Inactivation of the CDKN2A Tumor-Suppressor Gene by Deletion or Methylation Is Common at Diagnosis in Follicular Lymphoma and Associated with Poor Clinical Outcome
Inactivation of the CDKN2A Tumor-Suppressor Gene by Deletion or Methylation Is Common at Diagnosis in Follicular Lymphoma and Associated with Poor Clinical Outcome
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DOI：
10.1158/1078-0432.ccr-13-2175
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发表时间：
2014-03-15
影响因子：
11.5
通讯作者：
LeBrun, David P.
中科院分区：
文献类型：
--
作者：
Alhejaily, Abdulmohsen;Day, Andrew G.;LeBrun, David P.
目的：滤泡性淋巴瘤是最常见的惰性淋巴瘤，临床上具有异质性。 CDKN2A 编码肿瘤抑制因子 p16 (INK4a) 和 p14(ARF)，并且经常遭受癌症中的有害改变。我们研究了这样的假设：CDKN2A 的缺失或高甲基化可能会识别具有不同临床或病理特征的滤泡性淋巴瘤病例，可能适合定制的临床管理。实验设计：使用基于单核苷酸多态性的方法或终点 PCR 在治疗前活检标本中检测到 CDKN2A 的缺失，并通过甲基化特异性 PCR 定量 CDKN2A 中 CpG 元件的甲基化。使用标准统计方法对 106 例病例中的 CDKN2A 状态与病理或临床特征（包括总生存期 (OS)）之间的相关性进行了调查。结果：在 111 个样本中的 9 个样本中检测到 CDKN2A 缺失（8%），在 113 个样本中的 22 个样本中检测到甲基化（19%）。 106 例中的 29 例 (27%) 中 CDKN2A 被删除或甲基化，这种状态与 OS 较差相关，尤其是在接受利妥昔单抗治疗的患者中 (P = 0.004)。 CDKN2A 缺失或甲基化与年龄较大 (P = 0.012) 和血红蛋白正常 (P = 0.05) 相关，但与性别、FLIPI 评分、ECOG 分期、LDH、体能状态、受累淋巴结部位数量、B 症状、组织学分级、弥漫性大 B 细胞淋巴瘤成分的存在、增殖指数或其他病理因素无关。 结论：我们的结果表明 CDKN2A 的缺失或甲基化与在治疗前滤泡性淋巴瘤活检标本中相对常见，并且可能基于更具侵袭性的疾病生物学，定义了一组与利妥昔单抗时代生存率降低相关的病例。
Purpose: Follicular lymphoma, the most common indolent lymphoma, is clinically heterogeneous. CDKN2A encodes the tumor suppressors p16 (INK4a) and p14(ARF) and frequently suffers deleterious alterations in cancer. We investigated the hypothesis that deletion or hypermethylation of CDKN2A might identify follicular lymphoma cases with distinct clinical or pathologic features potentially amenable to tailored clinical management.Experimental Design: Deletion of CDKN2A was detected in pretreatment biopsy specimens using a single nucleotide polymorphism-based approach or endpoint PCR, and methylation of CpG elements in CDKN2A was quantified by methylation-specific PCR. Correlations between CDKN2A status and pathologic or clinical characteristics, including overall survival (OS), were investigated in 106 cases using standard statistical methods.Results: Deletion of CDKN2A was detected in 9 of 111 samples (8%) and methylation was detectable in 22 of 113 (19%). CDKN2A was either deleted or methylated in 29 of 106 cases (27%) and this status was associated with inferior OS especially among patients treated with rituximab (P = 0.004). CDKN2A deletion or methylation was associated with more advanced age (P = 0.012) and normal hemoglobin (P = 0.05) but not with sex, FLIPI score, ECOG stage, LDH, performance status, number of involved nodal sites, B symptoms, histologic grade, the presence of a component of diffuse large B-cell lymphoma, proliferation index, or other pathologic factors.Conclusions: Our results show that deletion or methylation of CDKN2A is relatively common in pretreatment follicular lymphoma biopsy specimens and defines a group of cases associated with reduced survival in the rituximab era presumably on the basis of more aggressive disease biology.