Skip to main content
PMC home page
PLOS ONE logoLink to PLOS ONE
. 2015 Aug 14;10(8):e0135822. doi: 10.1371/journal.pone.0135822

The hMLH1 −93G>A Polymorphism and Risk of Ovarian Cancer in the Chinese Population

Leilei Niu 1, Shumin Li 2, Huamao Liang 1, Hua Li 1,2,*
Editor: Yifeng Zhou3
PMCID: PMC4537278  PMID: 26275295

Abstract

Background

As a mismatch repair (MMR) gene, hMLH1 plays an important role in the maintenance of chromosomal integrity. Several studies have investigated the associations of hMLH1 -93G>A (rs1800734) and Ile219Val (rs1799977) in diverse tumor types with discordant results, but their roles in ovarian cancer in the Chinese population remains to be elucidated.

Methods

In a case-control analysis, we assessed the association between these two polymorphisms and ovarian cancer risk in 421 ovarian cancer patients and 689 control subjects in the Chinese population using logistic regression.

Results

We found that the variant hMLH1 genotypes (-93AA and AG) are associated with risk of ovarian cancer (adjusted odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.42–2.89) compared with the -93GG genotype. The A allele increases the risk of ovarian cancer in a dose-dependent manner (P<10−4). Functional test showed that -93A allele increased hMLH1 promoter transcriptional activity and the luciferase activity. However, no significant difference was found in the genotype frequencies at the Ile219Val site between the cases and controls.

Conclusions

These findings indicate that the -93G>A polymorphism in hMLH1 may affect ovarian cancer susceptibility in the Chinese population.

Introduction

Ovarian cancer is one of the most common types of gynecological malignancies [1]. Globally, as of 2010, approximately 160,000 people had died from ovarian cancer, up from 113,000 in 1990 [2]. Epidemiological surveys have demonstrated that some etiologic factors, including early age at menarche, late age at menopause, obesity, use of estrogen and hormone-replacement therapy, and inherited susceptibility, are positively associated with ovarian cancer [3, 4]. Additionally, the incidence of ovarian cancer increases with increasing age. Because a standard therapy exists but does not obtain ideal outcomes, ovarian cancer remains a therapeutic challenge. Recent studies indicate that there is significant difference in the clinical outcomes of radical operation and adjuvant platinum-based chemotherapy for individuals with different genetic polymorphisms, suggesting that genetic susceptibility plays an important role in an individual’s risk of developing ovarian cancer [5, 6]

DNA repair systems have an essential role in maintaining genomic integrity and stability. It well known that genetic variants of repair genes may affect the function of the encoded proteins and alter their ability to repair DNA, which in turn may lead to susceptibility to different types of cancer and can also be adverse prognostic factors once cancer has developed [7, 8]. As a key component of the DNA mismatch repair (MMR) system, hMLH1 (human mutL homolog 1) physically interacts with other components of MMR and plays a crucial role in maintaining genome stability in responses to replication errors and physical or chemical damage to DNA [9]. Several findings have suggested the essential role of hMLH1 in the control of the cell cycle and apoptosis [10–12]. Dysfunction of the hMLH1 gene may result in failure to accomplish all the functions of the MMR system and may be associated with a predisposition for cancer [13, 14]. Several polymorphisms have been identified in the hMLH1 gene [15–17]. Recently, studies have explored the association of an important and frequent polymorphism, namely -93G>A (rs1800734), which is located in the core promoter region of hMLH1, with susceptibility to developing various human malignancies, including tobacco-related oral carcinoma [18], lung cancer [19], colorectal cancer [20] and papillary thyroid carcinoma (PTC) [21]. Another widely studied missense polymorphic site in the hMLH1 gene is Ile219Val, an A to G transition occurring in codon 219 that leads to an amino acid change that has been studied in cancers in European populations [22, 23]. Though the fact that the hMLH1 gene have been linked to several types of cancer, the association of these variations with ovarian cancer in the Chinese population has not been studied. We hypothesized that the hMLH1gene polymorphisms -93G>A and Ile219Val (rs1799977) may cause individual susceptibility to ovarian cancer by affecting the DNA mismatch repair capacity.

