Acquired TNFRSF14 Mutations in Follicular Lymphoma Are Associated with Worse Prognosis
Acquired TNFRSF14 Mutations in Follicular Lymphoma Are Associated with Worse Prognosis
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DOI：
10.1158/0008-5472.can-10-2460
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发表时间：
2010-11-15
期刊：
影响因子：
11.2
通讯作者：
Horsman, Douglas E.
中科院分区：
文献类型：
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作者：
Cheung, K-John J.;Johnson, Nathalie A.;Horsman, Douglas E.
临床相关研究表明 1p36 缺失与滤泡性淋巴瘤 (FL) 的预后较差有关。在这项研究中，我们试图找出该区域中导致不良预后的关键基因。 BAC 阵列技术应用于 141 个 FL 样本，在其中 20% 的病例中检测到 1p36.32 内有类似 97 kb 的最小缺失区域 (MRD)。在该区域还发现了频繁的单核苷酸多态性检测到的杂合性拷贝中性丢失。 MRD 中启动子 CpG 的分析并未揭示 1p36 状态不同的样品中 DNA 甲基化的差异模式。 MRD 基因的外显子测序发现，11 名选定病例中有 3 名与正常 DNA 相匹配，其中 TNFRSF14 基因发生体细胞改变。由 251 个样本组成的扩展队列鉴定出 46 例 (18.3%) 存在影响 TNFRSF14 的非同义突变。在接受利妥昔单抗治疗的患者中，总生存期 (OS) 和疾病特异性生存期 (DSS) 与 TNFRSF14 突变的存在相关。我们进一步表明，在调整国际预后指数后，淋巴瘤同时含有 TNFRSF14 突变和 1p36 缺失的患者中，较差的 OS 和 DSS 最明显[风险比为 3.65（95% 置信区间，1.35-9.878，P = 0.011）和 3.19（95% 置信区间，1.06-9.57，P = 0.039），分别]。基于获得性突变的频繁发生及其与较差临床结果的相关性，我们的研究结果将 TNFRSF14 确定为与 FL 子集相关的候选基因。癌症研究； 70(22)； 9166-74。 (C) 2010 AACR。
Clinical correlative studies have linked 1p36 deletions with worse prognosis in follicular lymphoma (FL). In this study, we sought to identify the critical gene(s) in this region that is responsible for conferring inferior prognosis. BAC array technology applied to 141 FL specimens detected a minimum region of deletion (MRD) of similar to 97 kb within 1p36.32 in 20% of these cases. Frequent single-nucleotide polymorphism-detected copy-neutral loss of heterozygosity was also found in this region. Analysis of promoter CpGs in the MRD did not reveal differential patterns of DNA methylation in samples that differed in 1p36 status. Exon sequencing of MRD genes identified somatic alterations in the TNFRSF14 gene in 3 of 11 selected cases with matching normal DNA. An expanded cohort consisting of 251 specimens identified 46 cases (18.3%) with nonsynonymous mutations affecting TNFRSF14. Overall survival (OS) and disease-specific survival (DSS) were associated with the presence of TNFRSF14 mutation in patients whose overall treatment included rituximab. We further showed that inferior OS and DSS were most pronounced in patients whose lymphomas contained both TNFRSF14 mutations and 1p36 deletions after adjustment for the International Prognostic Index [hazard ratios of 3.65 (95% confidence interval, 1.35-9.878, P = 0.011) and 3.19 (95% confidence interval, 1.06-9.57, P = 0.039), respectively]. Our findings identify TNFRSF14 as a candidate gene associated with a subset of FL, based on frequent occurrence of acquired mutations and their correlation with inferior clinical outcomes. Cancer Res; 70(22); 9166-74. (C) 2010 AACR.