文献：Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes

A small pre-defined set of gene expression signatures

epithelial-to-mesenchymal transition (EMT)	上皮细胞向间充质细胞转化
microsatellite instability (MSI)	微卫星不稳定性
cytokine signaling	细胞因子信号
cell proliferation	细胞增殖
DNA methylation	DNA甲基化
TP53 activity	TP53活性
gastric tissue	胃组织

 

经典的分类方法是：Gastric cancer may be subdivided into 3 distinct subtypes—proximal, diffuse, and distal gastric cancer—based on histopathologic and anatomic criteria. Each subtype is associated with unique epidemiology.

我们用主成分分析Principal component anaylsis (PCA)

PC1

PC2

PC3

这三个主成分与上面的七个特征是相关联的。

根据我们的主成分分析，可以把我们的300个GC样本分成如下四组，命名如下：

Gene expression signatures define four molecular subtypes of GC:

MSI (n = 68),

MSS/EMT (n = 46),

MSS/TP53+ (n = 79)

MSS/TP53− (n = 107)

然后用本文的分类方法，测试了另外另个published数据，还是分成四个组

(MSI, MSS/EMT, MSS/TP53+ and MSS/TP53-)

分别是TCGA数据库的；n = 46, n = 62, n = 50 and n = 47.

Singapore的研究; n = 12, n = 85, n = 39 and n = 63 respectively

我们这样的分组可以得到一些规律：

(i) The MSS/EMT subtype occurred at a significantly younger age (P = 3e-2) than did other subtypes. The majority (>80%) of the subjects in this subtype were diagnosed with diffuse-type (P < 1e-4) at stage III/IV(P = 1e-3).

(ii) The MSI subtype occurred predominantly in the antrum (75%), >60% of subjects had the intestinal subtype, and >50% of subjects were diagnosed at an early stage (I/II).

(iii) Epstein-Barr virus (EBV) infection occurred more frequently in the MSS/TP53+ group (n = 12/18, P = 2e-4) than in the other groups.

 

然后我们对我们的300个样本做了生存分析：

预后： MSI  >   MSS/TP53+    >   MSS/TP53 >  MSS/EMT

Next, we validated the survival trend of GC subtypes in three independent cohorts: Samsung Medical Center cohort 2 (SMC-2,n = 277, GSE26253)31,

Singapore  cohort(n = 200, GSE15459)21 and

TCGA gastric cohort (n = 205).

We saw that the GC subtypes showed a significant association with overall survival

结论：我们这样的分类是最合理的，跟各个类别的预后非常相关。

 

然后我们看看突变模式：

the MSI~ hypermutation ~KRAS (23.3%), the PI3K-PTEN-mTOR pathway (42%), ALK (16.3%) and ARID1A (44.2%)18.

We observed enrichment of PIK3CA H1047R mutations in the MSI samples

we saw enrichment of E542K and E545K mutations in MSS tumors

The EMT subtype had a lower number of mutation events when compared to the other MSS groups(P = 1e−3).

The MSS/TP53− subtype showed the highest prevalence of TP53 mutations (60%), with a low frequency of other mutations

the MSS/TP53+ subtype showed a relatively higher prevalence (compared to MSS/TP53−) of mutations in APC, ARID1A, KRAS, PIK3CA and SMAD4.

再看看拷贝数变异情况：

再看看与另外两个研究团队的分类情况的比较

The TCGA study reported expression clusters (subtypes named C1–C4) and genomic subtypes (subtypes named EBV+, MSI, Genome Stable (GS) and Chromosomal Instability (CIN)).

A follow-up study of the Singapore cohort21 described three expression subtypes (Proliferative, Metabolic and Reactive)

However, a consensus on clinically relevant subtypes that encompasses molecular heterogeneity and that can be used in preclinical and clinical research has not been reported.

Here we report the molecular classification of GC linked not only to distinct patterns of genomic alterations, but also to recurrence pattern and prognosis across multiple GC cohorts.

 

 

microsatellite instability

英文简称 : MI
中文全称 : 微卫星不稳定性
所属分类 : 生物科学
词条简介 : 微卫星不稳定性（microsatellite instability,MI）检测是基于VNTR的发现，细胞内基因组含有大量的碱基重复序列，一般将6-7bp的串联重称为小卫星DNA（minisatellite DNA）,又称为VNTR。而将1-4bp的串联重复称为微卫星DNA，又称简单重复序列（simple repeat sequence,SRS）。SRS是一种最常见的重复序列之一，具有丰富的多态性、高度杂合性、重组纺低等优点。最常见的为双核苷酸重复，即（AC）n和（TG）n。研究表胆，在n≥104时，2bp重复序列在人群中呈高度多态性。SRS广泛存在于原核和真核基因组中，约占真核基因组的5％，是近年来快速发展起来的新的DNA多态性标志之一。策卫星稳定性（MI）是指简重复序列的增加或丢失。MI首先在结肠癌中观察到，1993年在HNPCC中观察到多条染色体均有（AC）n重复序列的增加或毛失，以后相继在胃癌、胰腺癌、肺癌、膀胱癌、乳腺癌、前列腺癌及其他肿瘤等也好现存在微卫星不稳定现象，提示MI可能是肿瘤细胞的另一重要分子结果显示 ，MI与肿瘤与发展有关，MI仅在肿瘤细胞中发现，从未在正常组织中检测到。在原发与移肿瘤中，MI均交分布于整个肿瘤。晚期胃癌的MI频率显著高于早期胃癌。