Considering the important role of hMLH1 in the carcinogenic process, we carried out a case-control study in a Chinese population to investigate the possible relationship between these two polymorphisms and the risk of ovarian cancer in the Chinese population.

Materials and Methods

Study population

Eligible patients (421) were those diagnosed ovarian cancer consecutively recruited from March 2003 to May 2009 at Peking University Third Hospital (Beijing) and the Cancer Hospital of the Chinese Academy of Medical Sciences (Beijing). The patients were from Beijing city and its surrounding regions under the age of 90 years. The controls (689) were frequency matched to the cases by age (±5 years) lived in the Beijing region and were selected randomly from those who underwent a physical examination in hospitals. The response rate was 96.5%. Physical examination included chest radiography, abdominal ultrasonography, gynecological and cervical cytological examinations. The selection criteria included no history of cancer or previous operations on ovary. The tumor histological status and clinical staging were based on the criteria of the International Federation of Gynecology and Obstetrics (FIGO) [24]. The clinical features of the patients for our study are presented in Table 1. At recruitment, all participants were asked to provide written informed consent for collecting blood of them and completed a structured questionnaire. The study procedure was approved by Peking University Third Hospital and the Cancer Hospital of the Chinese Academy of Medical Sciences.

Table 1. Clinical characteristics of ovarian cancer patients and healthy control subjects.

Characteristics Cases (421) Controls (689)
N (%) N (%)
Age (years)
    ≤40 58 (13.8) 81 (11.8)
    41–60 261 (62.0) 457 (66.3)
    ≥60 102 (24.2) 151 (21.9)
Body mass index (BMI)
    ≤20 116 (27.6) 171 (24.8)
    20–28 273 (64.8) 462 (67.1)
    ≥28 32 (7.6) 56 (8.1)
Pathological type
    Serous-papillary 166 (39.4)
    Mucinous 54 (12.9)
    Endometrioid 150 (35.6)
    Undifferentiated 51 (12.1)
FIGO stage
    I 61 (14.5)
    II 80 (19.0)
    III 226 (53.7)
    IV 54 (12.8)
Tumor grade
    G1 36 (8.6)
    G2 99 (23.5)
    G3 286 (67.9)
Open in a new tab

FIGO: International Federation of Gynecology and Obstetrics

Genotyping analysis

Genomic DNA was isolated from the peripheral blood of the study subjects using the DNA Blood Mini kit (QIAGEN, Valencia, CA). MALDI-TOF platform were used to genotype hMLH1 -93G>A and Ile219Val polymorphisms as described previously [25, 26]. For quality control, 5% samples were randomly selected to repeat, and 50 samples were included for direct sequence to confirm genotypes from the mass spectrometric analysis. Hardy-Weinberg was checked in all the sample groups.

Reporter plasmids, transfections and luciferase Assays

The 93G and 93A allelic reporter constructs were prepared by the Genewiz Company (Beijing, China) by amplifying the core promoter region of hMSH1, a 282-bp fragment from -299 to -17, as previously described [27], and then cloned into the pGL3-basic luciferase vector (Promega, Madison, WI, USA). 293T cells and SKOV-3 cells (ovarian cancer cell line) were used to transfect the above reporter plasmids with Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA) through previously published procedures [28, 29], the empty vector was used as a negative control. The Renilla luciferase activities were measured with the Dual-Luciferase Reporter assay system (Promega).

Real-Time Analysis of hMLH1 mRNA

The total RNA from twenty-eight ovarian cancer tissue samples obtained from biopsy-removed specimens of individual patients was extracted using the TRIzol reagent (Invitrogen, Inc.). The relative gene expression quantification of hMLH1 was conducted using the SYBR Green Assay using the ABI Prism 7500 sequence detection system (Applied Biosystems). β-actin was used as endogenous controls for hMLH1 expressions. The primers used for hMLH1 were 5’-CAGAGGAAGATGGTCCCAAA-3’ (F) and 5’-TCTTCGTCCCAATTCACCTC-3’ (R), and those for β-actin were 5’-GGCGGCACCACCATGTACCCT-3’ (F) and 5’-AGGGGCCGGACTCGTCATACT-3’ (R). The relative expression of hMLH1was performed by using the 2-ΔΔCT calculation.

