Gastric cancer with high-level microsatellite instability: target gene mutations, clinicopathologic features, and long-term survival
Gastric cancer with high-level microsatellite instability: target gene mutations, clinicopathologic features, and long-term survival
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DOI：
10.1016/j.humpath.2007.10.024
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发表时间：
2008-06-01
期刊：
影响因子：
3.3
通讯作者：
Ottini, Laura
中科院分区：
文献类型：
--
作者：
Falchetti, Mario;Saieva, Calogero;Ottini, Laura
胃癌是全球癌症死亡的主要原因之一，尽管西方国家的发病率有所下降，但意大利存在特定的高危地区。具有高水平微卫星不稳定性的胃癌(MST-H)是一种定义明确的肿瘤亚群，具有独特的临床病理特征。我们研究了来自托斯卡纳(意大利中部)高危人群的159例胃癌患者的临床病理相关性和长期存活率。MSI-H与肿瘤的胃窦位置(P=.001)、Lauren分类的肠型(P=.002)、明氏分类的膨胀型(P=.0001)、日本胃癌研究会的粘液组织学类型(P=.002)相关。此外，免疫组织化学显示，MSI-H与较高的15年生存率(P=.01)和hMLH1表达缺失(P=.001)密切相关。多变量分析显示，hMLH1反应性缺失与肿瘤类型扩大之间存在显著关联(P=0.002)。我们还通过分析靶基因中的编码重复序列来研究与MSI-H相关的基因变化，这些靶基因涉及控制细胞生长(转化生长因子βRII、IGFIIR、RIZ、TCF4、DP2)、细胞凋亡(Bax、Bcl10、Fas、CASPase 5、APAF1)和DNA修复基因(hMSH6、hMSH3、Medi、Rad50、BLm、ATR、BRCA2、Mre11)的途径。发现携带MSI-H的胃癌患者存在杂合性突变，影响多个分子通路和每个通路中的多个基因。有趣的是，在这个亚组中，TGFPRII突变似乎与BLM突变呈负相关(P=.006)，而Rad50突变携带者显示存活率显著降低(P=.03)。(C)2008 Elsevier Inc.保留所有权利。
Gastric cancer is one of the leading causes of cancer death worldwide, and although the incidence has decreased in Western countries, specific high-risk areas are present in Italy. Gastric cancer with high-level microsatellite instability (MST-H) represents a well-defined subset of carcinomas showing distinctive clinicopathologic features. We examined clinicopathologic associations and long-term survival in a series of 159 gastric cancer cases from a high-risk population in Tuscany (central Italy). MSI-H was associated with antral location of the tumor (P = .001), intestinal type according to Lauren classification (P = .002), expanding type according to Ming classification (P = .0001), and mucinous histologic type according to the Japanese Research Society for Gastric Cancer classification (P = .002). In addition, MSI-H was strongly associated with a higher survival at 15 years (P = .01) and with loss of hMLH1 expression, evaluated by immunohistochemistry (P = .001). Multivariate analyses showed a significant association between the absence of hMLH1 reactivity and the expanding tumor type (P = .002). We also investigated the MSI-H-related genetic changes by analyzing coding repeats within target genes involved in pathways that control cell growth (TGF beta RII, IGFIIR, RIZ, TCF4, DP2), apoptosis (BAX, BCL10, FAS, CASPASE5, APAF1), and DNA repair genes (hMSH6, hMSH3, MEDI, RAD50, BLM, ATR, BRCA2, MRE11). Gastric cancer cases with MSI-H were found to accumulate heterozygous mutations affecting multiple molecular pathways and multiple genes within each pathway. Intriguingly, in this subset, TGFPRII mutations appeared to be inversely related to BLM mutations (P = .006), whereas RAD50 mutation carriers showed significantly reduced survival (P = .03). (C) 2008 Elsevier Inc. All rights reserved.