Role of Noncoding RNA ANRIL in Genesis of Plexiform Neurofibromas in Neurofibromatosis Type 1

• Published in: JNCI : Journal of the National Cancer Institute 2011-11, Vol.103 (22), p.1713-1722
• Main Authors: Pasmant, Eric, Sabbagh, Audrey, Masliah-Planchon, Julien, Ortonne, Nicolas, Laurendeau, Ingrid, Melin, Lucie, Ferkal, Salah, Hernandez, Lucie, Leroy, Karen, Valeyrie-Allanore, Laurence, Parfait, Béatrice, Vidaud, Dominique, Bièche, Ivan, Lantieri, Laurent, Wolkenstein, Pierre, Vidaud, Michel
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biological and medical sciences; Chromosome Deletion; Chromosomes, Human, Pair 9; Cohort Studies; Comparative Genomic Hybridization; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Female; France; Gene Deletion; Gene Expression Regulation, Neoplastic; Gene Frequency; Genes; Genetic Predisposition to Disease; Genetic research; Genome-Wide Association Study; Genotype; Humans; Linkage Disequilibrium; Male; Medical sciences; Middle Aged; Neurofibroma, Plexiform - genetics; Neurofibromatosis 1 - genetics; Neurology; Oncology; Phenotype; Polymorphism, Single Nucleotide; Reverse Transcriptase Polymerase Chain Reaction; RNA, Long Noncoding; RNA, Messenger - metabolism; RNA, Untranslated - genetics; RNA, Untranslated - metabolism; Tumors; Tumors of the nervous system. Phacomatoses
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djr416

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.