Statistical analysis

Two-sided chi-square tests were used to assess differences in the age and body mass index (BMI) distributions as well as the allele and genotype frequencies between the cases and controls. The observed genotype frequencies in the cancer-free controls was tested for Hardy–Weinberg equilibrium (HWE) by goodness-of-fit x 2 tests. The associations of all genotypes with risk of ovarian cancer were calculated by odds ratios (OR) and corresponding 95% confidence intervals (CIs) followed by stratification analysis with adjustment for age and BMI. The statistical power was computed by applying the PS software (http://biostat.mc.vanderbilt.edu/twiki/bin/view/Main/PowerSampleSize, accessed Dec 14, 2010). The differences in the luciferase reporter activity and mRNA levels of hMLH1 in ovarian cancer tissues between different each allele were examined by one-way ANOVA and Student’s t test. The LD of the two SNPs was detected by the 2LD program and the PROC ALLELE statistical procedure in SAS/Genetics (SAS Institute, Inc., Cary, NC, USA) software. P<0.05 was used as the criterion for statistical significance, and all tests were two-sided and performed with the SAS software (version 9.1; SAS Institute, Cary, NC, USA).

Results

Genotypes and risk of ovarian cancer

The association of ovarian cancer with -93G>A was determined based on 421 cases and 689 controls. The genotyping results in Table 2showed that hMLH1 -93G>A was significantly associated with ovarian cancer risk. Compared to the healthy controls, -93AA and AG carriers were significantly associated with risk of ovarian cancer (adjusted odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.42–2.89). Additionally, the -93A allele frequency in cases (65.6%) was also significantly higher than that in the controls (52.4%) (P<10−4). However, there was no significant difference between the different genotypes of the variant Ile219Val and susceptibility to ovarian cancer. Linkage disequilibrium analysis showed that the linkage between -93G>A and Ile219Val was relatively weak (r2 = 0.051), suggesting that each may have an independent effect on the risk of ovarian cancer and therefore be unsuitable for haplotype analysis.

Table 2. Genotype freqencies of the two SNPs in hMLH1 among patients and controls and their associations with ovarian cancer.

Genotypes Controls (689) Cases (421)
N a (%) N a (%) OR (95%CI) b P trend
−93G>A
GG 150 (21.8) 51 (12.1) 1.00 (Reference)
AG 356 (51.7) 188 (44.7) 1.54 (1.05–2.27) <10−4
AA 183 (26.5) 182 (43.2) 2.92 (1.96–4.34)
AG+AA 539 (78.2) 370 (87.9) 2.02 (1.42–2.89)
G 656 (47.6) 290 (34.4) 1.00 (Reference)
A 722 (52.4) 552 (65.6) 1.73 (1.44–2.06)
Ile219Val
AA 613 (89.0) 386 (91.7) 1.00 (Reference)
AG 75 (10.9) 33 (7.8) 0.70 (0.43–1.08) 0.217
GG 1 (0.1) 2 (0.5) /
AG+GG 76 (11.0) 35 (8.3) 0.73 (0.48–1.13)
A 1301 (94.4) 805 (95.6) 1.00 (Reference)
G 77 (5.6) 37 (4.4) 0.78 (0.51–1.17)
Open in a new tab

aNumber of cases/number of controls.

bData were calculated by logistic regression analysis with adjusted for age and BMI.

The risk of ovarian cancer related to the hMLH1 -93G>A genotypes was further determined with stratification by age and BMI. No significant association between the variant genotypes and risk of ovarian cancer was observed.

Effects of the hMLH1 -93G>A polymorphism on transcriptional activity

Considering that -93G>A polymorphism could be associated with risk of ovarian cancer, two luciferase reporter constructs (pGL3-hMLH1-G-allele and pGL3-hMLH1-A-allele) were used to transiently transfect 293T cells to directly determine the effects of the -93G>A polymorphism on the transcriptional activity of the hMLH1 promoter. As shown in Fig 1A, compared with the construct containing the -93G allele, the construct containing the -93A allele exhibited significantly higher luciferase activity (P<0.001). Consistent with increased hMLH1 promoter transcriptional activity for the -93A allele in the 293T cells, the luciferase activity of the construct containing the -93A allele appeared to be higher in cell lines in SK-OV-3 cells (P = 0.002).

