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Bioinformatics analysis of miR-2861 and miR-5011-5p that function as potential tumor suppressors in colorectal carcinogenesis

BMC Medical Genomics volume 18, Article number: 1 (2025) Cite this article

Abstract

Background

The study aimed to was to investigate the relationship between miR-2861, miR-5011-5p, and colorectal carcinogenesis.

Method

In the present study, it was isolated RNA from both the tumor and non-tumor tissue of a total of 80 CRC patients and after synthesizing the cDNA, it was performed qRT-PCR to determine the expression levels of miR‑2861 and miR‑5011-5p. In addition, it was predicted that dysregulated miRNAs targets, pathways and functional gene annotations that may be important in colorectal carcinogenesis using KEGG pathway and GO analysis.

Results

The resulting data revealed that both expression levels of miR-2861 and miR-5011-5p were significantly decreased in tumor tissues compared with non-tumor tissues of CRC patients. The GO and KEGG pathway analysis showed that miR-2861 and miR-5011-5p may participate in multiple the biological process, cellular components, and molecular function subcategories such as mitotic cell cycle, regulation of small GTPase mediated signal transduction, cell death, and acid binding transcription factor activity. It was also revealed that target genes of miRNAs can be found in signaling pathways such as TGF-beta, Rap1, Ras, cAMP, Wnt, mTOR and, PI3K-Akt signaling pathways.

Conclusion

These findings imply that miR-2861 and miR-5011-5p might function as tumor suppressors in the development of CRC.

Peer Review reports

Introduction

One of the most prevalent gastrointestinal tract malignancies, colorectal cancer (CRC), affects both men and women equally and has a significant mortality rate throughout the World [1]. CRC is a different disease in terms of clinical and biological features and shows changes in both disease progression and treatment response [2]. The incidence of CRC in the young population is increasing in many countries [3]. By 2030, it is estimated that annual CRC diagnoses will exceed 2.2 million and deaths will be greater than 1.1 million [4]. Thus, the discovery of potential molecular targets for the early detection and treatment of CRC is important to decrease CRC-induced mortality.

The pathogenesis of some malignancies, including CRC, is heavily influenced by epigenetics, which are heritable alterations in gene expression that do not result in long-term changes in the DNA sequence [5]. Examination of epigenetic changes has contributed to the elucidation of the gene-CRC relationship by revealing differences in gene expression patterns and expression levels of some genes specific to CRC [6]. MicroRNAs (miRNAs) are one of the components of epigenetic mechanisms [7]. miRNAs are small, non-coding, single-stranded RNA molecules about 19–23 nucleotides long. miRNAs bind to the 3’ untranslated regions (UTR) of target mRNAs, causing mRNA degradation and thereby controlling gene expression [8]. Bioinformatics studies have shown that a single miRNA can target many different mRNAs and thus these miRNAs are involved in various cellular events such as cell proliferation, differentiation, apoptosis and, immune response [9]. Studies from the past to the present have shown that microRNAs may be associated with cancer progression and play a role in the pathogenesis of tumors by controlling oncogenes or tumor suppressor genes, which are cancer-related genes [10]. Because of their effects on gene expression, presence in body tissues and fluids, and potential utility as disease biomarkers, miRNAs are important molecules for translational research [11]. Recently studies were showed that dysregulation of miRNAs is responsible for the development of CRC [12]. miR-2861, which is located in the chromosome 2 region [13], has a negative and positive correlation to variety cancer types including chordomas, cervical cancer, papillary thyroid carcinoma and basal cell carcinoma [14,15,16,17]. There are also studies showing that miR-5011-5p is dysregulated in gastric cancer, glioma, and glioblastoma [18, 19]. To the best of our knowledge, there are no research on the significance of miR-2861 and miR-5011-5p in CRC even though numerous lines of evidence highlight the essential function of miRNAs in various human malignancies. In the present study, we aimed to examine the expression levels of these miRNAs in tumor and healthy tissues of CRC patients. Additionally, enrichment pathway analyses utilizing Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed.

