Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1 - PubMed (original) (raw)
. 2011 Nov 16;103(22):1713-22.
doi: 10.1093/jnci/djr416. Epub 2011 Oct 27.
Audrey Sabbagh, Julien Masliah-Planchon, Nicolas Ortonne, Ingrid Laurendeau, Lucie Melin, Salah Ferkal, Lucie Hernandez, Karen Leroy, Laurence Valeyrie-Allanore, Béatrice Parfait, Dominique Vidaud, Ivan Bièche, Laurent Lantieri, Pierre Wolkenstein, Michel Vidaud; NF France Network
Collaborators, Affiliations
- PMID: 22034633
- DOI: 10.1093/jnci/djr416
Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1
Eric Pasmant et al. J Natl Cancer Inst. 2011.
Abstract
Background: Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome with a worldwide birth incidence of one in 2500. Genetic factors unrelated to the NF1 locus are thought to influence the number of plexiform neurofibromas (PNFs) in patients with NF1, but no factors have been identified to date.
Methods: We used high-resolution array comparative genomic hybridization of tissue from 22 PNFs obtained from 18 NF1 patients to identify modifier genes involved in PNF development. We used a family-based association test for five previously identified cancer-susceptibility tag single-nucleotide polymorphisms (rs1063192, rs2151280, rs2218220, rs10757257, and rs7023329) located in chromosomal region 9p21.3 in 1105 subjects (740 NF1 patients and 365 non-affected relatives) from 306 families. To confirm the functional role of rs2151280, we used real-time quantitative reverse transcription-polymerase chain reaction to analyze the expression of cyclin-dependent kinase inhibitor 2A (CDKN2A), CDKN2B, alternate reading frame (ARF), and antisense noncoding RNA in the INK4 locus (ANRIL) in the peripheral blood of 124 NF1 patients. Relationships between CDKN2A, CDKN2B, ARF, and ANRIL expression and the rs2151280 genotype were tested by the Kruskal-Wallis test. All statistical tests were two-sided.
Results: In NF1-associated PNFs, 9p21.3 deletions (including the CDKN2A/B-ANRIL locus) were found as the only recurrent somatic alterations. Single-nucleotide polymorphism rs2151280 (located in ANRIL) was statistically significantly associated with the number of PNFs (P < .001) in NF1 patients. In addition, allele T of rs2151280 was statistically significantly associated with reduced ANRIL transcript levels (P < .001), suggesting that modulation of ANRIL expression mediates PNF susceptibility.
Conclusion: Identification of ANRIL as a modifier gene in NF1 may offer clues to the molecular pathogenesis of PNFs, particularly neurofibroma formation, and emphasizes the unanticipated role of large noncoding RNA in activation of critical regulators of tumor development.
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