Fig 1. The effect of the hMLH1 -93G>A genotype on hMLH1 expression.

Fig 1

Open in a new tab

(A) Schematic of reporter gene constructs containing the core promoter region of hMSH1 (a 282-bp fragment from -299 to -17) with the G or A allele at the -93 polymorphic site (upper). The luciferase expression of two constructs (pGL3-93G and pGL3-93A) in 293T and SK-OV-3 cells cotransfected with pRL-SV40 to standardize the transfection efficiency is shown (lower). Each group has six replicates, and the transfection experiments were repeated three times. The data are the means ± standard error of the mean. The asterisk indicates a significant change. (B) hMLH1 expression level in twenty-eight ovarian cancer tissues with different -93G>A genotypes (6 -93GG, 10 -93AG and 12 -93AA); the data are the means ± standard error of the mean. The expression level of the -93GG and -93AG genotypes were significantly higher than that of the AA genotype (P<0.001).

Association of hMLH1 -93G>A genotypes with hMLH1 expression

To further evaluate the effect of SNP -93G>A on ovarian cancer risk, we examined hMLH1 expression between different genotypes of the SNP in twenty-eight individual ovarian cancer tissues (6 -93GG, 10 -93AG and 12 -93AA) by real-time PCR. As shown in Fig 1B, in the twenty-eight ovarian cancer tissues, hMLH1 expression was significantly higher in those with the -93GG and -93AG genotypes than in those with the -93AA genotype (GG, 0.428±0.036; AG, 0.287±0.026; AA, 0.192±0.029; ANOVA test: P<0.001).

Discussion

In the present hospital-based case-control study, we sought to identify genetic factors that confer individual susceptibility to ovarian cancer. The results obtained by analyzing 421 patients and 689 healthy controls showed that hMLH1 -93G>A is associated with risk for ovarian cancer in the Chinese population. Our data showed that, compared with the GG genotype, subjects carrying the -93AA and AG genotypes had significantly increased risk for ovarian cancer (P<10−4).

Recently, the mutation of DNA repair genes in the etiology of several cancers has been receiving a great deal of attention. It has been proposed that genetic variants in DNA repair genes that potentially result in altered protein expression or function would lead to failure in DNA damage recognition and repair, which in turn would allow subsequent mutations to accumulate and thus might increase susceptibility to multiple cancers [30–32]. In humans, there are several DNA repair pathways that are essential for genome integrity, including base excision repair (BER), nucleotide excision repair (NER), DNA double-strand breaks (DSBs) and MMR [33]. A highly conserved set of MMR proteins has long been known to be primarily responsible for repairing bases mismatched during DNA replication [34, 35]. However, recent studies have commonly reported that hMLH1 plays a central role in the MMR system in mismatch strand excision and subsequent repair [36, 37]. The genetic variant of the MLH1 gene may affect the MMR capacity of the encoded protein and therefore might contribute to the risk of cancer. To date, there has been a great deal of interest in the association between two widely studied polymorphisms (-93G>A and Ile219Val) and different types of cancer; however, the results are contradictory. The common polymorphism hMLH1 -93G>A is located in the core promoter region, 93 nucleotides upstream of the transcription start site, contains putative consensus sequences for transcription factor binding sites, and may play an important role in regulating hMLH1 promoter activity, thereby modulating susceptibility to cancer [38]. The hMLH1 -93G>A polymorphism has been investigated in several studies, but the results are not consistent. Recently, hMLH1 -93G>A variant genotypes (AA, AG) have been associated with an increased risk of lung cancer [39], breast cancer [40] and colorectal cancer [41]. Interestingly, a recent study of Asian Indians using 242 oral carcinoma patients and 205 healthy controls found that the GG genotype showed significantly higher prevalence in patients compared to the healthy controls (P<0.0006) [18]. Our results indicated that the variant genotypes (AA, AG) of hMLH1 -93G>A may be related to cancer risk.

