UMR745 INSERM, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de l'Observatoire, Paris, France.
J Natl Cancer Inst. 2011 Nov 16;103(22):1713-22. doi: 10.1093/jnci/djr416. Epub 2011 Oct 27.
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.
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.
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.
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.
神经纤维瘤病 1 型（NF1）是一种肿瘤易感性综合征，全球发病率为每 2500 人中有 1 人。与 NF1 基因座无关的遗传因素被认为会影响 NF1 患者丛状神经纤维瘤（PNF）的数量，但迄今为止尚未确定任何因素。
我们使用组织的高分辨率阵列比较基因组杂交技术，对来自 18 名 NF1 患者的 22 个 PNF 进行分析，以确定参与 PNF 发展的修饰基因。我们使用基于家族的关联测试，对位于 9p21.3 染色体区域的五个先前确定的癌症易感性标记单核苷酸多态性（rs1063192、rs2151280、rs2218220、rs10757257 和 rs7023329）进行了测试，该测试共涉及 306 个家庭的 1105 名受试者（740 名 NF1 患者和 365 名无亲缘关系的亲属）。为了确认 rs2151280 的功能作用，我们使用实时定量逆转录聚合酶链反应分析了 124 名 NF1 患者外周血中细胞周期蛋白依赖性激酶抑制剂 2A（CDKN2A）、CDKN2B、交替阅读框（ARF）和 INK4 基因座（ANRIL）的反义非编码 RNA 的表达。通过 Kruskal-Wallis 检验测试了 CDKN2A、CDKN2B、ARF 和 ANRIL 表达与 rs2151280 基因型之间的关系。所有统计检验均为双侧检验。
在 NF1 相关的 PNF 中，发现 9p21.3 缺失（包括 CDKN2A/B-ANRIL 基因座）是唯一的复发性体细胞改变。单核苷酸多态性 rs2151280（位于 ANRIL 中）与 NF1 患者 PNF 的数量呈统计学显著相关（P <.001）。此外，rs2151280 的等位基因 T 与 ANRIL 转录本水平的降低呈统计学显著相关（P <.001），提示 ANRIL 表达的调节介导了 PNF 的易感性。
将 ANRIL 鉴定为 NF1 的修饰基因可能为 PNF 的分子发病机制提供线索，特别是神经纤维瘤的形成，并强调了长非编码 RNA 在激活肿瘤发展的关键调节剂中的意外作用。