Methods

Samples

Individuals who were operated on at Gaziantep University Faculty of Medicine, Department of General Surgery, and diagnosed with CRC were included in the current study. Ethics committee approval of the study that was conducted in accordance with the Helsinki Declaration was obtained from Gaziantep University Medical Ethics Committee (Approval number: 2021/179). The patients taking part in the investigation provided informed consent. The sample of the study, which included tumor, and non-tumor tissues, consisted of 80 CRC patients who participated in the study between 2017 and 2022. The inclusion criteria required patients to have a confirmed diagnosis of colon and rectum adenocarcinoma by histology and have no history of past chemotherapy or radiotherapy treatments (Fig. 1). In contrast, the persons who had autoimmune or inflammatory disorders, had undergone treatments that could affect miRNA expression, had various malignancies, were experiencing active infections, or had experienced cardiovascular disease within the last six months were excluded from the study. Before moving on to the next phase, RNA isolation, the acquired tumor and non-tumor tissues were kept in RNAlatter solution at -80 ℃.

Fig. 1
figure 1

Patient flow diagram. Flow diagram of included patients with CRC

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RNA isolation

Tissue samples were homogeneously lysed prior to miRNA isolation. miRNA was extracted using the mirVanaTM miRNA isolation kit and phenol (AM1560, Invitrogen, USA) with folllowing the producer instructions. A spectrophotometer (NanoDrop, Maestrogen) was used to measure the quantity of miRNAs, which were stored at -80 ℃.

cDNA synthesis

TaqMan™ Advanced miRNA cDNA Synthesis Kit (A28007, Applied Biosystems, USA) was utilized for cDNA synthesis. Prior to use in the quantitative Real-Time Polymerase Chain Reaction (RT-qPCR), cDNAs were stored at -20 ℃.

Quantitative real-time polymerase chain reaction (RT-qPCR)

RT-qPCR was carried out using Applied Biosystems (StepOne& StepOnePlus Real-Time PCR Systems) to assess the expression levels of miR-2861 and miR-5011-5p expression in the tumor and non-tumor tissues of CRC patients. TaqMan Primer Probe (Thermo Fisher Scientific), TaqManTM Advanced miRNA Assay (A25576, Applied Biosystems, USA), and TaqManTM Fast Advanced Master Mix (Thermo Fisher Scientific, 4444557, Applied Biosystems, USA) were used for RT-qPCR. RNU6B was used as an endogenous [20]. The sequences of primers are: miR-2861: Forward 5’- GGGCCTGGCGGT-3’, Revers 5’- GTTTTTTTTTTTTTTTCCGCCCA-3’; miR-5011-5p:5’-CGCAGTATATATACAGCCATGC-3’,Revers 5’- GGTCCAGTTTTTTTTTTTTTTTGAGT − 3’; RNU6B:Forward 5’-GCTTCGGCAGCACATATACTAAAAT-3’; Revers 5’-CGCTTCACGAATTTGCGTGTCAT-3’. All reactions were performed in triplicate and analysis of the expression levels of miR-5011-5p and miR-2861 were carried out by applying the 2−∆∆Ct technique [21].

Functional enrichment analysis of miRNAs

The Kyoto Encyclopedia of Genes and Genomes (KEGG) is a collection of databases that can be used to clarify the key characteristics and outcomes of biological systems [22]. The Gene Ontology (GO) is a high-quality database that exhibited the functional gene annotation and cell localization of genes [23]. DIANA-miRPath v3.0 that is provide accurate statistics is a miRNA pathway analysis online tool [24]. The GO and KEGG pathway enrichment of these miRNAs was examined using the online tool DIANA-miRPath v3.0 in order to further clarify the biological roles of target genes controlled by downregulated miR-2861 and miR-5011-5p (http://www.microrna.gr/miRPathv3). The GO enrichment analysis consisted of three categories. These were the biological process, the cellular component, and the molecular function. The online tool Venny 2.1.0 was used to create the Venn diagram by overlapping the target genes of miRNAs (https://bioinfogp.cnb.csic.es/tools/venny).