Another commonly studied hMLH1 polymorphism, Ile219Val, is a non-synonymous mutation that changes Ile 219 to Val, possibly altering the function of the hMLH1 protein. Several studies have reported that the hMLH1 Ile219Val polymorphism is closely related to the onset of a variety of cancers, including lung cancer [42], breast cancer [40] and gastric cancer [43]. However, the association between hMLH1 Ile219Val variant genotypes and cancer risk is not the same in different cancers and ethnic groups. For example, in prostate cancer, Burmester et al. found that the hMLH1 Ile219Val polymorphism is significantly associated with higher rates of prostate cancer in people of European ancestry, whereas Fredriksson et al. showed that hMLH1 did not have a major role in prostate cancer in a Finnish population [22]. Our results suggested that there is no association between this polymorphism and ovarian cancer in the Chinese population.

Certain limitations may exist in the present study because of its hospital-based design limited to Chinese population. Additionally, inherent selection bias that introduces unbalanced confounding factors might affect the conclusions of the current our results, because cases and controls were from different centers. However, the genotype frequencies among the controls fit the Hardy-Weinberg disequilibrium law, suggesting random subject selection, and we achieved a more than 90% study power (two-sided test, α = 0.05) to detect an OR of 2.02 for the hMLH1–93 AA+AG genotypes (which occurred at a frequency of 78.2% in the controls) compared with the -93GG genotype, suggesting that this finding is noteworthy.

In conclusion, the present study indicates that in the Chinese population, carriers of the -93AA and AG genotypes have increased risk of ovarian cancer compared with GG carriers. To the best of our knowledge, this study provided the first evidence that the -93G>A polymorphism in hMLH1 is associated with a significant risk of developing ovarian cancer in the Chinese population. Further independent population-based case-control studies are warranted to validate our results in larger sample sizes, as well as in different populations.

Data Availability

All relevant data are within the paper.

Funding Statement

This study was supported by the National Natural Scientific Foundation of China grants (No. 81202040 to HL), Beijing Municipal Natural Science Foundation (No. 7142167 to HL) and Beijing Nova Program (No. 2009B03 to HL).

