Oncogenic pathway combinations predict clinical prognosis in gastric cancer.
Oncogenic pathway combinations predict clinical prognosis in gastric cancer.
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DOI：
10.1371/journal.pgen.1000676
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发表时间：
2009-10
期刊：
影响因子：
4.5
通讯作者：
Tan P
中科院分区：
文献类型：
--
作者：
Ooi CH;Ivanova T;Wu J;Lee M;Tan IB;Tao J;Ward L;Koo JH;Gopalakrishnan V;Zhu Y;Cheng LL;Lee J;Rha SY;Chung HC;Ganesan K;So J;Soo KC;Lim D;Chan WH;Wong WK;Bowtell D;Yeoh KG;Grabsch H;Boussioutas A;Tan P
已知许多实体癌在其不同致癌途径的失调中表现出高度异质性。我们试图确定胃癌（GC）中与患者生存率有显著关系的主要致癌途径。利用基因表达特征，我们设计了一种计算机策略来绘制301例原发性胃癌（全球癌症死亡率的第二高原因）中致癌途径激活的模式。我们确定了三种致癌途径（增殖/干细胞、NF-κB和Wnt/β-连环蛋白）在大多数（>70%）胃癌中失调。我们在一组胃癌细胞系中功能性地验证了这些通路预测。通过致癌通路组合对患者进行分层，在多个队列中显示出可重复的显著生存差异，表明通路相互作用可能在影响疾病行为方面发挥重要作用。单个GC可以通过致癌途径活性成功地分类为生物学和临床相关亚组。因此，通过表达特征预测途径活性允许以目前其他平台无法实现的规模研究原发性癌症中同时相互作用的多种癌症相关途径。胃癌是全球癌症死亡率的第二大原因。根据目前的治疗方法，只有不到四分之一的患者在手术后存活超过五年。个体胃癌的细胞特征和对标准化疗药物的反应高度不同，使得胃癌成为一种复杂的疾病。基于途径的方法，而不是单基因研究，可能有助于解开这种复杂性。在这里，我们利用计算方法来确定分子途径和癌症特征之间的联系。在一项超过300名患者的大规模研究中，我们确定了胃癌的亚组，这些亚组可通过其驱动分子途径的模式进行区分。我们发现，这些确定的亚组在预测生存期方面具有临床相关性，并可能有助于指导设计用于干扰这些分子途径的靶向治疗的选择。我们还确定了反映这些通路亚组的特定胃癌细胞系，这将有助于临床前评估每个亚组对靶向治疗的反应。
Many solid cancers are known to exhibit a high degree of heterogeneity in their deregulation of different oncogenic pathways. We sought to identify major oncogenic pathways in gastric cancer (GC) with significant relationships to patient survival. Using gene expression signatures, we devised an in silico strategy to map patterns of oncogenic pathway activation in 301 primary gastric cancers, the second highest cause of global cancer mortality. We identified three oncogenic pathways (proliferation/stem cell, NF-κB, and Wnt/β-catenin) deregulated in the majority (>70%) of gastric cancers. We functionally validated these pathway predictions in a panel of gastric cancer cell lines. Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior. Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Predicting pathway activity by expression signatures thus permits the study of multiple cancer-related pathways interacting simultaneously in primary cancers, at a scale not currently achievable by other platforms. Gastric cancer is the second leading cause of global cancer mortality. With current treatments, less than a quarter of patients survive longer than five years after surgery. Individual gastric cancers are highly disparate in their cellular characteristics and responses to standard chemotherapeutic drugs, making gastric cancer a complex disease. Pathway based approaches, rather than single gene studies, may help to unravel this complexity. Here, we make use of a computational approach to identify connections between molecular pathways and cancer profiles. In a large scale study of more than 300 patients, we identified subgroups of gastric cancers distinguishable by their patterns of driving molecular pathways. We show that these identified subgroups are clinically relevant in predicting survival duration and may prove useful in guiding the choice of targeted therapies designed to interfere with these molecular pathways. We also identified specific gastric cancer cell lines mirroring these pathway subgroups, which should facilitate the pre-clinical assessment of responses to targeted therapies in each subgroup.
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DOI：
10.1111/j.1349-7006.2001.tb02153.x
发表时间：
2001-12
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Choi JH;Kwon HJ;Yoon BI;Kim JH;Han SU;Joo HJ;Kim DY
通讯作者：
Kim DY
炎症引起的白细胞跨淋巴管内皮迁移的机制。
影响因子：
15.3
作者：
Johnson, Louise A;Clasper, Steven;Holt, Andrew P;Lalor, Patricia F;Baban, Dilair;Jackson, David G
通讯作者：
Jackson, David G
影响因子：
8.8
作者：
Klein Kranenbarg E;Hermans J;van Krieken JH;van de Velde CJ
通讯作者：
van de Velde CJ
影响因子：
8
作者：
Hinata, K;Gervin, AM;Khavari, PA
通讯作者：
Khavari, PA
影响因子：
11.2
作者：
Ganesan, Kumaresan;Ivanova, Tatiana;Tan, Patrick
通讯作者：
Tan, Patrick