How Molecular Profiling and Tiny RNAs Are Revolutionizing Treatment
When Jack, a vibrant New Yorker in his mid-30s, began experiencing difficulty swallowing, he never imagined he'd become part of a revolution in cancer treatment. Diagnosed with gastroesophageal junction cancer where the esophagus meets the stomach, he faced a disease that has long been one of oncology's toughest challenges. "I came to MSK to do my due diligence," Jack recalls. "At my first appointment, I fell in love with the whole team and the facility" 2 .
Jack's story represents both the tragedy and promise of gastric cancer care. For decades, this disease has been notoriously difficult to treat, with limited treatment options and often late-stage detection. But thanks to groundbreaking research into the molecular and genetic fingerprints of gastric cancer, we're witnessing a transformation in how we understand, classify, and treat this disease. New discoveries about microRNAs—tiny genetic regulators that can make or break cancer cells—are opening doors to earlier detection and more personalized treatments that are dramatically improving outcomes for patients like Jack.
For over half a century, doctors classified gastric cancer primarily by how it looked under a microscope. The Lauren classification system, developed in 1965, divided gastric cancer into intestinal (G-INT) and diffuse (G-DIF) types based on their cellular structure and organization 6 . While this system helped doctors predict some aspects of how the cancer might behave, it provided limited guidance for selecting specific treatments.
The critical challenge has been gastric cancer's staggering diversity. What we call "gastric cancer" actually represents multiple different diseases, each with distinct characteristics.
The turning point came when research consortia around the world decided to map gastric cancer's molecular landscape in unprecedented detail. Two landmark efforts—The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG)—systematically analyzed hundreds of gastric cancer samples, creating comprehensive molecular portraits that have transformed our understanding of the disease 6 .
Published in 2013, the TCGA study analyzed 295 gastric cancers using multiple genomic technologies, identifying four distinct molecular subtypes 6 :
| Subtype | Prevalence | Key Characteristics | Potential Treatment Approaches |
|---|---|---|---|
| EBV-positive | 9% | Epstein-Barr virus present, PIK3CA mutations, PD-L1 overexpression | Immunotherapy (checkpoint inhibitors) |
| Microsatellite Unstable (MSI) | 22% | High mutation rates, DNA methylation | Immunotherapy |
| Genomically Stable (GS) | 20% | Diffuse histology, CDH1 mutations | Targeted therapies |
| Chromosomally Unstable (CIN) | 50% | Tumor protein p53 (TP53) mutations, receptor tyrosine kinase activation | Chemotherapy, targeted therapies |
The ACRG classification, developed similarly through multi-platform molecular analysis, identified four subtypes with distinct clinical outcomes 6 :
Best prognosis, often found in older patients
Worst prognosis, frequently seen in younger patients with diffuse-type cancer
Intermediate prognosis
Intermediate prognosis
While the TCGA and ACRG classifications represented massive steps forward, scientists discovered that some of the most exciting biomarkers were among the smallest—microRNAs (miRNAs). These tiny RNA molecules, only about 22 nucleotides long, don't code for proteins but instead fine-tune gene expression by binding to messenger RNAs and preventing their translation into proteins .
In gastric cancer, specific miRNAs function as either oncomiRNAs that drive cancer growth or tumor suppressor miRNAs that protect against it 3 . For example:
Acts as an oncomiRNA, promoting tumor growth and spread
Serves as a tumor suppressor, with its downregulation linked to worse outcomes
| miRNA Panel | Target | Accuracy | Sensitivity | Specificity | Key miRNAs Included |
|---|---|---|---|---|---|
| Multi-Cancer Panel | 13 cancer types | 96.1% | 98.6% | 96% | hsa-miR-8073, hsa-miR-614, hsa-miR-548ah-5p, hsa-miR-1258 |
| Gastric Cancer Panel | Gastric cancer only | 87% | 89% | 90% | hsa-miR-1228-5p, hsa-miR-1343-3p, hsa-miR-6765-5p, hsa-miR-6787-5p |
| miRNA | Expression in Gastric Cancer | Role | Clinical Significance | Impact on Survival |
|---|---|---|---|---|
| miR-21-5p | Upregulated | OncomiRNA | Predicts lymph node metastasis, advanced stage | Reduced 3-year survival |
| miR-145-5p | Downregulated | Tumor suppressor | Predicts lymph node metastasis, improved outcome | Improved 3-year survival |
| miR-382-5p | Variable | Angiogenesis | Associated with non-mucinous carcinoma type | Under investigation |
The remarkable progress in miRNA research has been powered by sophisticated laboratory tools and technologies :
| Tool/Reagent | Function | Application in miRNA Research |
|---|---|---|
| Next-Generation Sequencing (NGS) | High-throughput RNA sequencing | Comprehensive miRNA profiling, discovery of novel miRNAs |
| RT-qPCR (Quantitative Reverse Transcription PCR) | Precise quantification of specific miRNAs | Validation of miRNA expression, diagnostic testing |
| Locked Nucleic Acid (LNA) Probes | Modified nucleotides for enhanced binding | Improved detection sensitivity in northern blotting |
| Microarrays | Simultaneous measurement of hundreds of miRNAs | miRNA expression profiling, biomarker identification |
| RNA Isolation Kits | Purification of high-quality miRNA from samples | Preparation of samples for downstream analysis |
| Multiclass SVM Algorithms | Machine learning classification | Categorizing miRNAs into families, identifying patterns |
The impact of molecular classification extends beyond treatment selection. We're seeing a quiet revolution in early detection 7 . Between 2004 and 2021, diagnoses of early-stage stomach cancer rose by approximately 53%, while advanced cases dropped significantly. In 2021, for the first time, early-stage gastric cancer became the most common stage at diagnosis 7 .
Refining molecular classifications to target therapies more precisely
Using biomarkers to personalize treatment regimens
Non-invasive monitoring using circulating miRNAs
Early detection strategies to improve survival rates
The journey from the Lauren classification to molecular subtyping and miRNA profiling represents one of the most exciting transformations in modern oncology. We've moved from viewing gastric cancer as a single entity to recognizing it as multiple distinct diseases, each with its own molecular signature and treatment vulnerabilities.
The discovery that tiny miRNAs can serve as powerful biomarkers and therapeutic targets highlights how science's smallest discoveries can make the biggest differences in patients' lives. As research continues, the dream of turning gastric cancer from a deadly disease into a manageable condition is becoming increasingly tangible.
"At MSK, you can see the compassion and the dedication to treating cancer. I tell people you don't go to a fruit store for steaks. Treating cancer is MSK's business. This is what they do. And they are the best at it." 2