References

  • 1. Gloeckler Ries LA, Reichman ME, Lewis DR, Hankey BF, Edwards BK. Cancer survival and incidence from the Surveillance, Epidemiology, and End Results (SEER) program. Oncologist. 2003;8(6):541–52. Epub 2003/12/06. . [DOI] [PubMed] [Google Scholar]
  • 2. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095–128. Epub 2012/12/19. 10.1016/S0140-6736(12)61728-0S0140-6736(12)61728-0 [pii]. . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Vo C, Carney ME. Ovarian cancer hormonal and environmental risk effect. Obstet Gynecol Clin North Am. 2007;34(4):687–700, viii. Epub 2007/12/07. S0889-8545(07)00090-3 [pii] 10.1016/j.ogc.2007.09.008 . [DOI] [PubMed] [Google Scholar]
  • 4. Bandera CA. Advances in the understanding of risk factors for ovarian cancer. J Reprod Med. 2005;50(6):399–406. Epub 2005/07/30. . [PubMed] [Google Scholar]
  • 5. Kang S, Ju W, Kim JW, Park NH, Song YS, Kim SC, et al. Association between excision repair cross-complementation group 1 polymorphism and clinical outcome of platinum-based chemotherapy in patients with epithelial ovarian cancer. Exp Mol Med. 2006;38(3):320–4. Epub 2006/07/05. doi: 2006063016 [pii] 10.1038/emm.2006.38 . [DOI] [PubMed] [Google Scholar]
  • 6. Green H, Soderkvist P, Rosenberg P, Horvath G, Peterson C. mdr-1 single nucleotide polymorphisms in ovarian cancer tissue: G2677T/A correlates with response to paclitaxel chemotherapy. Clin Cancer Res. 2006;12(3 Pt 1):854–9. Epub 2006/02/10. doi: 12/3/854 [pii] 10.1158/1078-0432.CCR-05-0950 . [DOI] [PubMed] [Google Scholar]
  • 7. Banescu C, Tilinca M, Benedek EL, Demian S, Macarie I, Duicu C, et al. XRCC3 Thr241Met polymorphism and risk of acute myeloid leukemia in a Romanian population. Gene. 2013;526(2):478–83. Epub 2013/06/12. 10.1016/j.gene.2013.05.054S0378-1119(13)00704-X [pii]. . [DOI] [PubMed] [Google Scholar]
  • 8. Yan L, Yanan D, Donglan S, Na W, Rongmiao Z, Zhifeng C. Polymorphisms of XRCC1 gene and risk of gastric cardiac adenocarcinoma. Dis Esophagus. 2009;22(5):396–401. Epub 2009/08/13. . [DOI] [PubMed] [Google Scholar]
  • 9. Ilyas M, Straub J, Tomlinson IP, Bodmer WF. Genetic pathways in colorectal and other cancers. Eur J Cancer. 1999;35(14):1986–2002. Epub 2000/03/11. doi: S0959-8049(99)00298-1 [pii]. . [DOI] [PubMed] [Google Scholar]
  • 10. Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol. 2006;7(5):335–46. Epub 2006/04/14. doi: nrm1907 [pii] 10.1038/nrm1907 . [DOI] [PubMed] [Google Scholar]
  • 11. Stojic L, Brun R, Jiricny J. Mismatch repair and DNA damage signalling. DNA Repair (Amst). 2004;3(8–9):1091–101. Epub 2004/07/29. 10.1016/j.dnarep.2004.06.006S1568786404001788 [pii]. . [DOI] [PubMed] [Google Scholar]
  • 12. McDaid JR, Loughery J, Dunne P, Boyer JC, Downes CS, Farber RA, et al. MLH1 mediates PARP-dependent cell death in response to the methylating agent N-methyl-N-nitrosourea. Br J Cancer. 2009;101(3):441–51. Epub 2009/07/23. 10.1038/sj.bjc.66051866605186 [pii]. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Okada T, Noji S, Goto Y, Iwata T, Fujita T, Matsuzaki Y, et al. Immune responses to DNA mismatch repair enzymes hMSH2 and hPMS1 in patients with pancreatic cancer, dermatomyositis and polymyositis. Int J Cancer. 2005;116(6):925–33. Epub 2005/04/28. 10.1002/ijc.21118 . [DOI] [PubMed] [Google Scholar]
  • 14. Peltomaki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol. 2003;21(6):1174–9. Epub 2003/03/15. . [DOI] [PubMed] [Google Scholar]
  • 15. Kim JC, Roh SA, Koo KH, Ka IH, Kim HC, Yu CS, et al. Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients. Fam Cancer. 2004;3(2):129–37. Epub 2004/09/02. 10.1023/B:FAME.0000039919.66461.8f5381548 [pii]. . [DOI] [PubMed] [Google Scholar]
