Relationship of the MSH3 exon4 polymorphism with clinical parameters in pc patients
The relationship of MSH3 exon4 polymorphisms with clinicopathological parameters including age at onset, Gleason sum, pT, and smoking status in PC patients was evaluated. There was no statistically significant association of the MSH3 exon4 genotypes with these parameters (data not shown). We also found no association between smoking status and the MSH3 polymorphism.
The effect of both p53codon72 polymorphism and MSH3 and MSH6 polymorphisms in pc patients
Among p53 codon72 Arg/Pro+Pro/Pro carriers, the frequency of the G/A+A/A genotype of MSH3 exon4 tended to increase in PC patients compared to controls (OR, 1.78; 95%CI, 0.79–4.02; p = 0.16). With regard to MSH3 exon23, a significant increase in the AG+GG genotype of MSH3 exon23 was observed in patients compared to controls (OR, 2.1; 95%CI, 1.05–4.34; p = 0.04) (Table 4).
Table 4.
(a) p53 genotyping (b) Association of the MSH3 MSH6 polymorphisms in the p53 Arg/Pro+Pro/Pro
| (a)
| |||
|---|---|---|---|
| Genotype p53 Arg/Pro | Cases(n=110) n(%) |
Controls(n=110) n(%) |
Crude OR (95%CI) |
| Arg/Arg | 39 (35.0 %) | 47 (43.0 %) | |
| Arg/Pro | 59 (54.0 %) | 49 (45.0 %) | |
| Pro/Pro | 12 (11.0 %) | 14 (12.0 %) | 0.84 (0.37–1.91) |
| Arg/Pro+Pro/Pro | 71 (65.0 %) | 63 (57.0 %) | 1.35 (0.78–2.34) |
| (b)
| ||||
|---|---|---|---|---|
|
p53 Arg/Pro+Pro/Pro
|
Crude OR (95% CI) | p-value | ||
| Case (n=71) | Control (n=63) | |||
| MSH3 ex4
|
||||
| GG | 13 (18) | 18 (29) | ||
| GA+AA | 58 (82) | 45 (71) | 1.78 (0.79–4.02) | 0.16 |
| MSH3 ex23
|
||||
| AA | 37 (52) | 44 (70) | ||
| AG+GG | 34 (48) | 19 (30) | 2.1 (1.05–4.34) | 0.04 |
| MSH6 ex1
|
||||
| GG | 28 (39) | 26 (41) | ||
| GA+AA | 43 (61) | 37 (59) | 1.1 (0.54–2.15) | 0.83 |
| MSH6 int2
|
||||
| CC | 10 (14) | 11 (17) | ||
| CT+TT | 61 (86) | 52 (83) | 1.3 (0.51–3.28) | 0.59 |
Discussion
In the eukaryotic MMR system, mispaired DNA bases are recognized by heterodimeric complexes including MSH2–MSH3 (MutSβ) and MSH2–MSH6 (MutSα). MSH2 has a central role in DNA recognition. Prtilo et al.14 investigated MSH2 expression with respect to Gleason sum and survival of prostate cancer. They reported that higher Gleason sum correlated with higher MSH2 expression and low MSH2 expression correlated with prolonged survival.14 However Chen et al observed a reduction of MSH2 protein in prostate cancer compared to normal adjacent prostate tissue.15 This discrepancy may be caused by mutation status or other reasons.
MSH3 and MSH6 proteins form a complex with MSH2 that binds to DNA mismatches, initiating strand-specific repair of DNA replication errors.16 Umar et al observed that transfection of MSH3 or MSH6 protein into a human tumor cell line corrected instability at the microsatellite loci and restored MMR activity.16 Therefore MSH3 and MSH6 may complement the MMR system independently. Many of the MMR gene polymorphism studies have focused on HNPCC (hereditary non-polyposis colorectal carcinoma). With regard to MSH3 gene polymorphisms, Orimo et al. found a frameshift mutation in sporadic colon cancer.17 They also found three SNPs in the MSH3 gene and frequency of the G693 (G/A) allele was high in sporadic colon cancer patients.18 Song et al systematically investigated all the common genes in the MMR system and confirmed the effect of SNPs on ovarian cancer risk. In their study, MSH3 SNPs were not associated with the risk of ovarian cancer.10 This is the first case-control study to investigate the relationship between MSH3 and MSH6 polymorphisms and prostate cancer susceptibility. In our study, the MSH3 exon4 SNP does not result in an amino acid substitution in the protein sequence, although it was significantly associated with the susceptibility of prostate cancer (OR, 1.87; 95%CI, 1.00–3.50). The frequency of MSH3 exon23 A/G + G/G genotype also tended to be higher in prostate cancer patients (OR=1.57; 95% CI: 0.92–2.72). In addition, we investigated the relationship between MSH6 rs1042821 G/A and rs3136245 C/T SNPs and prostate cancer risk, but found no evidence supporting an association. Several studies have investigated the effect of the p53 codon72 polymorphism. Suzuki et al. found a significant association between the p53 Arg72Pro polymorphism and prostate cancer risk in Japanese.19 Although Henner et al. found a decreased risk for this same polymorphism in Caucasians.20 One possible explanation for this discrepancy is the effect of racial differences. We demonstrated that the frequency of the Arg/Pro+Pro/Pro genotype of p53 Arg72Pro tended to increase in PC patients compared to controls (OR = 1.35, 95%CI = 0.78–2.34) suggesting that the p53 codon72 polymorphism alone might not influence prostate cancer risk.
We also examined the added effect of the p53 Arg72Pro polymorphism on MSH3 and MSH6 polymorphisms on prostate cancer risk. Among p53 Pro/Pro + Arg/Pro genotype carriers, the frequency of MSH3 exon23 AG + GG genotypes is significantly higher in PC patients (OR = 2.1, 95%CI = 1.05–4.34, p=0.04). Such an effect was not observed between p53 Arg72Pro and MSH3 exon4 G/A (OR = 1.8, 95%CI = 0.79–4.02, p=0.16). In conclusion, this is the first report to show an association of MSH3 gene polymorphisms in PC. In addition the p53 codon 72 polymorphism may increase the risk of the MSH3 polymorphism for prostate cancer.
Acknowledgments
We thank Dr. Roger Erickson for his support and assistance with the preparation of the manuscript. This study was supported by Grants RO1CA101844, RO1AG21418, R01CA111470, R01CA108612, T32-DK07790 from the NIH, VA REAP award, Merit Review grants (PI: Rajvir Dahiya), and Yamada Science Foundation.
Abbreviations and acronyms
- PCR
polymerase chain reaction
- RFLP
restriction fragment length polymorphism
- SNP
single nucleotide polymorphism
Footnotes
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