Comprehensive genomic meta-analysis identifies intra-tumoural stroma as a predictor of survival in patients with gastric cancer

Wu, Yuchen; Grabsch, Heike; Ivanova, Tatiana; Tan, Iain Beehuat; Murray, Jacinta; Ooi, Chia Huey; Wright, Alexander; West, Nicholas P.; Hutchins, Gordon; Wu, Jeanie; Lee, Ming‐Hui; Lee, Julian; Koo, Jun Hao; Yeoh, Khay Guan; Grieken, Nicole C.T. van; Ylstra, Bauke; Rha, Sun Young; Ajani, Jaffer A.; Cheong, Jae Ho; Noh, Sung Hoon; Lim, Kiat Hon; Boussioutas, Alex; Lee, Ju Seog; Tan, Patrick

doi:10.1136/gutjnl-2011-301373

Cited by 144 publications

(128 citation statements)

References 57 publications

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“…It was also reported that gene sets defining poor prognosis in colorectal cancer subtypes were predominantly expressed in CAFs. Furthermore, a recent study demonstrated that tumors with a high stromal gene expression in reality contained a high stromal content in GCs [28]. Thus, the proportion of intratumor stroma may serve as a surrogate marker for stromal gene expression levels that have been validated as an excellent prognostic indicator in numerous studies [28,29], as we demonstrated the prognostic implications of the intratumor stromal proportion in gastric SRC carcinomas in the present study.…”

Section: Discussionsupporting

confidence: 57%

Intratumor stromal proportion predicts aggressive phenotype of gastric signet ring cell carcinomas

et al. 2016

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Objective The aim of this study was to evaluate the prognostic significance of the intratumor stromal proportion in gastric signet ring cell (SRC) carcinomas. Background Cancer stroma, as exemplified by cancer-associated fibroblasts (CAFs), plays critical roles in cancer proliferation, invasion, and metastasis. Methods One hundred seventy-five SRC carcinoma cases were classified according to the intratumor desmoplastic stromal proportion to then analyze the clinicopathologic characteristics of stroma-rich cases. We also investigated the impact of CAFs on the migration as well as on the phenotypic changes of gastric SRC carcinomas in vitro.Furthermore, we performed RNA sequencing of a pair of CAFs and normal-tissue-associated fibroblasts. Results Stroma-rich SRC carcinomas (64 of 175 cases, 36.5%) were associated with female patients (P = 0.045), large tumor size (P = 0.007), higher T category (P \ 0.001), and the presence of perineural invasion (P = 0.018). Patients with stroma-rich SRC carcinomas had a significantly shorter disease-free survival (P \ 0.001) and overall survival (P \ 0.001). However, in a subgroup analysis, the prognostic significance of the stromal proportion correlated only with patients with T3/4 disease. From multivariate analysis, the high stromal proportion is an independent prognostic factor to predict worse disease-free survival (hazard ratio 2.288; P = 0.001) and overall survival (hazard ratio 2.503; P = 0.001). We found that CAFs enhanced the migratory abilities of cancer cells through the epithelial-mesenchymal transition, and RNA sequencing results confirmed these findings. Conclusions The intratumor stromal proportion could be a useful prognostic biomarker and a potential therapeutic target in gastric SRC carcinomas.

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Section: Discussionsupporting

confidence: 57%

Intratumor stromal proportion predicts aggressive phenotype of gastric signet ring cell carcinomas

et al. 2016

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“…We and others have used gene-expression profiling to classify cases according to groups of coexpressed gene signatures (14,16,19). Often, such signatures are associated with histopathological and clinical phenotype, such as drug response, metastatic spread, or overall survival.…”

Section: Resultsmentioning

confidence: 99%

“…Gene signatures derived from gene-expression data have previously been used by us and others to diagnose gastric cancer (36), predict patient prognosis (19,37,38), and distinguish cancer stage and grade (39). Indeed, through our collaborators, we have previously published on a stromal signature derived from a Singapore cohort and validated on a group of Australian samples from our laboratory (19).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, through our collaborators, we have previously published on a stromal signature derived from a Singapore cohort and validated on a group of Australian samples from our laboratory (19). A number of stromal signatures have been described by others in different cancer contexts (30,31,40), which have distinct gene lists.…”