  • 16. Beiner ME, Rosen B, Fyles A, Harley I, Pal T, Siminovitch K, et al. Endometrial cancer risk is associated with variants of the mismatch repair genes MLH1 and MSH2. Cancer Epidemiol Biomarkers Prev. 2006;15(9):1636–40. Epub 2006/09/21. doi: 15/9/1636 [pii] 10.1158/1055-9965.EPI-06-0257 . [DOI] [PubMed] [Google Scholar]
  • 17. Tanaka Y, Zaman MS, Majid S, Liu J, Kawakami K, Shiina H, et al. Polymorphisms of MLH1 in benign prostatic hyperplasia and sporadic prostate cancer. Biochem Biophys Res Commun. 2009;383(4):440–4. Epub 2009/04/15. 10.1016/j.bbrc.2009.04.025S0006-291X(09)00707-4 [pii]. . [DOI] [PubMed] [Google Scholar]
  • 18. Jha R, Gaur P, Sharma SC, Das SN. Single nucleotide polymorphism in hMLH1 promoter and risk of tobacco-related oral carcinoma in high-risk Asian Indians. Gene. 2013;526(2):223–7. Epub 2013/06/04. 10.1016/j.gene.2013.05.014S0378-1119(13)00650-1 [pii]. . [DOI] [PubMed] [Google Scholar]
  • 19. Shih CM, Chen CY, Lee IH, Kao WT, Wang YC. A polymorphism in the hMLH1 gene (-93G—>A) associated with lung cancer susceptibility and prognosis. Int J Mol Med. 2010;25(1):165–70. Epub 2009/12/04. . [PubMed] [Google Scholar]
  • 20. Hubner RA, Houlston RS. Re: MLH1 93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer. J Natl Cancer Inst. 2007;99(19):1490; author reply -1. Epub 2007/09/27. doi: djm137 [pii] 10.1093/jnci/djm137 . [DOI] [PubMed] [Google Scholar]
  • 21. Shi WP, Bian JC, Jiang F, Ni HX, Zhu QX, Tang HW, et al. [Study on genetic polymorphism of human mismatch repair gene hMLH1 and susceptibility of papillary thyroid carcinoma in Chinese Han people]. Zhonghua Yu Fang Yi Xue Za Zhi. 2010;44(3):235–41. Epub 2010/05/11. . [PubMed] [Google Scholar]
  • 22. Fredriksson H, Ikonen T, Autio V, Matikainen MP, Helin HJ, Tammela TL, et al. Identification of germline MLH1 alterations in familial prostate cancer. Eur J Cancer. 2006;42(16):2802–6. Epub 2006/09/12. doi: S0959-8049(06)00647-2 [pii] 10.1016/j.ejca.2006.04.024 . [DOI] [PubMed] [Google Scholar]
  • 23. Burmester JK, Suarez BK, Lin JH, Jin CH, Miller RD, Zhang KQ, et al. Analysis of candidate genes for prostate cancer. Hum Hered. 2004;57(4):172–8. Epub 2004/12/08. doi: 81443 [pii] 10.1159/000081443 . [DOI] [PubMed] [Google Scholar]
  • 24. Odicino F, Pecorelli S, Zigliani L, Creasman WT. History of the FIGO cancer staging system. Int J Gynaecol Obstet. 2008;101(2):205–10. Epub 2008/01/18. 10.1016/j.ijgo.2007.11.004S0020-7292(07)00690-X [pii]. . [DOI] [PubMed] [Google Scholar]
  • 25. Jiang L, Zhang C, Li Y, Yu X, Zheng J, Zou P, et al. A non-synonymous polymorphism Thr115Met in the EpCAM gene is associated with an increased risk of breast cancer in Chinese population. Breast Cancer Res Treat. 2011;126(2):487–95. Epub 2010/08/05. 10.1007/s10549-010-1094-6 . [DOI] [PubMed] [Google Scholar]
  • 26. Jiang L, Deng J, Zhu X, Zheng J, You Y, Li N, et al. CD44 rs13347 C>T polymorphism predicts breast cancer risk and prognosis in Chinese populations. Breast Cancer Res. 2012;14(4):R105. Epub 2012/07/14. doi: bcr3225 [pii] 10.1186/bcr3225 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Shin KH, Shin JH, Kim JH, Park JG. Mutational analysis of promoters of mismatch repair genes hMSH2 and hMLH1 in hereditary nonpolyposis colorectal cancer and early onset colorectal cancer patients: identification of three novel germ-line mutations in promoter of the hMSH2 gene. Cancer Res. 2002;62(1):38–42. Epub 2002/01/10. . [PubMed] [Google Scholar]
  • 28. Zheng J, Jiang L, Zhang L, Yang L, Deng J, You Y, et al. Functional genetic variations in the IL-23 receptor gene are associated with risk of breast, lung and nasopharyngeal cancer in Chinese populations. Carcinogenesis. 2012;33(12):2409–16. Epub 2012/10/09. 10.1093/carcin/bgs307bgs307 [pii]. . [DOI] [PubMed] [Google Scholar]
  • 29. Zheng J, Liu B, Zhang L, Jiang L, Huang B, You Y, et al. The protective role of polymorphism MKK4-1304 T>G in nasopharyngeal carcinoma is modulated by Epstein-Barr virus' infection status. Int J Cancer. 2012;130(9):1981–90. Epub 2011/06/28. 10.1002/ijc.26253 . [DOI] [PubMed] [Google Scholar]
