Pan-Cancer Study on Variants of Canonical miRNA Biogenesis Pathway Components: A Pooled Analysis
by
, ,
Rami M. Elshazli
1,†
,
Eman A. Toraih
2,3,*,†
,
Mohammad H. Hussein
2,
Emmanuelle M. Ruiz
4,
Emad Kandil
2 and
Manal S. Fawzy
5,6
1
Department of Biochemistry and Molecular Genetics, Faculty of Physical Therapy, Horus University–Egypt, New Damietta 34517, Egypt
2
Endocrine and Oncology Division, Department of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
3
Medical Genetics Unit, Department of Histology and Cell Biology, Suez Canal University, Ismailia 41522, Egypt
4
Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
5
Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
6
Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar 1321, Saudi Arabia
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2023, 15(2), 338; https://doi.org/10.3390/cancers15020338
Submission received: 25 October 2022
/
Revised: 23 December 2022
/
Accepted: 3 January 2023
/
Published: 4 January 2023
(This article belongs to the Collection miRNAs: New Insights in Tumor Biology)
Simple Summary
Previous relations between microRNA machinery gene variants and human cancer risk have not reach the required statistical power. For the first time, the authors pooled data from 33 studies in “The Cancer Genome Atlas” database that cover 8176 pan-cancer samples which yielded 22 eligible variants within 11 genes subjected to further testing under different genetic association models, Cox regression, and trail sequential analyses. The potential roles of miRNA biogenesis genes in cancer development and prognosis have been concluded.
Abstract
Single nucleotide polymorphisms in genes involved in microRNA processing/maturation and release may deregulate the microRNAome expression levels. We aimed to assess the relationship between miRNA machinery genetic variants and human cancer risk using integrative bioinformatics analyses to identify the role of these genes in cancer aggressiveness. Mutations of 8176 pan-cancer samples were retrieved from 33 studies in “TCGA” database, and a Cox regression model for survival was performed. Next, 22 computationally identified variants within 11 genes were selected based on their high citation rate and MAF. Relevant articles through March 2020 were included. Pooled estimates under the five genetic association models were calculated. Publication bias and heterogeneity between articles were evaluated. Trial Sequential Analysis (TSA) was applied to assess the power and reliability of the draw conclusions. TCGA patients with different cancer types revealed significant alterations in miRNA machinery genes, with mutation frequency ranging from 0.6–13% of samples. RAN was associated with LN metastasis, while TARBP2 and PIWIL1 gene mutations exhibited better overall survival. In the meta-analysis, 45 articles (74,593 cases and 89,198 controls) met the eligibility criteria. Pooled analysis revealed an increased cancer risk with DROSHArs10719*G, RANrs3803012*G, DGCR8rs417309*A, and GEMIN3rs197414*A. In contrast, both DICER1rs1057035*T and GEMIN4rs2743048*G conferred protection against developing cancer. TSA showed the cumulative evidence is inadequate, and the addition of further primary studies is necessary. This study suggests a potential role of miRNA biogenesis genes in cancer development/prognosis. Further functional studies may reveal biological explanations for the differential risks of the machinery variants in different cancer types.
Keywords:
machinery genes; non-coding RNA; malignancy; polymorphisms
