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New Stomach Cancer Subtypes Uncovered With Proteomics

NEW YORK (GenomeWeb) – New research suggests proteomic profiles in the tumor and microenvironment can provide an additional layer of information in personalized treatments for a form of stomach cancer that is particularly difficult to treat and often has poor patient outcomes.

Members of a research team based in China and the US used a combination of immunohistochemistry, liquid chromatography/mass spectrometry, targeted sequencing, and other approaches to profile proteomic, mutation, and microsatellite stability patterns in tumor and microenvironment samples from 84 individuals with diffuse-type gastric cancer (DGC). The profiles, described yesterday in Nature Communications, led them to three new proteomic subtypes dubbed PX1, PX2, and PX3.

The investigators went on to delve into potential treatment susceptibilities in these subtypes. In a PX3 subtype marked by relatively poor chemotherapy response, for example, they uncovered immune-related features expected to respond to cancer immunotherapies. On the other hand, cell cycle pathways were most frequently altered in the PX1 subtype, while PX2 tumors contained both cell cycle and epithelial-to-mesenchymal (EMT) transition pathway shifts.

"Our proteomic analysis has further separated DGC into three subtypes, revealing the heterogeneity and diversity of DGC at the proteome level," co-corresponding authors Jun Qin, Lin Shen, and Fuchu He, translational medicine researchers affiliated with Peking University Cancer Hospital, and their colleagues wrote, noting that proteomic subtypes in DCG "feature distinctively altered signaling pathways and clinical outcomes."

Stomach cancer, known for its diversity and genetic heterogeneity, is especially common in East Asia, the team noted. Past efforts such as the Cancer Genome Atlas project have placed gastric cancers into molecular subtypes marked by microsatellite instability, chromosomal instability, genome stability, or Epstein-Barr virus infection.

When it comes to DGC, prior analyses have typically put the tumors into a genome stable TCGA subtype, though four further subtypes were identified based on gene expression profiles generated for an Asian Cancer Research Group study: one subgroup made up of microsatellite instable tumors, along with three microsatellite stable subgroups showing EMT transitions, TP53 activity, or TP53 inactivity.

For their new analysis, Qin, Shen, and He added in another level of information for DGC, using targeted exome sequencing, fast mass spectrometry (fast-seq), and a liquid chromatography gradient to assess tumor and neighboring tissues for 84 individuals with DGC from a Beijing Cancer Hospital tissue bank.

The team focused on expression profiles for 11,340 proteins and potential driver mutations in 274 cancer-related genes for its analyses of tumor and microenvironment patterns, uncovering 7,200 somatic mutations in 183 of the genes.

More than three dozen genes were mutated in at least 5 percent of the tumors, for example. On the proteomic side, the researchers picked up 7,443 gene products present in tumor and microenvironment samples. Almost 1,500 more gene products appeared to be specific to the DGC tumors, while 261 gene products turned up in the microenvironment samples alone.

In addition to exploring the sorts of genes that were recurrently mutated, upregulated, or downregulated in the stomach tumors, the team subsequently defined the PX1, PX2, and PX3 proteomic subtypes, along with their ties to documented tumor-microenvironment gene mutations, survival patterns and, possible treatment targets.

For example, the authors noted that proteomic profiles for the tumors did not always contain the products of genes with suspicious or potentially targetable mutations from the DNA sequence data.

"[S]everal oncogene products were not detected in the tumors but were detected in the nearby tissues," they wrote, adding that such findings "add a cautionary note on nominating treatment candidates based solely on DNA mutations and further strengthen the necessity of measuring proteins in precision medicine."