  • 30. Guo S, Li X, Gao M, Li Y, Song B, Niu W. The relationship between XRCC1 and XRCC3 gene polymorphisms and lung cancer risk in northeastern Chinese. PLoS One. 2013;8(2):e56213 Epub 2013/02/15. 10.1371/journal.pone.0056213PONE-D-12-16724 [pii]. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Zheng J, Zhang C, Jiang L, You Y, Liu Y, Lu J, et al. Functional NBS1 polymorphism is associated with occurrence and advanced disease status of nasopharyngeal carcinoma. Mol Carcinog. 2011;50(9):689–96. Epub 2011/06/10. 10.1002/mc.20803 . [DOI] [PubMed] [Google Scholar]
  • 32. Li N, Xu Y, Zheng J, Jiang L, You Y, Wu H, et al. NBS1 rs1805794G>C polymorphism is associated with decreased risk of acute myeloid leukemia in a Chinese population. Mol Biol Rep. 2013;40(5):3749–56. Epub 2013/01/04. 10.1007/s11033-012-2451-9 . [DOI] [PubMed] [Google Scholar]
  • 33. Bernstein C, Bernstein H, Payne CM, Garewal H. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutat Res. 2002;511(2):145–78. Epub 2002/06/08. doi: S1383574202000091 [pii]. . [DOI] [PubMed] [Google Scholar]
  • 34. Kolodner RD. Mismatch repair: mechanisms and relationship to cancer susceptibility. Trends Biochem Sci. 1995;20(10):397–401. Epub 1995/10/01. doi: S0968-0004(00)89087-8 [pii]. . [DOI] [PubMed] [Google Scholar]
  • 35. Hsieh P. Molecular mechanisms of DNA mismatch repair. Mutat Res. 2001;486(2):71–87. Epub 2001/06/27. doi: S092187770100088X [pii]. . [DOI] [PubMed] [Google Scholar]
  • 36. Hibi K, Takahashi T, Yamakawa K, Ueda R, Sekido Y, Ariyoshi Y, et al. Three distinct regions involved in 3p deletion in human lung cancer. Oncogene. 1992;7(3):445–9. Epub 1992/03/01. . [PubMed] [Google Scholar]
  • 37. Goodfellow PJ, Buttin BM, Herzog TJ, Rader JS, Gibb RK, Swisher E, et al. Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci U S A. 2003;100(10):5908–13. Epub 2003/05/07. doi: 10.1073/pnas.1030231100 1030231100 [pii]. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Ito E, Yanagisawa Y, Iwahashi Y, Suzuki Y, Nagasaki H, Akiyama Y, et al. A core promoter and a frequent single-nucleotide polymorphism of the mismatch repair gene hMLH1. Biochem Biophys Res Commun. 1999;256(3):488–94. Epub 1999/03/19. doi: S0006-291X(99)90368-6 [pii] 10.1006/bbrc.1999.0368 . [DOI] [PubMed] [Google Scholar]
  • 39. Park SH, Lee GY, Jeon HS, Lee SJ, Kim KM, Jang SS, et al. -93G—>A polymorphism of hMLH1 and risk of primary lung cancer. Int J Cancer. 2004;112(4):678–82. Epub 2004/09/24. 10.1002/ijc.20359 . [DOI] [PubMed] [Google Scholar]
  • 40. Lee KM, Choi JY, Kang C, Kang CP, Park SK, Cho H, et al. Genetic polymorphisms of selected DNA repair genes, estrogen and progesterone receptor status, and breast cancer risk. Clin Cancer Res. 2005;11(12):4620–6. Epub 2005/06/17. doi: 11/12/4620 [pii] 10.1158/1078-0432.CCR-04-2534 . [DOI] [PubMed] [Google Scholar]
  • 41. Raptis S, Mrkonjic M, Green RC, Pethe VV, Monga N, Chan YM, et al. MLH1 -93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer. J Natl Cancer Inst. 2007;99(6):463–74. Epub 2007/03/22. doi: 99/6/463 [pii] 10.1093/jnci/djk095 . [DOI] [PubMed] [Google Scholar]
  • 42. An Y, Jin G, Wang H, Wang Y, Liu H, Li R, et al. Polymorphisms in hMLH1 and risk of early-onset lung cancer in a southeast Chinese population. Lung Cancer. 2008;59(2):164–70. Epub 2007/09/18. doi: S0169-5002(07)00439-4 [pii] 10.1016/j.lungcan.2007.08.003 . [DOI] [PubMed] [Google Scholar]
  • 43. Li JH, Shi XZ, Lu S, Liu M, Cui WM, Liu LN, et al. HMLH1 gene mutation in gastric cancer patients and their kindred. World J Gastroenterol. 2005;11(20):3144–6. Epub 2005/05/27. . [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All relevant data are within the paper.

Articles from PLoS ONE are provided here courtesy of PLOS

RESOURCES