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首页> 外文期刊>BMC Medical Genomics >Genetic lineages of undifferentiated-type gastric carcinomas analysed by unsupervised clustering of genomic DNA microarray data
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Genetic lineages of undifferentiated-type gastric carcinomas analysed by unsupervised clustering of genomic DNA microarray data

机译：基因组DNA微阵列数据的无监督聚类分析未分化型胃癌的遗传谱系

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Background It is suspected that early gastric carcinoma (GC) is a dormant variant that rarely progresses to advanced GC. We demonstrated that the dormant and aggressive variants of tubular adenocarcinomas (TUBs) of the stomach are characterized by loss of MYC and gain of TP53 and gain of MYC and/or loss of TP53 , respectively. The aim of this study is to determine whether this is also the case in undifferentiated-type GCs (UGCs) of different genetic lineages: one with a layered structure (LS+), derived from early signet ring cell carcinomas (SIGs), and the other, mostly poorly differentiated adenocarcinomas, without LS but with a minor tubular component (TC), dedifferentiated from TUBs (LS?/TC+). Methods Using 29 surgically resected stomachs with 9 intramucosal and 20 invasive UGCs (11 LS+?and 9 LS?/TC+), 63 genomic DNA samples of mucosal and invasive parts and corresponding reference DNAs were prepared from formalin-fixed, paraffin-embedded tissues with laser microdissection, and were subjected to array-based comparative genomic hybridization (aCGH), using 60K microarrays, and subsequent unsupervised, hierarchical clustering. Of 979 cancer-related genes assessed, we selected genes with mean copy numbers significantly different between the two major clusters. Results Based on similarity in genomic copy-number profile, the 63 samples were classified into two major clusters. Clusters A and B, which were rich in LS+?UGC and LS?/TC+?UGC, respectively, were discriminated on the basis of 40 genes. The aggressive pattern was more frequently detected in LS?/TC+?UGCs, (20/26; 77%), than in LS+UGCs (17/37; 46%; P?=?0.0195), whereas no dormant pattern was detected in any of the UGC samples. Conclusions In contrast to TUBs, copy number alterations of MYC and TP53 exhibited an aggressive pattern in LS+?SIG at early and advanced stages, indicating that early LS+?UGCs inevitably progress to an advanced GC. Cluster B (enriched in LS?/TC+) exhibited more frequent gain of driver genes and a more frequent aggressive pattern than cluster A, suggesting potentially worse prognosis in UGCs of cluster B.
机译：背景技术怀疑早期胃癌（GC）是一种休眠变体，很少进展为晚期GC。我们证明胃的管状腺癌（TUBs）的休眠和侵略性变体的特征分别是MYC和TP53的增加以及MYC和/或TP53的减少。这项研究的目的是确定在不同遗传谱系的未分化型GC（UGC）中是否也是如此：一种具有分层结构（LS +），源自早期的印戒细胞癌（SIG），另一种，大多数为低分化腺癌，无LS但有少量肾小管成分（TC），与TUBs（LS？/ TC +）脱分化。方法使用29个经手术切除的胃，9个黏膜内UGC和20个浸润性UGC（11个LS +α和9个LSα/ TC +），从福尔马林固定，石蜡包埋的组织中提取63个黏膜和浸润部位的基因组DNA样本和相应的参考DNA。激光显微切割，并使用60K微阵列进行基于阵列的比较基因组杂交（aCGH），以及随后的无监督分级聚类。在评估的979个与癌症相关的基因中，我们选择了两个主要簇之间平均拷贝数显着不同的基因。结果根据基因组拷贝数图谱的相似性，将63个样品分为两个主要类群。基于40个基因区分出分别富含LS +ΔUGC和LSα/ TC +ΔUGC的簇A和B。在LSα/ TC +ΔUGC中（20/26; 77％）比在LS + UGC（17/37; 46％; P？=？0.0195）中更频繁地检测到侵略性模式，而未检测到休眠模式在任何教资会样本中。结论与TUBs相比，MYC和TP53的拷贝数变化在早期和晚期在LS +？SIG中表现出攻击性模式，这表明早期LS +？UGCs不可避免地会发展为高级GC。与簇A相比，簇B（富含LSα/ TC +）显示出更频繁的驱动基因获得和更频繁的侵袭性模式，提示簇B的UGC预后可能更差。

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