Next Article in Journal
Management and Outcomes in Anal Canal Adenocarcinomas—A Systematic Review
Previous Article in Journal
Peripheral Blood Biomarkers Predictive of Efficacy Outcome and Immune-Related Adverse Events in Advanced Gastrointestinal Cancers Treated with Checkpoint Inhibitors
Previous Article in Special Issue
Impact of Tumor Localization and Molecular Subtypes on the Prognostic and Predictive Significance of p53 Expression in Gastric Cancer
 
 
Article

Consensus Molecular Subtypes Efficiently Classify Gastric Adenocarcinomas and Predict the Response to Anti-PD-1 Immunotherapy

1
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350122, China
2
Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou 350122, China
3
Department of Pathology, Zhongshan Hospital, Xiamen University, Xiamen 361004, China
4
Department of Gastroenterology and Hepatology, Augusta University, Augusta, GA 30912, USA
5
Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
*
Author to whom correspondence should be addressed.
Academic Editor: Jeffrey A. Norton
Cancers 2022, 14(15), 3740; https://doi.org/10.3390/cancers14153740
Received: 18 May 2022 / Revised: 14 July 2022 / Accepted: 29 July 2022 / Published: 31 July 2022
(This article belongs to the Special Issue Molecular Mechanisms of Gastric Cancer Development)
Gastric adenocarcinoma (GAC) is most commonly classified based on a system developed by the Cancer Genome Atlas in 2014. However, this subtyping system cannot efficiently identify suitable candidates for immunotherapy. Because GAC is highly heterogeneous and closely related to CRC at the molecular and functional levels, we explored the clinical utility of CMS classification originally developed for CRC and found that the CMS subtyping system can efficiently classify GAC. CMS1-4 classifications in GAC recapitulated their corresponding CRC subtype characteristics. Notably, CMS1 predicted a favorable response to anti-PD-1 therapy, and CMS4 outperformed the classical TCGA subtyping prognostic prediction and identified patients with an unfavorable anti-PD-1 response. Strikingly, partitioning the CMS4 subtype by EMT activation identified an additional anti-PD-1-susceptible patient subgroup. These results provide new insights that may help to improve clinical outcomes in immunotherapy candidates.
Background: Gastric adenocarcinoma (GAC) is highly heterogeneous and closely related to colorectal cancer (CRC) both molecularly and functionally. GAC is currently subtyped using a system developed by TCGA. However, with the emergence of immunotherapies, this system has failed to identify suitable treatment candidates. Methods: Consensus molecular subtypes (CMSs) developed for CRC were used for molecular subtyping in GAC based on public expression cohorts, including TCGA, ACRG, and a cohort of GAC patients treated with the programmed cell death 1 (PD-1) inhibitor pembrolizumab. All aspects of each subtype, including clinical outcome, molecular characteristics, oncogenic pathway activity, and the response to immunotherapy, were fully explored. Results: CMS classification was efficiently applied to GAC. CMS4, characterized by EMT activation, stromal invasion, angiogenesis, and the worst clinical outcomes (median OS 24.2 months), was the predominant subtype (38.8%~44.3%) and an independent prognostic indicator that outperformed classical TCGA subtyping. CMS1 (20.9%~21.5%) displayed hypermutation, low SCNV, immune activation, and best clinical outcomes (median OS > 120 months). CMS3 (17.95%~25.7%) was characterized by overactive metabolism, KRAS mutation, and intermediate outcomes (median OS 85.6 months). CMS2 (14.6%~16.3%) was enriched for WNT and MYC activation, differentiated epithelial characteristics, APC mutation, lack of ARID1A, and intermediate outcomes (median OS 48.7 months). Notably, CMS1 was strongly correlated with immunotherapy biomarkers and favorable for the anti-PD-1 drug pembrolizumab, whereas CMS4 was poorly responsive but became more sensitive after EMT-based stratification. Conclusions: Our study reveals the practical utility of CMS classification for GAC to improve clinical outcomes and identify candidates who will respond to immunotherapy. View Full-Text
Keywords: molecular characteristic; tumor microenvironment; pembrolizumab; microsatellite instability; epithelial–mesenchymal transition; companion biomarker molecular characteristic; tumor microenvironment; pembrolizumab; microsatellite instability; epithelial–mesenchymal transition; companion biomarker
Show Figures

Figure 1

MDPI and ACS Style

Wu, X.; Ye, Y.; Vega, K.J.; Yao, J. Consensus Molecular Subtypes Efficiently Classify Gastric Adenocarcinomas and Predict the Response to Anti-PD-1 Immunotherapy. Cancers 2022, 14, 3740. https://doi.org/10.3390/cancers14153740

AMA Style

Wu X, Ye Y, Vega KJ, Yao J. Consensus Molecular Subtypes Efficiently Classify Gastric Adenocarcinomas and Predict the Response to Anti-PD-1 Immunotherapy. Cancers. 2022; 14(15):3740. https://doi.org/10.3390/cancers14153740

Chicago/Turabian Style

Wu, Xiangyan, Yuhan Ye, Kenneth J. Vega, and Jiannan Yao. 2022. "Consensus Molecular Subtypes Efficiently Classify Gastric Adenocarcinomas and Predict the Response to Anti-PD-1 Immunotherapy" Cancers 14, no. 15: 3740. https://doi.org/10.3390/cancers14153740

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop