Evidence for an age-related influence of microsatellite instability on colorectal cancer survival
Evidence for an age-related influence of microsatellite instability on colorectal cancer survival
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DOI：
10.1002/ijc.10264
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发表时间：
2002-04-20
影响因子：
6.4
通讯作者：
Dunlop, MG
中科院分区：
文献类型：
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作者：
Farrington, SM;McKinley, AJ;Dunlop, MG
众所周知，与微卫星稳定 (MSS) 肿瘤相比，微卫星不稳定性 (MSI) 是有缺陷的 DNA 错配修复 (MMR) 的标志，与结直肠癌的延长生存期相关。散发性结直肠肿瘤中的 MSI 主要是由于 MLH1 的表观遗传沉默所致。然而，目前还没有针对患有种系 MMR 基因突变的癌症患者的生存情况进行前瞻性人群研究。尽管 MSI 在 HNPCC 家族成员的肿瘤中几乎普遍存在，但确定和其他偏差可能会产生潜在的混杂效应，这可以解释 HNPCC 家族中明显的生存获益。解决种系 MMR 基因突变是否影响生存很重要，因为它可能会破坏突变携带者监测的基本原理。在这里，我们报告了一项在临床病理变量背景下 MSI 对癌症患者队列（诊断时年龄 < 30 岁，n = 118；非年龄选择，n = 181）生存影响的调查。肿瘤 MSI 状态对生存有显着的年龄相关影响。在患有肿瘤 MSI 的年轻患者中，65% 的 MSI 肿瘤患者存在种系 MSH2 或 MLH1 突变。研究了该队列的临床病理学变量和肿瘤 MSI 的生存情况，并与对照组进行比较。与老年病例相比，年轻患者的 MSI 肿瘤过多（p < 0.000001）、粘液性肿瘤（p < 0.01）、晚期疾病（p 与 0.001 相似）且 5 年生存率较差。 Cox比例风险分析将Dukes的分期、诊断年龄和治疗日历年确定为生存的独立预测因子。尽管我们证实了之前的观察结果，即 MSI 与晚发队列中更好的预后相关，但肿瘤 MSI 与年轻患者的生存率之间没有可检测到的关联。这些发现强调了监测和早期识别 MMR 基因携带者肿瘤的基本原理，并加深了对 MSI 对癌症进展影响的理解。 (C) 2002 年威利-利斯。公司
It is well established that microsatellite instability (MSI), the hallmark of defective DNA mismatch repair (MMR), is associated with prolonged survival in colorectal cancer compared with tumours that are microsatellite stable (MSS). MSI in sporadic colorectal tumours is primarily due to epigenetic silencing of MLH1. However, there are no prospective population-based studies of survival in patients with germline MMR gene mutations who develop cancer. Although MSI is almost universal in tumours from HNPCC family members, there is a potential confounding effect of ascertainment and other biases that could explain the apparent survival benefit in HNPCC families. Resolving whether germline MMR gene mutations impact on survival is important because it potentially undermines the rationale for surveillance of mutation carriers. Here, we report an investigation of the influence of MSI on survival in cohorts of cancer patients (aged < 30 years at diagnosis, n = 118; non-age-selected, n = 181) in the context of clinicopathologic variables. There was a substantial age-related influence of tumour MSI status on survival. In young patients with tumour MSI, 65% of patients with MSI tumours had germline MSH2 or MLH1 mutations. Clinicopathologic variables and tumour MSI of the cohort were studied with respect to survival and compared with control groups. Young patients had excess MSI tumours (p < 0.000001), mucinous tumours (p < 0.01), advanced disease (p similar to 0.001) and poorer 5-year survival compared with older cases. Cox proportional hazard analysis identified Dukes' stage, age at diagnosis and calendar year of treatment as independent predictors of survival. There was no detectable association between tumour MSI and survival in young patients, although we confirmed previous observations that MSI is associated with better prognosis in later onset cohorts. These findings underscore the rationale for surveillance and early identification of tumours in MMR gene carriers as well as refining understanding of the influence of MSI on cancer progression. (C) 2002 Wiley-Liss. Inc.