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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 6  |  Page : 1279-1284

Genetic variants in the microRNA machinery gene (Dicer) have a prognostic value in the management of endometrial cancer


1 Department of Obstetrics and Gynecology, Cumhuriyet University School of Medicine, 58140 Sivas, Turkey
2 Department of Medical Genetics, Cumhuriyet University School of Medicine, 58140 Sivas, Turkey
3 Department of Nutrition and Dietetics, Cumhuriyet University School of Health Sciences, 58140 Sivas, Turkey
4 Department of Biochemistry, Cumhuriyet University School of Medicine, 58140 Sivas, Turkey

Date of Web Publication28-Nov-2018

Correspondence Address:
Savas Karakus
Department of Obstetrics and Gynecology, Cumhuriyet University School of Medicine, 58140 Sivas
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.187291

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 > Abstract 


Aim: Although several associations were found between Dicer rs3742330 single nucleotide polymorphism (SNP) and development and prognosis of some epithelial cancers, relationship between the SNP rs3742330 and endometrial cancer (EC) has not yet been studied. We aimed to investigate the prognostic role of rs3742330 SNP of Dicer gene in EC patients.
Subjects and Methods: A total of 80 EC patients and 80 control subjects included in the study. Real-time polymerase chain reaction and the allele discrimination technique was used for genotyping of rs3742330 SNP.
Results: There was no significant difference between EC patients and control subjects with regard to the genotype and allele frequencies for Dicer rs3742330 SNP (P > 0.05). Despite Dicer rs3742330 SNP had no prognostic value in terms of stage, grade, lymphovascular invasion, myometrial invasion, tumor size, and histopathology; malignant peritoneal cytology has been detected higher in the patients bearing AA genotype compare with AG genotype (P = 0.023). Higher recurrence rate and shorter time to recurrence were found in patients bearing AG and GG genotype compare with AA genotype (P = 0.009).
Conclusion: Dicer rs3742330 AG and GG genotypes may have the potential to be used as a predictor of poor prognosis in the management of EC case.

Keywords: Dicer, endometrial cancer, microRNA, single nucleotide polymorphism


How to cite this article:
Oz M, Karakus S, Yildirim M, Bagci B, Sari I, Bagci G, Yildiz C, Akkar O, Cetin A, Yanik A. Genetic variants in the microRNA machinery gene (Dicer) have a prognostic value in the management of endometrial cancer. J Can Res Ther 2018;14:1279-84

How to cite this URL:
Oz M, Karakus S, Yildirim M, Bagci B, Sari I, Bagci G, Yildiz C, Akkar O, Cetin A, Yanik A. Genetic variants in the microRNA machinery gene (Dicer) have a prognostic value in the management of endometrial cancer. J Can Res Ther [serial online] 2018 [cited 2019 Sep 21];14:1279-84. Available from: http://www.cancerjournal.net/text.asp?2018/14/6/1279/187291




 > Introduction Top


Endometrial cancer (EC) is the fourth most common cancer type after breast, lung, and cervical cancer,[1] as well as the sixth leading cause of cancer-related deaths among women.[2] In the developed countries, EC is the most common cancer type among gynecologic cancers,[2] however, the most common cancer type among the gynecological cancers after cervical cancer worldwide.[1] About 2–3% of women will develop EC in in their lifetime.[1],[2] It is known that several risk factors including, obesity, diabetes mellitus, and hypertension had important roles in the etiology of EC; however, recently, genetic factors have increasingly come to forefront among EC risk factors. Previous molecular genetic studies including genome-wide association studies and linkage studies with candidate genes have emphasized that genetic factors increase the EC risk.[3],[4]

MicroRNAs (miRNAs) are small (about 21–24 nucleotide-long), single-stranded, highly conserved, and noncoding RNA molecules. miRNAs may control gene expression by targeting mRNA either through repression of translation or target mRNA degradation.[5] It has been predicted that miRNAs modulate 30% of human genes.[6] Many studies have indicated that miRNAs have possible roles in various biological processes, including cell differentiation, cell proliferation, tumorigenesis, and apoptosis.[7],[8] A growing body of evidence has suggested that aberrant miRNA expression is related to development and progression of various human cancers, by modulating the expression of tumor suppressor genes or proto-oncogenes.[7],[8],[9]