Statistical analysis

Results were analyzed using SPSS software (version 22.0; SPSS, Inc.). In calculating the difference in miRNAs expression levels in tumor and non-tumor adjacent tissues, ΔCttumor and ΔCtnon−tumor values were determined according to the 2−∆∆Ct method [21]. The results obtained from the Kolmogorov–Smirnov and Shapiro–Wilk normality tests show that the ∆Ct values obtained from tumor and non-tumor tissues in this study conform to a normal distribution. As a result, parametric Paired-t test was used to determine the changes in the expression levels of miRNAs between tumor and non-tumor tissues. The experimental data are presented as the mean ± standard deviation. Mann Whitney U test was applied to determine the relationship between clinical and pathological parameters of patients with CRC and fold change data showing the expression values of miRNAs (Non-parametric test was used because fold change data did not comply with normal distribution). p < 0.05 was considered to indicate a statistically significant difference.

Results

Clinical and pathological findings of CRC patients

Clinical and pathological features of a total of 80 patients with CRC are summarized in Table 1. The patient’s age range was 29–87 (mean 58.425 ± 14.79). According to the tissue type, 55 cancer cases were located in the colon and 25 in the rectum. Lymphovascular invasion was known in 27.5% of the cases, of these, 47.5% had lymph node metastasis. Histologically, 77.5% of the tumors were adenocarcinoma.

Table 1 Clinical and pathological characteristics of CRC patients
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Expressions levels of miR-2861 and mir-5011-5p in CRC tissues

In the current study, to evaluate the expression level of miR-2861 and miR-5011-5p in CRC tissues, we performed RT-qPCR. As shown in Fig. 2, the results of RT-qPCR revealed in the CRC tissue samples, the expression levels of both miR-2861 and miR-5011-5p were significantly decreased compared with the non-tumor tissue samples (Both p\(\:<\) 0.001).

Fig. 2
figure 2

Expression of miR-2861 (A) and miR-5011-5p (B) in tumor and non-tumor tissue samples of patients with CRC

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The relationship between expressions of miR-2861, mir-5011-5p and clinical-pathological features of patients with CRC

In this study, no significant relationship was found between the expression levels of both miR-2861 and miR-5011-5p and the clinical and pathological features of the patients (p > 0.05) (Table 2).

Table 2 The association between miRNAs expressions and clinical-pathological characteristics of CRC patients
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Functional enrichment analysis of downregulated miR-2861 and miR-5011-5p

GO analysis results showed that in terms of biological process, downregulated miRNAs were principally enriched in Cell junction assembly, Mitotic cell cycle, Regulation of small GTPase mediated signal transduction, Transcription from RNA polymerase II promoter, Protein complex assembly, Cell death, and Phospholipid metabolic process, etc.; that cellular component was enriched in Organelle, Protein complex, Cytosol, Nucleoplasm, Integral component of plasma membrane, Endosome; that molecular functions were mainly enriched in Ion binding, Nucleic acid binding transcription factor activity, Enzyme binding, Cytoskeletal protein binding, and Small conjugating protein binding, etc. As presented in Table 3, it was discovered that 1919, 2011, and 2021 genes were linked to biological processes, cellular components, and molecular functions, respectively.

