Molecular Testing for Gastrointestinal Cancer

Abstract

With recent advances in molecular diagnostic methods and targeted cancer therapies, several molecular tests have been recommended for gastric cancer (GC) and colorectal cancer (CRC). Microsatellite instability analysis of gastrointestinal cancers is performed to screen for Lynch syndrome, predict favorable prognosis, and screen patients for immunotherapy. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved in metastatic CRCs with wildtype RAS (KRAS and NRAS exon 2-4). A BRAF mutation is required for predicting poor prognosis. Additionally, amplification of human epidermal growth factor receptor 2 (HER2) and MET is also associated with resistance to EGFR inhibitor in metastatic CRC patients. The BRAF V600E mutation is found in sporadic microsatellite unstable CRCs, and thus is helpful for ruling out Lynch syndrome. In addition, the KRAS mutation is a prognostic biomarker and the PIK3CA mutation is a molecular biomarker predicting response to phosphoinositide 3-kinase/AKT/mammalian target of rapamycin inhibitors and response to aspirin therapy in CRC patients. Additionally, HER2 testing should be performed in all recurrent or metastatic GCs. If the results of HER2 immunohistochemistry are equivocal, HER2 silver or fluorescence in situ hybridization testing are essential for confirmative determination of HER2 status. Epstein-Barr virus-positive GCs have distinct characteristics, including heavy lymphoid stroma, hypermethylation phenotype, and high expression of immune modulators. Recent advances in next-generation sequencing technologies enable us to examine various genetic alterations using a single test. Pathologists play a crucial role in ensuring reliable molecular testing and they should also take an integral role between molecular laboratories and clinicians.

Keywords: Colorectal neoplasms; Gastric neoplasms; Molecular diagnosis; Prognosis; Targeted therapy.

Fig. 1.

Fragment pattern of microsatellite instability–high case by GeneScan analysis.

Fig. 2.

Epidermal growth factor receptor (EGFR)–related signaling pathway in metastatic colorectal cancer. Anti-EGFR antibodies are able to block downstream signal of EGFR in wild type RAS and RAF (left), but unable to block in mutant RAS or RAF (right). mTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase.

Fig. 3.

Algorithm of molecular testing in colorectal cancer (CRC) patients. MSI, microsatellite instability; IHC, immunohistochemistry; MSI-H, microsatellite instability–high; MSS, microsatellite stable.

Fig. 4.

Recommended gastric human epidermal growth factor receptor 2 (HER2) testing algorithm. IHC, immunohistochemistry.