A double-stranded RNA-specific enzyme, Dicer is a member of RNase III family. It catalyzes the first step in the RNA interference pathway to produce miRNA.[10] Aberrant miRNA expression was commonly found in various types of human tumors.[11],[12] In cancers, abnormal miRNA expression may be partly because of aberrant Dicer expression levels.[13] Interestingly, expressions of Dicer were found to be associated with clinical course and prognosis in several cancers including ovarian cancer,[14] lung cancer,[13] and nasopharyngeal carcinoma.[15] Single nucleotide polymorphisms (SNPs) in the miRNA genes, miRNA machinery genes, as well as their binding sites may be associated with cancer development, patient survival, and treatment response.[16]

Rs3742330 SNP is localized in the 3' untranslated region of Dicer gene, and this locus has possible significance for stability of mRNA transcript.[17] It contains multiple sites for target miRNA regulation, histone modification, DNA methylation, and transcription factor binding. There is no direct evidence demonstrating that rs3742330 SNP of Dicer gene is related to altered mRNA stability; however, the region of rs3742330 SNP has been defined as hsa-miR-5582-5p and miR-3622a-5p target site.[18],[19]

Although no association was found between Dicer rs3742330 SNP and hepatocellular carcinoma,[20] bladder cancer,[21] and primary ovarian failure,[22] it was found that Dicer rs3742330 AA genotype increases colorectal[23] and gastric cancer risk[24] and Dicer rs3742330 AA and AG genotypes decreases 5 years survival in T-cell lymphoma cases.[10] Dicer gene expression was found lower in EC tissues than that of normal endometrium.[25],[26] The findings of these studies imply that the determination of Dicer rs3742330 SNP status may provide an important contribution to the understanding of pathophysiology of EC in the gynecologic oncology practice. This study was carried out to examine the possible association between Dicer rs3742330 SNP and EC.


 > Subjects and Methods Top


The study protocol approval received from the Human Research Ethics Committee of our University. Participation in the study was voluntary and written informed consent was obtained from all those enrolled. The current study was conducted in a total of 160 women including 80 EC patients and 80 controls. Eighty patients who had a confirmed diagnosis of EC based on histopathological evaluation were included the study as a patient group. The International Federation of Gynecology and Obstetrics criteria was used for defining the clinical stage of EC.[27] Eighty age-matched women who admitted for benign gynecologic causes and routine control, not diagnosed as any type of cancer, and no family history of cancer, were included in this study as control group.

Demographic parameters of patients and controls including age, menopause age, menopause duration, gravidity, parity, body mass index (BMI), abortus, diabetes mellitus, hypertension, smoking, history of cancer, and family history of cancer were recorded. Tumor markers including cancer antigen (CA)-125, CA-19–9, CA-15–3, carcinogenic embryonic antigen, and hematologic parameters including creatinine, blood urea nitrogen (BUN), lactate dehydrogenase, fasting blood glucose, aspartate aminotransferase, and alanine aminotransferase were collected from routine laboratory tests of the subjects.

Genotyping

A total volume of 5 ml venous blood samples obtained from patients and controls were collected into the K3 EDTA containing tubes and stored −20°C until the analysis time. For extracting genomic DNA, a commercial genomic DNA extraction kit was used (IDPURE Universal Spin Column Genomic DNA Mini Kit Blood, Empire Genomics. New York, USA). Genotyping of Dicer rs3742330 SNP was performed with using real-time polymerase chain reaction and the allele discrimination technique in Rotor-Gene Q (QIAGEN, Germany) device, according to the manufacturer's instructions. For genotyping of Dicer rs3742330 SNP, 2.5 μl genomic DNA was added to a final of 10 μl reaction mixture containing 5 μl master mix, 0.5 μl primer/probe mix (PrimerDesign Ltd., UK), and 2 μl distilled water.

Statistical analysis

All statistical analyses of the current study were performed by SPSS version 22.0 (SPSS IBM Corporation, Armonk, NY, USA). Descriptive values were expressed as mean ± standard deviation, median (minimum–maximum) frequency, and percent as appropriate. The Chi-square test or Fisher's exact test was used in the comparison of categorical data. Student's t-test and Mann–Whitney U-test was used for the comparison of independent samples. Survival of EC patients according to Dicer rs3742330 SNP was compared with Kaplan–Meier survival analysis. 95% confidence intervals and odds ratios were calculated to estimate the risk associated with particular genotypes or alleles. The P < 0.05 was considered as the significant.