Table 3 GO analysis of the miR-2861 and miR-5011-5p genes of focus in the biological process, cellular component, and molecular function subcategories
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As a result of KEGG pathway analysis, it was determined that miR-2861 has 1 (AKT2) and miR-5011-5p has 10 (GSK3B, SMAD2, TCF4, PIK3CB, JUN, PIK3R1, MAPK3, AKT3, PIK3CA and TGFBR2) target genes in the pathogenesis of CRC (Fig. 3). The 16 KEGG pathways significantly enriched the downregulated miR-2861 and miR-5011-5p. These were signaling mechanisms that controlled the pluripotency of stem cells, TGF-beta signaling pathway, proteoglycans in cancer, Rap1 signaling pathway, Ras signaling pathway, transcriptional misregulation in cancer, choline metabolism in cancer, pathways in cancer, cAMP signaling pathway, insulin signaling pathway, T cell receptor signaling pathway, Wnt signaling pathway, endocytosis, mTOR signaling pathway, PI3K-Akt signaling pathway, platelet activation (Table 4). Since both miRNAs included in a total of 16 KEGG pathways had target genes and the target genes showed significant overlap among the signaling pathways, it was confirmed by Venn diagram, which showed that both miRNAs were commonly found in the four top-regulated pathways (Signaling pathways regulating pluripotency of stem cells, TGF-beta signaling pathway, Proteoglycans in cancer, Rap1 signaling pathway) shown in Table 4. Therefore, a Venn diagram was constructed to analyze the overlaps among the target genes of both miR-2861 and miR-5011-5p in Signaling pathways regulating pluripotency of stem cells, TGF-beta signaling pathway, Proteoglycans in cancer and Rap1 signaling pathways. The common target gene of miR-5011-5p in the first four pathways was found to be MAPK3 (Fig. 4A and Supplementary Table 1). The common target gene of miR-2861 in Signaling pathways regulating pluripotency of stem cells, Proteoglycans in cancer and Rap1 signaling pathway was AKT2 (Fig. 4B and Supplementary Table 2). Common signaling pathways involving target genes of both miRNAs were examined and target genes in these pathways were intersected with a Venn diagram. In these signaling pathways given in Table 4, it was detected 21 target genes of miR-2861, 253 target genes of miR-5011-5p and 1 common overlapping target gene (SP1) of both miRNAs (Fig. 5).

Fig. 3
figure 3

Signaling pathways and genes targeted by miR-2861 and miR-5011-p in CRC carcinogenesis

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Fig. 4
figure 4

Venn diagram showing the overlaps between target genes of miR-2861 (A) and miR-5011-5p (B), which regulate the first four KEGG pathways in Table 4. (Diagrams were drawn using Venny 2.1.0 website (https://bioinfogp.cnb.csic.es/tools/venny/, accessed 10 November 2024). The list of miRNAs and genes is reported in Supplementary Tables 1 and 2, respectively

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Fig. 5
figure 5

Target genes of miR-2861 and miR-5011-5p in common signaling pathways

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Table 4 KEGG analysis of downregulated miR-2861 and miR-5011-5p in tissues with CRC patients
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Discussion

There are many reasons for the high incidence of CRC worldwide, but the most important are genetic and environmental factors. Excessive body weight, smoking, drinking too much alcohol, eating a lot of red or processed meat, and not getting enough exercise are additional risk factors for CRC [25]. Although the incidence and mortality rate of CRC have decreased thanks to novel surveillance and treatment methods, identifying the molecular mechanisms causing the formation of CRC is crucial for the early detection of patients [26, 27]. Especially in recent years, researchers are paying a growing amount of attention to microRNAs as a result of the critical functions that they play in cell differentiation, the development of cancer [28]. However, considering the powerful role of miRNAs in various signaling pathways that are effective in cancer pathogenesis, it cannot be excluded that these small molecules will constitute an important area of study in future cancer management strategies.

As a result, many miRNAs have been discovered to act as oncogenes or tumor-suppressor miRNAs and to be up-or down-regulated in human cancers [29]. miRNAs expressed at abnormal levels in CRC may contribute to cancer formation by disrupting cell signaling and cellular survival pathways such as the Wnt signaling pathway, EGFR, and p53 [30]. Patient survival, tumor stage, the existence of lymph node metastases, and response to CRC treatment can all be determined using the miRNA expression profile [31]. Different expression levels have been reported in several studies of CRC. It was shown that the expression levels of miR-485-3p, miR-4728-5p, miR-143 downregulated [20, 32], while the expression levels of miR-17-5p, miR-20a-5p, miR-592, miR-584-5p, and miR-625-3p upregulated [33, 34].

