A Rare <i>EGFR</i>–<i>SEPT14</i> Fusion in a Patient with Colorectal Adenocarcinoma Responding to Erlotinib

Li, Yong; Zhang, Hai Bo; Chen, Xian; Yang, Xiaobing; Ye, Yongsong; Bekaii‐Saab, Tanios; Zheng, Yaojie; Zhang, Yihong

doi:10.1634/theoncologist.2019-0405

Cited by 16 publications

(22 citation statements)

References 26 publications

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“…The EGFP-SEPT14 fusion deregulates downstream STAT3 signaling and affects the sensitivity of inhibitors in this signaling pathway. (3) A rare EGFR-SEPT14 fusion has been identified in colorectal cancer and highlights a new target for therapeutic intervention [65]. In both this and a previous study, we identified two SEPT14 mutations (SEPT14 A123T and SEPT14 I333T ) in teratozoospermia cases.…”

Section: Genetic Changes Of Sept14 In Parkinson's Disease and Cancersupporting

confidence: 50%

ACTN4 Mediates SEPT14 Mutation-Induced Sperm Head Defects

Lin

Huang

et al. 2020

Biomedicines

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Septins (SEPTs) are highly conserved GTP-binding proteins and the fourth component of the cytoskeleton. Polymerized SEPTs participate in the modulation of various cellular processes, such as cytokinesis, cell polarity, and membrane dynamics, through their interactions with microtubules, actin, and other cellular components. The main objective of this study was to dissect the molecular pathological mechanism of SEPT14 mutation-induced sperm head defects. To identify SEPT14 interactors, co-immunoprecipitation (co-IP) and nano-liquid chromatography-mass spectrometry/mass spectrometry were applied. Immunostaining showed that SEPT14 was significantly localized to the manchette structure. The SEPT14 interactors were identified and classified as (1) SEPT-, (2) microtubule-, (3) actin-, and (4) sperm structure-related proteins. One interactor, ACTN4, an actin-holding protein, was selected for further study. Co-IP experiments showed that SEPT14 interacts with ACTN4 in a male germ cell line. SEPT14 also co-localized with ACTN4 in the perinuclear and manchette regions of the sperm head in early elongating spermatids. In the cell model, mutated SEPT14 disturbed the localization pattern of ACTN4. In a clinical aspect, sperm with mutant SEPT14, SEPT14A123T (p.Ala123Thr), and SEPT14I333T (p.Ile333Thr), have mislocalized and fragmented ACTN4 signals. Sperm head defects in donors with SEPT14 mutations are caused by disruption of the functions of ACTN4 and actin during sperm head formation.

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Section: Genetic Changes Of Sept14 In Parkinson's Disease and Cancersupporting

confidence: 50%

ACTN4 Mediates SEPT14 Mutation-Induced Sperm Head Defects

Lin

Huang

et al. 2020

Biomedicines

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“…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].…”

Section: Mutations Within the Intracellular And Kinase Domains Of Egfrmentioning

confidence: 99%

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

Uribe

Marrocco

Yarden

2021

Cancers

177

145

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The epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function. High abundance of EGFR and large internal deletions are frequently observed in brain tumors, whereas point mutations and small insertions within the kinase domain are common in lung cancer. For these reasons EGFR and its preferred heterodimer partner, HER2/ERBB2, became popular targets of anti-cancer therapies. Nevertheless, EGFR research keeps revealing unexpected observations, which are reviewed herein. Once activated by a ligand, EGFR initiates a time-dependent series of molecular switches comprising downregulation of a large cohort of microRNAs, up-regulation of newly synthesized mRNAs, and covalent protein modifications, collectively controlling phenotype-determining genes. In addition to microRNAs, long non-coding RNAs and circular RNAs play critical roles in EGFR signaling. Along with driver mutations, EGFR drives metastasis in many ways. Paracrine loops comprising tumor and stromal cells enable EGFR to fuel invasion across tissue barriers, survival of clusters of circulating tumor cells, as well as colonization of distant organs. We conclude by listing all clinically approved anti-cancer drugs targeting either EGFR or HER2. Because emergence of drug resistance is nearly inevitable, we discuss the major evasion mechanisms.

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“…That previous case indicated that a tumor harboring this fusion would be sensitive to EGFR inhibitors[ 11 ]. Recently, the EGFR-SEPT14 fusion was reported in colorectal adenocarcinoma by using a comprehensive NGS assay on tumor samples[ 5 ].…”

Section: Discussionmentioning

confidence: 99%

“…The fusion site reported in that study is the same as that in the present study, and the patient was administered erlotinib therapy to which the EGFR-SEPT14 fusion is known to be sensitive[ 10 ]. However, soon after treatment, an EGFR variant III was detected and can result in resistance to erlotinib[ 5 ]. To confirm the treatment effect and disease progression in AGC, further studies are needed.…”

Section: Discussionmentioning

confidence: 99%

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

Kim¹,

Kim²,

Cho³

et al. 2021

WJCC

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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.

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A Rare EGFR–SEPT14 Fusion in a Patient with Colorectal Adenocarcinoma Responding to Erlotinib

Cited by 16 publications

References 26 publications

ACTN4 Mediates SEPT14 Mutation-Induced Sperm Head Defects

ACTN4 Mediates SEPT14 Mutation-Induced Sperm Head Defects

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

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

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