 > Results Top


Demographic characteristics of EC patients and controls were demonstrated in [Table 1]. The mean age of EC patients was 59.71 ± 10.32, and the mean age of control group was 59.15 ± 6.11. No significant difference was found between the two groups with regard to mean age (P > 0.05). BMI, parity and gravidity were found statistically significantly higher in EC patients compare with those control group (P = 0.001). No significant difference was found the other demographic parameters between EC patients and controls (P > 0.05). The median follow-up period after primary surgery was 21 months (range, 3–98 months).
Table 1: Characteristics of endometrial cancer patients and controls

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Histologically, endometrium carcinomas were divided into two categories: endometroid carcinoma and nonendometroid carcinoma. Histological subtypes of endometroid carcinoma were following: endometrioid adenocarcinoma in fifty cases (62.5%), adenocarcinoma with squamous differentiation in 12 cases (15.0%), and villoglandular adenocarcinoma in one case (1.3%). Histological subtypes of the nonendometroid carcinoma were following: serous carcinoma in five cases (6.3%), clear cell carcinoma in three cases (3.8%), mucinous carcinoma in two cases (2.5%), and mixed carcinoma in seven cases (8.6%).

[Table 2] shows the laboratory findings of EC patients and controls. CA-125, BUN, and creatinine level were found significantly lower in EC patients than those control group (P = 0.029, 0.001 and 0.009, respectively). No significant difference was found for the other parameters between EC patients and controls (P > 0.05).
Table 2: Laboratory findings of patient and control groups

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[Table 3] demonstrates Dicer rs3742330 genotype and allele frequencies of EC patients and controls. One case in the control group could not be genotyped for technical reasons. Dicer rs3742330 AA, AG, and GG genotype frequencies were found as 77.5% (n = 62), 21.25% (n = 17), and 1.25% (n = 1), respectively in patients and 70.9% (n = 56), 22.8% (n = 18), and 6.3% (n = 5), respectively in controls. When AA genotype frequency was compared to AG, GG, and AG + GG genotype frequency, no significant difference was found (P = 0.68, P = 0.12 and P = 0.34, respectively). Minor G allele frequency was found as 0.119 and 0.178 in EC patients and controls, respectively. However, the difference between patients and controls was not significant (P = 0.14).
Table 3: Genotype and allele frequencies of Dicer rs3742330 polymorphism in patients with endometrial cancer and controls

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When patients were compared according to pathological features, no statistically significant association was found between Dicer rs3742330 SNP and tumor stage, grade, size, histopathology, lymphovascular invasion, and myometrial invasion (P > 0.05) (data were not shown). Rate of malignant peritoneal cytology in patients bearing AA genotype was significantly higher than patients bearing AG genotype (P = 0.023). Recurrence rate was found higher in patients bearing AG and GG genotype compare with AA genotype, (P = 0.009). In addition, the patients with AG genotype and GG genotype had a shorter time to recurrence compare with AA genotype (P = 0.019); [Figure 1].
Figure 1: Cumulative recurrence probability in endometrial cancer patients. Patients with AG genotype and GG genotype had a shorter time to recurrence compare with AA genotype (P = 0.019)

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 > Discussion Top


In this study, the relationship between the Dicer gene rs3742330 SNP and EC predisposition, and disease prognosis was examined for the first time. No significant difference was found between patients and controls in terms of genotype and allele frequencies. On the other hand, malignant peritoneal cytology has been detected higher in the patients bearing AA genotype compared to those with AG genotype. However, no significant association was found between Dicer gene rs3742330 SNP and stage, grade, lymphovascular invasion, myometrial invasion, tumor size, and histopathology. Higher recurrence rate and shorter time to recurrence were found in patients with AG and GG genotype compared with those with AA genotype.

Recent evidence suggest that in addition to other risk factors, genetic factors play a role in the development and progression of EC.[3],[4] miRNAs are involved in many physiological processes including cell differentiation and cell-type determination. In various cancers, miRNAs play regulatory role like oncogenes or tumor suppressor genes, thereby contributing to cancer development by stimulating cell invasion, proliferation, and angiogenesis. Similarly, miRNAs can reduce expressions of different proteins by their oncogenic activity.[7],[8],[9]

In cancer development, abnormal miRNA expression may be related to aberrant Dicer expression levels.[28] A growing body of evidence show that aberrant expression levels of Dicer is associated with increased cancer risk.[11],[12],[14] Expression of Dicer and other enzymes involved in miRNA biogenesis have been associated with the clinical course and prognosis in various cancers.[14],[15] Aberrant Dicer gene expression also was observed in many types of cancer including ovarian,[14],[29] breast,[30],[31] prostate,[32] neuroblastoma,[33] lung,[34] and hepatocellular carcinoma.[35] As it is understood from the above-mentioned studies, tissue- and tumor-specific alterations may observed in Dicer mRNA level.