In this study, we evaluated the expression levels of miR-2861 and miR-5011-5p in tumor and non-tumor tissue samples collected from CRC patients. As a result of the study, expression levels of both miR-5011-5p and miR-2861 were reduced in CRC tissues compared with non-tumor subjects. Vastard et al. (2017) reported that miR-5011-5p showed lower expression in glioma and glioblastoma, which is consistent with our findings [35]. In another study, the downregulation of miR-5011-5p was observed in gastric cancer tissues and cell lines, and an inverse association was found between miR-5011-5p and its target gene, PAK2 [18]. Decreased expression of miR-5011-5p was also detected in blood samples of cervical dystonia patients compared to healthy controls [36]. In this research, KEGG pathway analysis showed that the common target gene of miR-5011-5p in Signaling pathways regulating pluripotency of stem cells, TGF-beta signaling pathway, Proteoglycans in cancer and Rap1 signaling pathway was MAPK3 gene, and Slattery et al. exhibited that MAPK3 was associated with colon cancer [37]. These results suggest that MAPK3 should be investigated as a target gene of miR-5011-5p in CRC. Another miRNA, miR-2861 has been found to be downregulated in endometriotic tissues, and its lower expression may be connected to endometriosis’s ectopic endometrial cell growth and death. Additionally, it was discovered in this study that miR-2861 targets STAT3 and MMP2 in cell growth and death [38]. Shi et al. found that miR-2861 showed low expression in diabetic retinopathy compared to the control group. In the same study, they showed that miR-2861 can inhibit the proliferation and promote apoptosis of human retinal vascular endothelial cells by targeting NDUFB7 [39]. In the another study, miR-2861 expression was decreased in cervical cancer patients [40]. Also, a different study in cervical cancer revealed that miR-2861 targets the CCND1, AKT2, and EGFR pathways [15]. In our study, KEGG pathway analysis revealed that the common target gene of miR-2861 in Signaling pathways regulating pluripotency of stem cells, Proteoglycans in cancer and Rap1 signaling pathway was AKT2. PI3K/AKT signaling pathway plays an important role in cell proliferation, survival, migration and invasion in various cancers including colorectal cancer [41]. Previous studies have shown that AKT2 is the predominant isoform involved in CRC carcinogenesis and plays an important role in CRC metastasis [42]. Considering this information, AKT2 may be a target gene for miR-2861 in the formation of colorectal carcinogenesis. Contrary to our study findings, lung cancer stem cells (LCSCs), it has been shown that miR-2861 expression level was increased and HDAC expression was positively related with to miR-2861 [43]. Based on the RT-qPCR results, it can be thought that both miR-2861 and miR-5011-5p play a role as tumor suppressor in CRC.

