CpG island methylator phenotype-positive tumors in the absence of MLH1 methylation constitute a distinct subset of duodenal adenocarcinomas and are associated with poor prognosis.
CpG island methylator phenotype-positive tumors in the absence of MLH1 methylation constitute a distinct subset of duodenal adenocarcinomas and are associated with poor prognosis.
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DOI：
10.1158/1078-0432.ccr-12-0707
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发表时间：
2012-09-01
期刊：
影响因子：
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通讯作者：
Ahuja N
中科院分区：
文献类型：
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作者：
Fu T;Pappou EP;Guzzetta AA;Jeschke J;Kwak R;Dave P;Hooker CM;Morgan R;Baylin SB;Iacobuzio-Donahue CA;Wolfgang CL;Ahuja N
关于十二指肠腺癌的遗传和表观遗传变化的信息很少。目的是根据微卫星不稳定性 (MSI)、DNA 甲基化、KRAS 和 BRAF 基因突变、临床病理特征和预后来识别十二指肠腺癌的可能亚型。获得了 99 名十二指肠腺癌患者的人口统计数据、肿瘤特征和生存率。对 KRAS 和 BRAF 突变、MSI、MLH1 甲基化和 CpG 岛甲基化表型 (CIMP) 状态进行了测试。建立 Cox 比例风险模型来预测生存率。与 CIMP- 肿瘤相比，在 99 例十二指肠腺癌中有 27 例 (27.3%) 检测到 CIMP+，并且与 MSI (P = 0.011) 和 MLH1 甲基化 (P < 0.001) 相关，但与 KRAS 突变无关 (P = 0.114)。未检测到 BRAF V600E 突变。在 CIMP+ 肿瘤中，15 个（55.6%）为 CIMP+/MLH1 非甲基化（MLH1-U）。 Kaplan-Meier 分析显示，按 CIMP、CIMP/MLH1 甲基化状态或 CIMP/MSI 状态分类的肿瘤可以预测总生存期（OS；分别为 P = 0.047、0.002 和 0.002），而 CIMP/MLH1 甲基化状态还可以预测复发时间（TTR；P = 0.016）。在多变量分析中，CIMP/MLH1 甲基化状态对 OS (P < 0.001) 和 TTR (P = 0.023) 均显示出显着的预后价值。 CIMP+/MLH1-U 肿瘤患者的 OS 和 TTR 最差。我们的结果证明十二指肠腺癌中存在 CIMP。 CIMP+/MLH1-U 的组合似乎与十二指肠腺癌患者的不良预后独立相关。这项研究还表明 BRAF 突变不参与十二指肠肿瘤发生、MSI 或 CIMP 发展。
Little information is available on genetic and epigenetic changes in duodenal adenocarcinomas. The purpose was to identify possible subsets of duodenal adenocarcinomas based on microsatellite instability (MSI), DNA methylation, mutations in the KRAS and BRAF genes, clinicopathologic features, and prognosis. Demographics, tumor characteristics and survival were available for 99 duodenal adenocarcinoma patients. Testing for KRAS and BRAF mutations, MSI, MLH1 methylation and CpG island methylator phenotype (CIMP) status was performed. A Cox proportional hazard model was built to predict survival. CIMP+ was detected in 27 of 99 (27.3%) duodenal adenocarcinomas, and was associated with MSI (P = 0.011) and MLH1 methylation (P < 0.001), but not with KRAS mutations (P = 0.114), as compared to CIMP− tumors. No BRAF V600E mutation was detected. Among the CIMP+ tumors, 15 (55.6%) were CIMP+/MLH1-unmethylated (MLH1-U). Kaplan-Meier analysis showed tumors classified by CIMP, CIMP/MLH1 methylation status or CIMP/MSI status could predict overall survival (OS; P = 0.047, 0.002, and 0.002, respectively), while CIMP/MLH1 methylation status could also predict time-to-recurrence (TTR; P = 0.016). In multivariate analysis, CIMP/MLH1 methylation status showed a significant prognostic value regarding both OS (P < 0.001) and TTR (P = 0.023). Patients with CIMP+/MLH1-U tumors had the worst OS and TTR. Our results demonstrate existence of CIMP in duodenal adenocarcinomas. The combination of CIMP+/MLH1-U appears to be independently associated with poor prognosis in patients with duodenal adenocarcinomas. This study also suggests that BRAF mutations are not involved in duodenal tumorigenesis, MSI or CIMP development.