The human Dicer gene is located within the subtelomeric region 14q32. According to a hypothesis that explain the relationship between Dicer and development of cancer, this locus has been reported to be significantly affected by various mutations such as common mutations, copy number variations, and epimutations.[36],[37] Interestingly, Fujino et al. reported loss of heterozygosity (LOH) on chromosome 14q in the high percentage of EC patients, indicating a strong correlation between LOH on chromosome 14q and death from diseases. Furthermore, they have defined a minimal region of deletion (chromosome 14q32).[38] In addition, they observed a strong correlation between poor clinical outcome and 14q LOH.

Although studies investigating rs3742330 SNP and cancer risk in several cancer types have been performed to date, conflicting findings were found from these studies.[10],[20],[21],[23],[24] No association was found between Dicer rs3742330 SNP and hepatocellular carcinoma,[20] and bladder cancer.[21] Contrary to above-mentioned studies, in a study carried out with colorectal cancer patients, patients bearing rs3742330 AA genotype were found higher compared to AG + GG genotype, suggesting patients bearing AA genotype have increased risk for cancer development.[23] Xie et al. showed that patients with rs3742330 AA genotype have an increased risk of gastric cancer.[24] In patients with T-cell lymphoma, Li et al. investigated the relationship between rs3742330 and survival. They found that AG genotype and AA genotype increased the mortality risk 8.95 times and 10.14 times, respectively.[10]

Dicer expression levels in EC patients were previously examined;[25],[26] however, there is no study investigating Dicer rs3742330 SNP and EC risk. To our knowledge, our study is the first study to examine Dicer rs3742330 SNP in patients with EC. In the current study, no significant difference was found between EC patients and control subjects in terms of genotype and allele frequencies of Dicer rs3742330 SNP. However, malignant peritoneal cytology, one of the prognostic factors, showed a significant association with rs3742330 SNP in EC patients. The frequency of malignant peritoneal cytology was found higher in patients with AA genotype compared to AG and GG genotype. No statistically significant association was found between Dicer rs3742330 SNP and the other prognostic factors including tumor stage, grade, tumor size, histopathology, lymphovascular invasion, and myometrial invasion.

In the current study, significant association was found between rs3742330 SNP and recurrence rate in EC patients. The recurrence rate was found higher AG and GG genotype compared to AA genotype. Despite the frequency of malignant peritoneal cytology was found higher in patients bearing AA genotype, the recurrence rate was found higher in those with AG and GG genotype. Dicer rs3742330 SNP may has a role in the enhancing of malignancy. Despite the presence of malignant peritoneal cytology, the absence of an increase in recurrence rate leads us to the idea.

Interestingly, in the current study, serum CA-125 levels were detected higher in the control group than that of EC patients. Elevated serum CA-125 levels have been reported in individuals with a variety of nonmalignant conditions including cirrhosis, hepatitis, smoking, endometriosis, first-trimester pregnancy, ovarian cysts, uterine fibroids (benign tumors), pancreatitis, menstruation, diverticulitis, and pelvic inflammatory disease.[39],[40] We think that aforementioned conditions may be possible causes of elevated levels of CA-125 in the controls.

The current study had some limitations suggest the relatively small sample size for the SNP analysis and difference between the study groups with regard to BMI, parity and gravidity. Since we could not rule out the other factors of recurrent EC and the follow-up periods of patients were considerably short for the assessment of 5-year survival and recurrence, it was not possible to evaluate the association of tumoral parameters with the Dicer rs3742330 SNP status.


 > Conclusion Top


Dicer rs3742330 SNP was associated with increased tumor recurrence rate and shorter time to tumor recurrence, indicating that the analysis of miRNA processing-related gene SNPs may help to identify EC patients at high risk for tumor recurrence. By investigating Dicer rs3742330 SNP in EC patients, patients carrying AG and GG genotype which is high-risk genotypes for EC may be followed up closely for recurrence. By early diagnosis of patients with the risk of recurrence, mortality, and morbidity of patients may be reduced with early intervention. Further studies with larger population size to support our findings are needed.

Financial support and sponsorship

This work is supported by the Scientific Research Project Fund of Cumhuriyet University under the project number “T-620.”

Conflicts of interest

There are no conflicts of interest.



 
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