Molecular Advances in Gastrointestinal Pathology

Area of Science:

• Oncology
• Genomics
• Pathology

Background:

• Gastrointestinal adenocarcinomas, including colorectal cancer (CRC) and gastroesophageal junction (GEJ) carcinoma, pose a significant global health challenge.
• Large-scale multi-omics profiling, notably The Cancer Genome Atlas (TCGA), has elucidated the genetic heterogeneity and biology of these cancers.
• Integrating molecular biomarkers with histopathology is crucial for classification, prognosis, and targeted interventions.

Purpose of the Study:

• To review molecularly defined subgroups, actionable biomarkers, and evolving therapeutic paradigms in CRC and GEJ carcinoma from a pathologist's perspective.
• To highlight the role of molecular profiling in advancing precision oncology for gastrointestinal cancers.

Main Methods:

• Review of multi-omics data from TCGA and other large-scale profiling initiatives.
• Analysis of established and emerging molecular biomarkers (e.g., MSI, POLE, RAS, BRAF, HER2, NTRK, PIK3CA, TMB, EBV, PD-L1, CLDN18.2, KRAS G12C).
• Integration of histopathology with molecular findings for classification and therapeutic guidance.

Main Results:

• CRC subtypes include hypermutated (MSI/POLE) with high TMB and response to immunotherapy, and non-hypermutated with chromosomal instability and targets like RAS, BRAF, HER2, NTRK.
• GEJ carcinomas classify into four subgroups: EBV-associated, MSI, chromosomal instability, and genomically stable, each with distinct targets (HER2, PD-L1, CLDN18.2).
• Established biomarkers (MSI, PD-L1, HER2) and emerging ones (CLDN18.2, TMB, KRAS G12C) expand targeted therapy options.

Conclusions:

• Molecular subtyping and biomarker identification are essential for precision oncology in CRC and GEJ carcinoma.
• Combination therapies, including immunotherapy and targeted agents, represent a paradigm shift in managing these cancers.
• A pathologist-centered approach integrating molecular and histopathological data optimizes patient stratification and treatment selection.