In the current study, GO and the KEGG Pathway databases were consulted in order to investigate target genes that are predictive of probable pathways in relation to downregulated miRNAs. According to GO analysis, both miR-2861 and miR-5011-5p are associated with 1919 genes with biological process, 2011 genes with cellular components, and 2021 genes with molecular functions. Numerous cancer-related pathways were found by KEGG Pathway analysis (Table 4). These pathways include TGF-beta, Rap1, Ras, cAMP, Wnt, mTOR, and PI3K-Akt signaling pathways. An important pathway for controlling cellular growth, differentiation, extracellular matrix remodeling, angiogenesis, and inflammation is the TGF- signaling system. Slattery et al. (2017) showed that the TGF-β signaling pathway is involved in the formation of colon and rectal tumors through the effects of various miRNAs, including miR-2861 [44]. In a recent study of CRC and TGF-β/Smad signaling pathway, it was reported that Smad3 expression is quite high in CRC, indicating that the TGF-/Smad signaling pathway is abnormally active during the formation and growth of tumors [45]. The RAS signaling pathway is highly important in mediating cellular growth and malignant transformation [46]. Jeon et al. (2012) exhibited that APC (WNT pathway) mutations can increase Ras stability in CRC, which can up-regulate the Ras pathway [47]. Ras-associated protein-1 (Rap1) plays a crucial role in controlling several important cancerous cell movements, spread, and metastasis-related activities [48]. In a previous study, downregulation of SIPA1, exhibiting GAP activities on Ras-related Protein 1 (RAP1) and Ras-related Protein 2 (RAP2), has been reported to increase the invasive ability of cells in colon cancer [49]. Any change in the Wingless/Integrated (Wnt) signaling pathway can lead to cancer progression because it plays a role in the change in the shape or structure of an organism through growth, differentiation, and regeneration of stem cells in different parts of the organism. Many CRC patients have damage to important Wnt signaling pathway components [50]. WNT5a regulates WNT/β-catenin-dependent single pathway. WNT5a regulates the single WNT/β-catenin-dependent pathway. Sun et al. reported that WNT5a expression in CRC cells was inversely associated with tumor grade in CRC patients [51]. However, increased expression of the PI3K/AKT/mTOR signaling pathway has been exhibited in a variety of malignancies, including CRC [52]. At the same time, 21 target genes of miR-2861, 253 target genes of miR-5011-5p and 1 common overlapping target gene (SP1) of both miRNAs were detected in the signaling pathways given in Table 4. SP1, which plays an important role in tumor survival, progression and metastasis, showed increased expression in various cancers including CRC [53]. Considering this important role of SP1 in colorectal cancer, it can be said that it can be considered as a target gene for both miRNAs investigated in this study.

Conclusion

In conclusion, the findings of this study showed that the expression of both miR-2861 and miR-5011-5p was downregulated in CRC tissues. As a result, both miR-2861 and miR-5011-5p may play a tumor suppressor role in colorectal carcinoma, suggesting that both miRNAs could be used as candidate biomarkers for the detection of CRC. However, functional studies are still needed to reveal the roles of these miRNAs in CRC.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

miRNA:

MicroRNA

CRC:

Colorectal cancer

RT-qPCR:

Quantitative real time PCR

KEGG:

Kyoto encyclopedia of genes and genomes

3’UTR:

3’ untranslated region

Ct:

Threshold cycle

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Acknowledgements

Not applicable.

Funding

This study was supported by Gaziantep University, Scientific Research Projects Governing Unit (Project Number: FEF.YLT.21.18).

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Authors and Affiliations

  1. Department of General Surgery, Faculty of Medicine, Gaziantep University, Gaziantep, 27310, Turkey

    Alper Aytekin

  2. Department of Biology, Faculty of Art and Science, Gaziantep University, Gaziantep, 27310, Turkey

    Hikmet Kadakal & Turkan Gurer

  3. Department of Nutrition and Dietetics, Faculty of Health Science, SANKO University, Gaziantep, 27090, Turkey

    Deniz Mihcioglu

Authors
  1. Alper Aytekin
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Contributions

AA operated on patients, collected the samples and evaluated clinical findings, analyzed bioinformatics data, discussed the results, performed revisions for important intellectual content, and commented on the manuscript. HK performed the RT-qPCR experiments. DM analyzed data, discussed the results, performed revisions for important intellectual content, and commented on the manuscript. TG supervised the research, designed and performed experiments, analyzed data, discussed the results, performed revisions for important intellectual content, and commented on the manuscript. All authors contributed to the design of the present study, read and approved the submitted version.

Corresponding author

Correspondence to Alper Aytekin.

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Ethical approval

The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the local ethics committee of Gaziantep University, Turkey (approval numbers: 2021/179). Informed consent was obtained from all individuals included in this study.

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Not applicable.

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The authors declare no competing interests.

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Aytekin, A., Kadakal, H., Mihcioglu, D. et al. Bioinformatics analysis of miR-2861 and miR-5011-5p that function as potential tumor suppressors in colorectal carcinogenesis. BMC Med Genomics 18, 1 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12920-024-02080-6

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Keywords

BMC Medical Genomics

ISSN: 1755-8794

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