Comprehensive molecular characterization of gastric adenocarcinoma

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.

Related collections

Most cited references 24

Record: found
Abstract: found
Article: not found

Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis.

Ronglai Shen, Adam B. Olshen, Marc Ladanyi (2009)

The molecular complexity of a tumor manifests itself at the genomic, epigenomic, transcriptomic and proteomic levels. Genomic profiling at these multiple levels should allow an integrated characterization of tumor etiology. However, there is a shortage of effective statistical and bioinformatic tools for truly integrative data analysis. The standard approach to integrative clustering is separate clustering followed by manual integration. A more statistically powerful approach would incorporate all data types simultaneously and generate a single integrated cluster assignment. We developed a joint latent variable model for integrative clustering. We call the resulting methodology iCluster. iCluster incorporates flexible modeling of the associations between different data types and the variance-covariance structure within data types in a single framework, while simultaneously reducing the dimensionality of the datasets. Likelihood-based inference is obtained through the Expectation-Maximization algorithm. We demonstrate the iCluster algorithm using two examples of joint analysis of copy number and gene expression data, one from breast cancer and one from lung cancer. In both cases, we identified subtypes characterized by concordant DNA copy number changes and gene expression as well as unique profiles specific to one or the other in a completely automated fashion. In addition, the algorithm discovers potentially novel subtypes by combining weak yet consistent alteration patterns across data types. R code to implement iCluster can be downloaded at http://www.mskcc.org/mskcc/html/85130.cfm

0 comments Cited 317 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy.

Michael Green, Scott J. Rodig, Przemyslaw Juszczynski … (2012)

Programmed cell death ligand 1 (PD-L1) is a molecule expressed on antigen-presenting cells that engages the PD-1 receptor on T cells and inhibits T-cell receptor signaling. The PD-1 axis can be exploited by tumor cells to dampen host antitumor immune responses and foster tumor cell survival. PD-1 blockade has shown promise in multiple malignancies but should be directed toward patients in whom it will be most effective. In recent studies, we found that the chromosome 9p24.1 amplification increased the gene dosage of PD-L1 and its induction by JAK2 in a subset of patients with classical Hodgkin lymphoma (cHL). However, cHLs with normal 9p24.1 copy numbers also expressed detectable PD-L1, prompting analyses of additional PD-L1 regulatory mechanisms. Herein, we utilized immunohistochemical, genomic, and functional analyses to define alternative mechanisms of PD-L1 activation in cHL and additional EBV(+) lymphoproliferative disorders. We identified an AP-1-responsive enhancer in the PD-L1 gene. In cHL Reed-Sternberg cells, which exhibit constitutive AP-1 activation, the PD-L1 enhancer binds AP-1 components and increases PD-L1 promoter activity. In addition, we defined Epstein-Barr virus (EBV) infection as an alternative mechanism for PD-L1 induction in cHLs with diploid 9p24.1. PD-L1 was also expressed by EBV-transformed lymphoblastoid cell lines as a result of latent membrane protein 1-mediated, JAK/STAT-dependent promoter and AP-1-associated enhancer activity. In addition, more than 70% of EBV(+) posttransplant lymphoproliferative disorders expressed detectable PD-L1. AP-1 signaling and EBV infection represent alternative mechanisms of PD-L1 induction and extend the spectrum of tumors in which to consider PD-1 blockade.

0 comments Cited 247 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Recent patterns in gastric cancer: a global overview.

Paola Bertuccio, Liliane Chatenoud, Fabio Levi … (2009)

Until the mid-1990s, gastric cancer has been the first cause of cancer death worldwide, although rates had been declining for several decades and gastric cancer has become a relatively rare cancer in North America and in most Northern and Western Europe, but not in Eastern Europe, Russia and selected areas of Central and South America or East Asia. We analyzed gastric cancer mortality in Europe and other areas of the world from 1980 to 2005 using joinpoint regression analysis, and provided updated site-specific incidence rates from 51 selected registries. Over the last decade, the annual percent change (APC) in mortality rate was around -3, -4% for the major European countries. The APC were similar for the Republic of Korea (APC = -4.3%), Australia (-3.7%), the USA (-3.6%), Japan (-3.5%), Ukraine (-3%) and the Russian Federation (-2.8%). In Latin America, the decline was less marked, but constant with APC around -1.6% in Chile and Brazil, -2.3% in Argentina and Mexico and -2.6% in Colombia. Cancers in the fundus and pylorus are more common in high incidence and mortality areas and have been declining more than cardia gastric cancer. Steady downward trends persist in gastric cancer mortality worldwide even in middle aged population, and hence further appreciable declines are likely in the near future.

0 comments Cited 228 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Title: Nature

Abbreviated Title: Nature

Publisher: Springer Science and Business Media LLC

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Created: September 2014

Publication date (Electronic): July 23 2014

Publication date (Print): September 2014

Volume: 513

Issue: 7517

Pages: 202-209

Article

DOI: 10.1038/nature13480

SO-VID: c70ab42f-f302-403e-b5e6-ce197e109ea3

License:

https://creativecommons.org/licenses/by-nc-sa/3.0/

History

Data availability:

Comments

Comment on this article

scite_

Cited by 2,466

See all cited by

- Version 1

Comprehensive molecular characterization of gastric adenocarcinoma

Read this article at

Abstract

Related collections

Genes & Diseases

Most cited references 24

Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis.

Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy.

Recent patterns in gastric cancer: a global overview.

Author and article information

Journal

Article

History

Comments

Comment on this article

Similar content 1,854

Cited by 2,466