Profiling of gene fusion involving targetable genes in Chinese gastric cancer

Abstract

BACKGROUND Approximately half of all new cases of gastric cancer (GC) and related deaths occur in China. More than 80% of patients with GC are diagnosed at an advanced stage, which results in poor prognosis. Although HER2 -directed therapy and immune checkpoint inhibitors have been somewhat successful, new drugs are still needed for the treatment of GC. Notably, several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors, including GC, such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers. However, gene fusions involving targetable genes have not been well characterized in Chinese patients with GC. AIM To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC. METHODS We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC. Clinicopathological characteristics were obtained from their medical records. Genetic alterations, such as single nucleotide variants, indels, amplifications, and gene fusions, were identified using a targeted sequencing panel containing 825 genes. Fusions were validated by fluorescence in situ hybridization (FISH) using break-apart probes. The microsatellite instability (MSI) status was evaluated using MSIsensor from the targeted sequencing panel data. Tumor mutational burden (TMB) was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region. Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC. RESULTS We found that 1.68% (16/954) of patients harbored 20 fusion events involving targetable genes. RARA fusions ( n = 5) were the most common, followed by FGFR2 , BRAF , MET , FGFR3 , RET, ALK, EGFR, NTRK2, and NRG1 fusions. Two of the RARA fusions, EML4-ALK (E6:E20) and EGFR-SEPTIN14 (E7:E10) , have been identified in other tumors but not in GC. Surprisingly, 18 gene fusion events were previously not reported in any cancer types. Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes, such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA- and ligand-binding domains of RARA . Consistent with the results of detection using the targeted sequencing fusion panel, the...

Tumor-Type Agnostic, Targeted Therapies: BRAF Inhibitors Join the Group

“…In addition, rare BRAF gene fusions have been described in various cancer subtypes (frequency 0.3%), particularly in Spitzoid melanomas, pilocytic astrocytomas, papillary thyroid carcinomas, acinar pancreatic carcinomas, gastric carcinomas, serous ovarian carcinomas (both low-and highgrade), salivary gland carcinomas, and histiocytic neoplasms (pediatric and adult xanthogranulomas) (64)(65)(66)(67)(68)(69)(70)(71)(72)(73). BRAF gene fusions and point mutations have recently been found in a subset of adult and pediatric soft tissue tumors with spindle cell morphology and infantile fibrosarcoma-like growth pattern (74)(75)(76).…”