Detection of EGFA-SEPT14 fusion in cell-free DNA of a patient with advanced gastric cancer: A case report

Abstract

BACKGROUND Gastric cancer is the fifth most diagnosed cancer worldwide and the third most common cause of cancer-related death. In recent decades, increasing application of next-generation sequencing has enabled detection of molecular aberrations, including fusions. In cases where tissue is difficult to obtain, cell-free DNA (cfDNA) is used for detecting mutations to identify the molecular profile of cancer. Here, we report a rare case of EGFR-SEPT14 fusion detected from cfDNA analysis in a patient with gastric cancer. CASE SUMMARY A 49-year-old female diagnosed with advanced gastric cancer in July 2019 received capecitabine and then combination chemotherapy of ramucirumab and paclitaxel, but ascites was detected. The therapy was switched to nivolumab, but disease progression was observed on a positron emission tomography/computed tomography scan in May 2020. Therapy was discontinued, and cfDNA next-generation sequencing was immediately evaluated. All genomic variants, including fusions, were analyzed from cfDNA. The following somatic alterations were detected from the patient’s cfDNA: an APC frameshift mutation (NM_000038.5:c.6579del, p.V2194fs) with variant allele frequency of 0.5%, an EGFR amplification with a copy number of 17.3, and an EGFR-SEPT14 fusion with variant allele frequency of 45.3%. The site of the fusion was exon 24 of EGFR fused to exon 10 of SEPT14. The fusion was in-frame and considered to be protooncogenic. Although the patient refused to continue therapy, we suggest that EGFR -targeted therapies be tried in such future cases. CONCLUSION The expanded applications of the cfDNA assay may open a new horizon in treatment of patients with advanced gastric cancer.

EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance

“…The origin of recurring mutagenesis is attributable to the strong apoptosis-inducing effects of TKIs, which triggers down-regulation of mismatch repair and homologous recombination DNA-repair genes, along with concomitant up-regulation of error-prone DNA polymerases [43]. Additional mutant forms of EGFR, such as an EGFR fused with SEPT-14 (EGFR-SEPT14) [44,45], as well as EGFRs with a kinase domain duplication (EGFR-KDD) [46], have been identified in GBM, gastrointestinal and other tumors. [37], amplification of MET [47] or HER2 [48], overexpression of AXL [49] or HGF [50,51], mutations in downstream molecules [52,53], phenotypic transformation [54].…”

Identification of Potential Genomic Alterations Using Pan-Cancer Cell-Free DNA Next-Generation Sequencing in Patients With Gastric Cancer

“…Patient No. 29 reportedly had an EGFR – SEPT14 fusion, which is considered a noteworthy fusion in GC ( Supplemental Data Table S3 ) [ 24 ]. The tier I and II mutations detected in the 81 patients are shown in Fig.…”

“…This method takes longer than the PCR-based enrichment method but is effective for targeting large genomic regions [ 28 ]. Furthermore, assay B provides MSI information and can detect unexpected fusions such as EGFR – SEPT14 [ 24 ].…”

“…Our study suggests that the genetic profiling of GC can be useful for finding not only novel molecular pathways but also biomarkers that may be targeted by existing therapies effective in other cancer types. We detected an EGFR – SEPT14 fusion that has been reported in glioblastoma, non-small cell lung cancer, and colorectal cancer [ 24 , 40 ]. This fusion can be a novel target for patients with GC that may be treatable with EGFR tyrosine kinase inhibitors, which is effective in other cancer types [ 24 ].…”

Complete remission in leptomeningeal metastasis of NSCLC with rare EGFR-SEPT14 fusion treated with osimertinib combined with intrathecal chemotherapy with pemetrexed

“…EGFR-SEPT14 fusion is the most frequent functional gene fusion in human glioblastoma but is extremely rare in other tumors. Only four cases have been reported in the previous studies, including one case of salivary gland secretory carcinoma [7], one case of colorectal cancer [6], one case of gastric cancer [8] and one case of lung adenocarcinoma [9]. More details were shown in Table 2.…”