Turkiye Klinikleri Journal of Biostatistics

.: ORIGINAL RESEARCH
Whole Genome microRNA Expression Data in Childhood Acute Lymphoblastic Leukemia and Evaluation of microRNA Pathways Using Fuzzy C-means
Çocukluk Çağı Akut Lenfoblastik Lösemide Tüm Genom mikroRNA İfade Verileri ve Bulanık C-ortalamaları Kullanılarak mikroRNA Yolaklarının Değerlendirilmesi
Su ÖZGÜRa, Mehmet Nurullah ORMANa, Bakiye GÖKER BAĞCAb, Muhterem DUYUc, Özgür ÇOĞULUd
aDepartment of Biostatistics and Medical Informatics, Ege University Faculty of Medicine, İzmir, TURKEY
bDepartment of Medical Biology, Ege University Faculty of Medicine, İzmir, TURKEY
cDepartment of Pediatric Health and Diseases, Medeniyet University Göztepe Training and Research Hospital, İstanbul, TURKEY
dDepartment of Medical Genetics, Ege University Faculty of Medicine, İzmir, TURKEY
Turkiye Klinikleri J Biostat. 2021;13(1):70-81
doi: 10.5336/biostatic.2020-79777
Article Language: EN
Full Text
ABSTRACT
 Objective: Hard clustering approaches may cause some of the relationships to be overlooked due to their nature of algorithms especially in genetic datasets. But hidden relationships can be revealed by fuzzy approaches. Purpose of this study was evaluating effect of microRNAs (miRNA) on children with acute lymphoblastic leukaemia (ALL) by using miRNA expression data obtained from bone marrow samples with sets containing different numbers of elements of fuzzy C-means (FCM). Material and Methods: miRNA expression levels of 43 newly diagnosed ALL patients and 14 healthy subjects were analysed via FCM. Clusters containing different numbers of miRNAs were evaluated, common properties in messenger RNA (mRNA) pathways were investigated and new pathways associated with ALL and cancer were described via miRNA target prediction tools. Results: Significant miRNA profile was compared to control cases. Only 46 out of 108 miRNAs were found to be significantly upregulated or downregulated. Of forty six miRNAs: 8 miRNAs were labelled as tumour suppressor (17.4%), 17 miRNAs were labelled as onco-miR (37.0%) and 21 miRNAs could not be labelled (45.6%) for hematological malignancy. Fourteen (%30.4) miRNAs were found to be apoptosis-related, 27 miRNAs were in leukemia-related (58.7%) and 15 labelled miRNAs were related with cancer pathways (32.6%). hsa-miR-181b, hsa-miR-146a, hsa-miR-155, hsa-miR-181c-5p, hsa-miR-7-1-3p, hsa-miR-708-5p onco-miRs constituted a set. These miRNAs targeted 801 common mRNAs (p<0.05). When this sub-cluster was searched in the literature and miRNA target prediction tools system, it was found to be involved in cancer-related pathways except ALL. Conclusion: Hidden relation-ships can be defined by fuzzy approaches and those pathways may pro-vide guidance to open up new horizons in the field of miRNA studies.

Keywords: Fuzzy C means algorithm; miRNA; childhood cancers; miRNA target prediction tools
ÖZET
 Amaç: Sert kümeleme yaklaşımları, özellikle genetik veri setle-rinde algoritmaların doğası gereği bazı ilişkilerin gözden kaçmasına neden olabilmektedir. Ancak gizli ilişkiler, bulanık yaklaşımlarla ortaya çıkarılabilir. Bu çalışmanın amacı, mikroRNA'ların (miRNA) akut lenfoblastik lösemili (ALL) çocuklar üzerindeki etkisini, bulanık C-ortalaması (FCM) ile elde edilen ve farklı sayıda kümeleri içeren setlerle kemik iliği örneklerinden elde edilen miRNA ekspresyon verilerini kul-lanarak değerlendirmektir. Gereç ve Yöntemler: Kırk üç yeni tanılı ALL hastası ve 14 sağlıklı çocuğun miRNA ekspresyon seviyeleri FCM ile analiz edilmiştir. Farklı sayıda miRNA içeren kümeler değerlendiri-lerek, mesajcı RNA (mRNA) yolaklarındaki ortak özellikler araştırılmış, ALL ve kanserle ilişkili yeni yolaklar miRNA hedef tahmin araçlarıyla tanımlanmıştır. Bulgular: Anlamlı miRNA düzeyleri, kontrol vakalarıy-la karşılaştırılmıştır. Yüz sekiz miRNA'dan sadece 46'sının önemli öl-çüde yüksek regüle veya düşük regüle edildiği bulunmuştur. Kırk altı miRNA'dan, 8 (%17,4) miRNA tümör baskılayıcı, 17 (%37,0) miRNA onco-miR olarak tanımlanırken, 21 (%45,6) miRNA hematolojik malignite için tanımlanamamıştır. Tanımlanan 14 (%30,4) miRNA apoptozla ilişkili, 27 (%58,7) miRNA lösemi ile ilişkili ve 15 (%32,6) miRNA kanser yolakları ile ilişkili saptanmıştır. hsa-miR-181b, hsa-miR-146a, hsa-miR-155, hsa-miR-181c-5p, hsa-miR-7-1-3p, hsa-miR-708-5p onko-miR'leri bir küme oluşturmaktadır. Bu miRNA'lar, 801 ortak mRNA'yı hedeflemiştir (p<0,05). Literatürde ve miRNA hedef tahmin araçları sisteminde, bu alt küme ilişkisi araştırıldığında, ALL dışındaki kansere bağlı yolaklarda rol oynadıkları görülmüştür. Sonuç: Gizli ilişkiler bulanık yaklaşımlarla tanımlanabilir ve bu yolaklar, miRNA çalışmaları alanında yeni ufuklar açmak için rehberlik sağlaya-bilir.

Anahtar Kelimeler: Bulanık C ortalamalar algoritması; miRNA; çocukluk çağı kanserleri; miRNA hedef tahmin araçları
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