Association of ANRIL Polymorphism With Overall Survival in Adult Patients With Hematologic Malignancies After Allogeneic Hematopoietic Stem Cell Transplantation

Background/Aim: Genetic variations of the non-coding RNA gene, ANRIL, have been associated with human diseases including cancer, type-2 diabetes, and atherosclerosis. In the present study, we investigated the potential associations of select ANRIL single nucleotide polymorphisms (SNPs) with overall survival and other clinical outcomes in adult patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients and Methods: Genomic DNA was extracted from whole blood samples from 103 adult patients with hematologic malignancies who had received allo-HSCT followed by oral tacrolimus therapy. The genotypes of four select ANRIL SNPs, rs564398, rs1063192, rs2151280, and rs2157719 were determined using qRT-PCR-based genotyping assays. Results: rs2151280 (C->T) in ANRIL was associated with worse overall survival in these patients (CT/CC vs. TT). Contrarily, rs2151280 and the other select ANRIL SNPs were not associated with death at Day-100 after transplantation, the incidence of graft-versus-host disease (GVHD), acute kidney injury (AKI), and neurotoxicity in the study cohort. Conclusion: rs2151280 represents a potential prognostic biomarker for overall survival in adult patients with hematologic malignancies after allo-HSCT.

[1]  Vignesh Kumar,et al.  Comorbidities and its relation to performance status and estimated survival rate among cancer patients , 2019, Journal of Research in Pharmacy.

[2]  C. Hofmeister,et al.  Polymorphism in ANRIL is associated with relapse in patients with multiple myeloma after autologous stem cell transplant , 2017, Molecular carcinogenesis.

[3]  S. Vacher,et al.  Expression of ANRIL–Polycomb Complexes–CDKN2A/B/ARF Genes in Breast Tumors: Identification of a Two-Gene (EZH2/CBX7) Signature with Independent Prognostic Value , 2016, Molecular Cancer Research.

[4]  Y. Kotake,et al.  Transcriptional Regulation of the p16 Tumor Suppressor Gene. , 2015, Anticancer research.

[5]  Z. Gu,et al.  Increased expression of the long non-coding RNA ANRIL promotes lung cancer cell metastasis and correlates with poor prognosis , 2015, Diagnostic Pathology.

[6]  Jianxin Shi,et al.  Genetic polymorphisms in the 9p21 region associated with risk of multiple cancers. , 2014, Carcinogenesis.

[7]  J. Weber,et al.  ARF tumor suppression in the nucleolus. , 2014, Biochimica et biophysica acta.

[8]  G. Peng,et al.  Long non-coding RNA ANRIL (CDKN2B-AS) is induced by the ATM-E2F1 signaling pathway. , 2013, Cellular signalling.

[9]  Ahmed Sadeque,et al.  Association of ANRIL polymorphism (rs1333049:C>G) with myocardial infarction and its pharmacogenomic role in hypercholesterolemia. , 2013, Gene.

[10]  C. Sherr.  Ink4‐Arf locus in cancer and aging , 2012, Wiley interdisciplinary reviews. Developmental biology.

[11]  G. Gaetano,et al.  Type 2 diabetes and polymorphisms on chromosome 9p21: a meta-analysis. , 2012, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[12]  T. Katsuya,et al.  Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B. , 2012, Atherosclerosis.

[13]  I. Bièche,et al.  Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1. , 2011, Journal of the National Cancer Institute.

[14]  Ming-Ming Zhou,et al.  Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression. , 2011, Cancer research.

[15]  D. Girelli,et al.  A polymorphism in the chromosome 9p21 ANRIL locus is associated to Philadelphia positive acute lymphoblastic leukemia. , 2011, Leukemia research.

[16]  Ming-Daw Tsai,et al.  Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer. , 2011, Biochemistry.

[17]  I. Bièche,et al.  ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  William R. Jeck,et al.  Expression of Linear and Novel Circular Forms of an INK4/ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk , 2010, PLoS genetics.

[19]  Deborah Hughes,et al.  Genome-wide association study identifies five new breast cancer susceptibility loci , 2010, Nature Genetics.

[20]  Bernard Keavney,et al.  Chromosome 9p21 SNPs Associated with Multiple Disease Phenotypes Correlate with ANRIL Expression , 2010, PLoS genetics.

[21]  D. Gudbjartsson,et al.  New common variants affecting susceptibility to basal cell carcinoma , 2009, Nature Genetics.

[22]  Karen L. Mohlke,et al.  INK4/ARF Transcript Expression Is Associated with Chromosome 9p21 Variants Linked to Atherosclerosis , 2009, PloS one.

[23]  I. Bièche,et al.  Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. , 2007, Cancer research.

[24]  N. Sharpless,et al.  The Regulation of INK4/ARF in Cancer and Aging , 2006, Cell.

[25]  G. Peters,et al.  Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all , 2006, Nature Reviews Molecular Cell Biology.

[26]  M. Barbacid,et al.  Cyclin D-dependent kinases, INK4 inhibitors and cancer. , 2002, Biochimica et biophysica acta.

[27]  Robert Gray,et al.  A Proportional Hazards Model for the Subdistribution of a Competing Risk , 1999 .

[28]  H. Drexler.  Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia–lymphoma cells , 1998, Leukemia.

[29]  Y. Yazaki,et al.  Recent progress in molecular mechanisms of leukemogenesis: the cyclin-dependent kinase 4-inhibitor gene in human leukemias. , 1997, Leukemia.

[30]  P. Grambsch,et al.  Proportional hazards tests and diagnostics based on weighted residuals , 1994 .