Section: Discussionmentioning

confidence: 99%

“…Gene-expression analysis of a whole tumor is the sum of the mRNA contributions from different cell lineages, driven by cell-autonomous genomic changes as well as non-cellautonomous cell-matrix and cell-cell interactions (17). We previously described a gene-expression signature of coexpressed genes exhibiting increased expression in malignant tissue (16,18,19). More recently, we found a highly related signature in a group of patients with ovarian cancer, which was associated with the poorest survival in the Australian Ovarian Cancer Study (AOCS) cohort (20).…”

Section: Introductionmentioning

confidence: 99%

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A Signature Predicting Poor Prognosis in Gastric and Ovarian Cancer Represents a Coordinated Macrophage and Stromal Response

Busuttil

George

Tothill

et al. 2014

Clinical Cancer Research

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Purpose: Gene-expression profiling has revolutionized the way we think about cancer and confers the ability to observe the synchronous expression of thousands of genes. The use of putative genome-level expression profiles has allowed biologists to observe the complex interactions of genes that constitute recognized biologic pathways. We used gastric and ovarian datasets to identify gene-expression signatures and determine any functional significance.Experimental Design: Microarray data of 94-tumor and 45-benign samples derived from patients with gastric cancer were interrogated using Hierarchical Ordered Partitioning and Collapsing Hybrid analysis identifying clusters of coexpressed genes. Clusters were further characterized with respect to biologic significance, gene ontology, and ability to discriminate between normal and tumor tissue. Tumor tissues were separated into epithelial and stromal compartments and immunohistochemical analysis performed to further elucidate specific cell lineages expressing genes contained in the signature.Results: We identified a "stromal-response" expression signature, highly enriched for inflammatory, extracellular matrix, cytokine, and growth factor proteins. The majority of genes in the signature are expressed in the tumor-associated stroma but were absent in associated premalignant conditions. In gastric cancer, this module almost perfectly differentiates tumor from nonmalignant gastric tissue and hence can be regarded as a highly tumor-specific gene-expression signature.Conclusions: We show that these genes are consistently coexpressed across a range of independent gastric datasets as well as other cancer types suggesting a conserved functional role in cancer. In addition, we show that this signature can be a surrogate marker for M2 macrophage activity and has significant prognostic implications in gastric and ovarian high-grade serous cancer. Clin Cancer Res; 20(10); 2761-72. Ó2014 AACR.

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Identification of a high‐risk subtype of intestinal‐type Japanese gastric cancer by quantitative measurement of the luminal tumor proportion

et al. 2018

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BackgroundWe hypothesized that the relative proportion of tumor (PoT) at the luminal surface can predict gastric cancer (GC) patient survival.MethodsWe measured the luminal PoT in resection specimens from 231 GC patients with stage II/III disease who had surgery at the Kanagawa Cancer Center, Yokohama, Japan. Tissue microarrays were used to assess the extent of immune cell infiltration by CD45 immunohistochemistry. Results were related to histopathological features and patient overall survival (OS).ResultsPoT was significantly lower in diffuse‐type (30%) compared to intestinal‐type GC (41%), P = 0.03. Patients with low PoT intestinal‐type GC survived significantly longer than patients with high PoT intestinal‐type GC (5 years OS: 78% vs 47%, P = 0.0112). Low PoT was an independent favorable prognostic factor in multivariate analysis in intestinal‐type GC. Low PoT was correlated with high content of CD45‐positive immune cells (P = 0.035). There was no relationship between PoT and survival in diffuse‐type GC.ConclusionsThis is the first study to identify a subgroup of patients with stage II/III intestinal‐type GC at high risk of recurrence by measuring PoT at the luminal surface. The relationship between PoT and immune cell content provides an initial insight into potential underlying biological mechanisms.

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Comprehensive genomic meta-analysis identifies intra-tumoural stroma as a predictor of survival in patients with gastric cancer

Cited by 144 publications

References 57 publications

Intratumor stromal proportion predicts aggressive phenotype of gastric signet ring cell carcinomas

Intratumor stromal proportion predicts aggressive phenotype of gastric signet ring cell carcinomas

A Signature Predicting Poor Prognosis in Gastric and Ovarian Cancer Represents a Coordinated Macrophage and Stromal Response

Identification of a high‐risk subtype of intestinal‐type Japanese gastric cancer by quantitative measurement of the luminal tumor proportion

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